HK1119080B - 2,3 substituted pyrazine sulfonamides as inhibitors of crth2 - Google Patents
2,3 substituted pyrazine sulfonamides as inhibitors of crth2 Download PDFInfo
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Description
Technical Field
The present invention relates to 2, 3-substituted pyrazine sulfonamides as pharmaceutically active compounds and pharmaceutical formulations containing said 2, 3-substituted pyrazine sulfonamides. The derivatives are useful for the treatment and/or prevention of allergic diseases and inflammatory skin diseases. In particular, the present invention relates to 2, 3-substituted pyrazine sulfonamides for modulating, in particular inhibiting, the activity of CRTH 2. The invention also relates to novel 2, 3-substituted pyrazine sulfonamides and methods for their preparation.
Background
Prostaglandin D2(PGD2) has long been implicated in inflammatory and atopic disorders, particularly allergic diseases such as asthma, rhinitis and atopic dermatitis (Lewis et al (1982) journal of immunology (j. immunol)129, 1627). PGD2 belongs to a class of compounds derived from the 20-carbon fatty acid backbone of arachidonic acid. During the acute allergic response, PGD2 is released in large quantities into the airways and the skin in response to antigen challenge. DP receptors belonging to members of the subfamily of G-protein coupled receptors (GPCRs) have long been considered to be the only receptor for PGD 2. The role of DP in allergic asthma has been demonstrated in DP deficient mice (Matsuoka et al (2000) Science 287, 2013-2017). However, although PGD2 has shown great interest in the role of inflammatory responses, a direct relationship between DP receptor activation and PGD 2-stimulated eosinophil migration has not been established (Woodward et al (1990) Octobalomol Vis. Sci.)31, 138-146; Woodward et al (1993) European journal of pharmacy (Eur. J. Pharmacol.)230, 327-333).
Recently, another G protein-coupled receptor, termed "chemoattractant receptor-homologous molecule expressed on T helper cell 2" (CRTH2) (Nagata et al (1999) J.Immunol.)162, 1278-1286, Hirai et al (2001) J.Med.193, 255-261) has been identified as a receptor for PGD2, and this finding has begun to reveal the mechanism of action of PDG 2. CRTH2, also known as DP2, GPR44 or DLIR, has little structural similarity to DP receptor and other prostanoid receptors. However, CRTH2 has a similar affinity for PDG 2. Among peripheral blood T lymphocytes, human CRTH2 is selectively expressed on Th2 cells and is highly expressed on cell types associated with allergic inflammation, such as eosinophils, basophils, and Th2 cells. Furthermore, CRTH2 also mediates PGD 2-dependent cell migration of blood eosinophils and basophils. Still further, an increased number of circulating T cells expressing CRTH2 was associated with the severity of atopic dermatitis (Cosmi et al (2000) European journal of immunology 30, 2972-2979). The interaction of CRTH2 and PGD2 plays a key role in allergen-induced recruitment of Th2 cells in allergic inflammation target tissues. Therefore, compounds that inhibit the binding of CRTH2 and PGD2 should be useful for the treatment of allergic diseases.
Allergic diseases, such as asthma and inflammatory skin diseases, represent a large complex and often chronic class of inflammatory diseases that currently affect about 10% of the population and appear to be increasing in number (Bush, r.k., Georgitis j.w., handbook of asthma and rhinitis, 1 st edition (1997), abindon: blakewell Science 270). Atopic dermatitis is a chronic skin disease, and the skin of a patient becomes itchy. This is true for 10-20% of all patients with dermatologists. The increasing incidence of allergic and inflammatory skin diseases worldwide has exacerbated the need for new methods of effectively treating or preventing such diseases. Currently, various types of drugs are widely used to treat these diseases, for example, antihistamines, decongestants, anticholinergics, methylxanthines, cromolyn sodium, corticosteroids, and leukotriene modifiers. However, the use of these drugs is often limited by their side effects and low efficacy.
It has recently been reported that 3-thio-substituted indole derivatives (a) exhibit CRTH2 activity (WO 04/106302, AstraZeneca AB), and are potentially useful for the treatment of various respiratory diseases.
WO 04/096777(Bayer Healthcare AG) relates to pyrimidine derivatives useful in the treatment of CRTH2 mediated diseases.
WO 04/035543 and WO 05/102338(Warner-Lambert Company LLC) disclose tetrahydroquinoline derivatives (C) as CRTH2 antagonists, which are also said to be effective in the treatment of neuropathic pain.
WO 04/032848(Millennium Pharmaceutical Inc.) and WO 05/007094(tularik Inc.) also provide specific tetrahydroquinoline derivatives as CRTH2 modulators. These tetrahydroquinoline derivatives are said to be useful in the treatment of diseases associated with the development of allergic inflammatory conditions.
Other subfamilies of G protein-coupled receptors, namely CCR's and CXCR's, are also discussed as potential drug targets for the treatment of allergic diseases and autoimmune conditions. WO 04/108692 and WO 04/108717(AstraZeneca AB) disclose pyrazine sulfonamide compounds that specifically modulate CCR 4.
Pyrazine sulfonamide compounds that interact with G protein-coupled receptors have also been disclosed in WO 04/058265.
Summary of The Invention
In one aspect, the present invention relates to the use of 2, 3-substituted pyrazine sulfonamides represented by general formula (I) as pharmaceutically active compounds. The compounds are suitable for the treatment and/or prophylaxis of allergic diseases and inflammatory skin diseases. The compounds modulate a specific member of the G protein-coupled family, namely CRTH 2. In particular, the present invention relates to 2, 3-substituted pyrazine sulfonamides of formula (I):
a, B, R therein1、R2、R3And m is defined as described in the detailed description below.
The invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient or carrier.
The invention further relates to the use of a compound of formula I for the preparation of a medicament for the treatment and/or prevention of a disease selected from the group consisting of allergic diseases, such as allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity reactions, and inflammatory dermatoses, such as atopic dermatitis, eczema, allergic contact dermatitis and urticaria, myositis, neurodegenerative diseases, such as neuropathic pain, and other inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, and Inflammatory Bowel Disease (IBD), as well as other diseases associated with the activity of CTRH 2. In particular, the invention relates to the use of compounds of formula I for modulating, in particular inhibiting, CRTH2 activity.
The invention further relates to a method for the treatment and/or prophylaxis of a disease selected from allergic diseases (e.g. allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity) and inflammatory dermatoses (e.g. atopic dermatitis, eczema, allergic contact dermatitis and urticaria, (myositis), neurodegenerative diseases (e.g. neuropathic pain) and other inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, osteoarthritis and Inflammatory Bowel Disease (IBD)) and other diseases associated with the activity of CTRH2 by administering a compound according to formula (I) to a patient.
The invention further relates to the use of compounds of formula I for the preparation of pharmaceutical compositions.
The invention finally relates to novel compounds of the formula I and to methods for synthesizing these molecules.
Description of the invention
The following paragraphs provide definitions of the various chemical groups that constitute the compounds of the present invention, and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader definition.
“C1-C6-alkyl "refers to a monovalent alkyl group having 1 to 6 carbon atoms. The term can be exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
"aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl groups include phenyl, naphthyl, phenanthryl, and the like. The aromatic ring may also be fused to a heterocycloalkyl group. Such fused aryl groups include dihydrobenzimidazol-2-one, benzo [1, 3] dioxoles, and the like.
“C1-C6-alkylaryl "means having an aryl substituentC1-C6Alkyl groups such as benzyl, phenethyl and the like.
"heteroaryl" refers to a monocyclic heteroaromatic or a bicyclic or tricyclic fused ring heteroaromatic group. Specific examples of heteroaryl groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, 1, 3, 4-thiadiazolyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2-a ] pyridyl, Benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, 2, 3-naphthyridinyl, quinoxalinyl, cinnolinyl, 1, 5-naphthyridinyl, pyridazinyl, pyrido [3, 4-b ] pyridyl, pyrido [3, 2-b ] pyridyl, pyrido [4, 3-b ] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5, 6, 7, 8-tetrahydroquinolyl, 5, 6, 7, 8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, or benzoquinolyl, and the like.
“C1-C6-Alkylheteroaryl "refers to a C having a heteroaryl substituent1-C6Alkyl radicals, e.g. 2-furylmethyl2-thienylmethyl, 2- (1H-indol-3-yl) ethyl and the like.
“C3-C8-cycloalkyl "refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl groups include cyclopentyl, cyclohexyl, norbornyl, and the like.
“C3-C8-heterocycloalkyl "means a radical of the above definition C3-C8Cycloalkyl in which up to 3 carbon atoms are substituted by a heteroatom selected from O, S, NR, R being defined as hydrogen or methyl. Preferred heterocycloalkyl groups include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.
“C1-C6-alkylcycloalkyl "denotes C with a cycloalkyl substituent1-C6Alkyl groups including cyclohexylmethyl, cyclopentylpropyl and the like.
“C1-C6-Alkylheterocycloalkyl "means a C having a heterocycloalkyl substituent1-C6Alkyl groups including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl, and the like.
“C2-C6-alkenyl "means an alkenyl group preferably having 2 to 6 carbon atoms and having at least 1 or more alkenyl unsaturation. Preferred alkenyl groups include vinyl (-CH ═ CH)2) N-2-propenyl (allyl, -CH)2CH＝CH2) And the like.
“C2-C6-alkynyl "means an alkynyl group preferably having 2 to 6 carbon atoms and having at least 1 or more alkynyl unsaturated bonds. Preferred alkynyl groups include ethynyl (-CH.ident.CH), propynyl (-CH)2C.ident.CH) and the like.
"carboxy" refers to the group-C (O) OR, wherein R includes hydrogen OR "C1-C6-an alkyl group ".
"acyl" refers to the group-C (O) R, wherein R includes "C1-C6-alkyl "," aryl "-,", alkyl, aryl, or aryl,"heteroaryl", "C3-C8-cycloalkyl "," C3-C8-heterocycloalkyl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl ".
"acyloxy" refers to the group-OC (O) R, where R includes H, "C1-C6-alkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl ".
"Arylacyl" refers to an aryl group having an acyl substituent, including 2-acetylphenyl and the like.
"heteroarylacyl" refers to heteroaryl groups having an acyl substituent, including 2-acetylpyridyl, and the like.
"alkoxy" refers to the group-O-R, where R includes "C1-C6-alkyl group "," C2-C6Alkenyl group "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.
“C1-C6-Alkylalkoxy "means C with an alkoxy substituent1-C6Alkyl groups including 2-ethoxyethyl and the like.
"alkoxycarbonyl" refers to the group-C (O) OR, wherein R includes "C1-C6-alkyl "or" aryl "or" heteroaryl "or" C1-C6-alkylaryl "or"C1-C6-alkylheteroaryl ".
"aminocarbonyl" refers to the group-C (O) NRR 'where R, R' independently includes hydrogen or C1-C6-alkyl or aryl or heteroaryl or "C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl ".
"acylamino" refers to the group-NR (CO) R ', wherein each R, R' is independently hydrogen or "C1-C6-alkyl "or" aryl "or" heteroaryl "or" C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl ".
"halogen" means a fluorine, chlorine, bromine, iodine atom.
"Sulfonyloxy" refers to the group-OSO2-R, wherein R is selected from H, "C1-C6-alkyl ", halogen-substituted" C1-C6Alkyl radicals "e.g. -OSO2-CF3、“C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
"Sulfonyl" refers to the group "-SO2-R ", wherein R is selected from H," aryl "," heteroaryl "," C1-C6-alkyl ", halogen-substituted" C1-C6-alkyl ", such as-SO2-CF3、“C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl ""heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
"sulfinyl" refers to the group "-S (O) R", wherein R is selected from H, "C1-C6-alkyl ", halogen-substituted" C1-C6Alkyl radicals "such as-SO-CF3、“C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
"Thioalkyl" refers to the group-S-R, where R includes H, "C1-C6-alkyl ", optionally halogen-substituted" C1-C6Alkyl radicals, e.g. -S-CF3、“C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
"Sulfonylamino" refers to the group-NRSO2-R ', wherein each R, R' independently comprises hydrogen, "C1-C6-alkyl group "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
"aminosulfonyl" refers to the group-SO2-NRR ', wherein each R, R' independently comprises hydrogen, "C1-C6-alkyl group "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ".
"amino" refers to the group-NRR 'where each R, R' is independently hydrogen, "C1-C6-alkyl group "," C2-C6-alkenyl "," C2-C6-alkynyl "," C3-C8-a cycloalkyl group"heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkylaryl "or" C1-C6-alkylheteroaryl "," C2-C6-alkenylaryl group "," C2-C6-alkenylheteroaryl "," C2-C6-alkynylaryl "," C2-C6-alkynylheteroaryl "," C1-C6-alkylcycloalkyl "," C1-C6-alkylheterocycloalkyl ", and wherein R' and R", together with the nitrogen atom to which they are attached, may optionally form a 3-8 membered heterocycloalkyl ring.
"substituted or unsubstituted": unless otherwise limited by the definition of each substituent, groups described above, such as "alkyl", "alkenyl", "alkynyl", "alkoxy", "aryl", and "heteroaryl", may be optionally substituted with 1 to 5 substituents selected from: "C1-C6-alkyl group "," C1-C6-alkylaryl group "," C1-C6-alkylheteroaryl "," C2-C6-alkenyl "," C2-C6Alkynyl groups, "primary, secondary, tertiary amino groups, or quaternary ammonium groups," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," aryl "," aryloxy "," heteroaryl "," heteroaryloxy ", carboxyl, cyano, halogen, hydroxyl, nitro, sulfanyl, sulfinyl (sulfoxy), sulfonyl, sulfonamido, alkoxy, sulfanyloxy, trihalomethyl, and the like. Within the framework of the present invention, said "substituted" also includes the case of ring closure of adjacent substituents, in particular when adjacent functional substituents are involved, for example lactams, lactones, cyclic anhydrides are formed, but also acetals, thioacetals, aminals are formed by ring closure, for example by obtaining protecting groups.
"pharmaceutically acceptable cationic salts or complexes (complex)" refers to salts such as alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium or magnesium), aluminum salts, ammonium salts, and salts with organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, N-Me-D-glucosamine, N '-bis (benzyl) -1, 2-ethylenediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, piperidine, benzathine (N, N' -dibenzylethylenediamine), choline, ethylenediamine, meglumine (N-methylglucamine), benzphetamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), Procaine and an amine of the formula-NR, R ', R ", wherein R, R', R" are independently hydrogen, alkyl or benzyl. Particularly preferred salts are sodium and potassium salts.
"pharmaceutically acceptable salt or complex" refers to salts or complexes of compounds of formula (I) as defined below which retain the desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; acid addition salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, 4' -methylenebis (3-hydroxy-2-naphthoic acid), alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, including in particular those of the formula-NR, R', R "+Z-Quaternary ammonium salts are shown wherein R, R', R "are independently hydrogen, alkyl or benzyl, and Z is a counterion, including chlorine, bromine, iodine, -O-alkyl, tosylate, mesylate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamate, mandelate, and diphenylacetate).
"pharmaceutically active derivative" refers to any compound that is capable of providing, directly or indirectly, the activity disclosed herein when administered to a recipient.
The compounds of formula I of the present invention are useful for the treatment and/or prevention of diseases selected from allergic diseases (e.g. allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity reactions) and inflammatory dermatoses (e.g. atopic dermatitis, eczema, allergic contact dermatitis, and urticaria), myositis, neurodegenerative diseases (e.g. neuropathic pain) and other inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, osteoarthritis and Inflammatory Bowel Disease (IBD)).
In one embodiment, the compounds of formula (I) are suitable as modulators, especially antagonists of CRTH 2. Accordingly, the compounds of the present invention are also particularly useful in the treatment and/or prevention of diseases mediated by CRTH2 activity. The treatment involves modulation of CRTH2, in particular inhibition of CRTH2 or antagonism of CRTH2 in mammals, especially humans. The CRTH2 modulator is selected from the group consisting of antagonists, inverse agonists, partial agonists, and agonists of CRTH 2.
In another embodiment, the CRTH2 modulator is an antagonist of CRTH 2.
In a specific embodiment, the CRTH2 modulator is an inverse agonist of CRTH 2.
In another specific embodiment, the CRTH2 modulator is a partial agonist of CRTH 2.
In another specific embodiment, the CRTH2 modulator is an agonist of CRTH 2.
The compounds of formula (I) are suitable for use as medicaments.
The compounds of formula (I) also include geometrical isomers thereof, optically active forms thereof such as enantiomers, diastereomers, racemic forms thereof and tautomers thereof, and pharmaceutically acceptable salts thereof, as well as isomers thereof and mixtures thereof for use as medicaments, wherein:
a may be an amine selected from the group consisting of:
or an alkyl, acyl, aminocarbonyl or ether selected from the group consisting of:
wherein each n is an integer independently selected from 0, 1, 2,3 or 4;
m is 1 or 2;
wherein R is7Selected from hydrogen, substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8-heterocycloalkyl, carboxyl, cyano, amino and hydroxyl;
R8selected from hydrogen, substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
b is selected from substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C3-C8-heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted monocyclic heteroaryl;
examples of B include ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyridyl, imidazolidinyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, isoxazolyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrimidinyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, carbazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, tetrazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, oxolanyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl;
according to a particular embodiment, B is selected from substituted or unsubstituted aryl, substituted or unsubstituted C3-C8-heterocycloalkyl and substituted or unsubstituted alkynyl;
according to a specific embodiment, B is a substituted or unsubstituted aryl group (e.g., phenyl). According to another embodiment, the phenyl group is mono-substituted in the ortho, meta or para position;
in another embodiment, B is C3-C8Heterocycloalkyl (for example piperazinyl, furyl or thienyl);
according to another embodiment, B is alkynyl (e.g., ethynyl or propynyl);
R1may be hydrogen or substituted or unsubstituted C1-C6-an alkyl group; in a preferred embodiment, R1Is hydrogen;
R2selected from substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8Cycloalkyl and substituted or unsubstituted C3-C8-a heterocycloalkyl group;
R2examples of (B) include methyl, ethyl, propyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyridinylImidazolidinyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, isoxazolylalkyl or morpholinyl, phenyl, naphthyl, pyrrolyl, pyrimidinyl, quinolizinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, carbazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, tetrazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, substituted or unsubstituted heteroaryl, Benzimidazolyl, benzothiazolyl, benzoxazolyl, oxolanyl, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyridyl, imidazolidinyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, isoxazolidinyl, quinazolinyl, 2, 3-naphthyridinyl, quinoxalinyl, cinnolinyl, 1, 5-naphthyridinyl, quinolinyl, isoquinolinyl, tetrazolyl, 5, 6, 7, 8-tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroisoquinolinyl, purinyl, pteridinyl, xanthenyl, or benzoquinolinyl;
according to one embodiment, R2Is a substituted or unsubstituted aryl group (e.g., phenyl);
substituted R2Wherein the substituents are selected from halogen, cyano, C1-C6Alkyl radical, C1-C6-alkoxy, thioalkoxy and thioalkyl;
in one embodiment, R2By one or more radicals selected from halogen, cyano, C1-C6Alkyl radical, C1-C6-substituents of alkoxy, thioalkoxy and thioalkyl are optionally substituted;
according to another embodiment, R2Substituted in the ortho, meta or para positions; in one embodiment, R2Is chlorophenyl;
according to anotherIn one embodiment, R2Is a substituted or unsubstituted heteroaryl (e.g., pyridyl or thienyl);
according to another embodiment, R2Is substituted or unsubstituted C1-C6-alkyl (e.g. methyl);
R3selected from substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8Cycloalkyl and substituted or unsubstituted C3-C8-a heterocycloalkyl group; wherein said substituted or unsubstituted aryl, heteroaryl, C3-C8-cycloalkyl or C3-C8Heterocycloalkyl which may be substituted or unsubstituted with one or more aryl, heteroaryl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl fused and may be substituted by one or more groups selected from C1-C6Alkyl, alkoxy, aryl, heteroaryl, carboxy, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulfoxy, sulfonyl, sulfonamido and trihalo-C1-C6-alkyl substitution;
R3examples of (b) include methyl, ethyl, propyl, butyl, tert-butyl, phenyl, naphthyl, phenanthryl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, carbazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, benzo (2, 1, 3) oxadiazolyl, benzo (1, 2, 5) oxadiazolyl, benzo [1, 3] oxadiazolyl]Dioxole, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, tetrazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro- ]]Benzofuranyl, 3, 4-dihydro-1H-benzo [1, 4]]Diazepine-2, 5-diones, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothiophenyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridazinyl, pyrimidineA group selected from the group consisting of a phenyl group, a quinolizinyl group, a quinazolinyl group, a 2, 3-diazanaphthyl group, a quinoxalinyl group, a cinnolinyl group, a 1, 5-diazanaphthyl group, a quinolyl group, an isoquinolyl group, a tetrazolyl group, a 5, 6, 7, 8-tetrahydroquinolyl group, a 5, 6, 7, 8-tetrahydroisoquinolyl group, a purinyl group, a pteridinyl group, a carbazolyl group, a xanthenyl group, a benzoquinolyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, an oxocyclopentyl group, a pyrrolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group, a pyridyl group, an imidazolidinyl group, a 1, 2, 4-oxadiazolyl group, a 1, 2;
according to one embodiment, R3Is a substituted or unsubstituted aryl group (e.g., phenyl or naphthyl); substituted R3Wherein the substituents are selected from halogen, cyano, C1-C6Alkyl radical, C1-C6-alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl;
in one embodiment, R3By one or more radicals selected from halogen, cyano, C1-C6Alkyl radical, C1-C6-substituents of alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl are optionally substituted;
examples of substituted phenyl are 4-trifluoromethoxyphenyl, 3-methoxyphenyl, 4-chlorophenyl, 3, 5-dimethylphenyl, 2-benzamide or 2-benzoic acid;
in another embodiment, R3Is a substituted or unsubstituted heteroaryl group (e.g., pyridyl, quinolyl, benzimidazolyl, indolyl, pyridazinyl, pyrazinyl, or 1, 3, 4-thiadiazolyl); an example of a substituted benzimidazole is 2-ethyl-2H-benzimidazolyl;
in another embodiment, R3Is fused to C3-C8Aryl radicals of heterocycloalkyl radicals (e.g. 1, 3-dihydrobenzimidazol-2-one, 3, 4-dihydro-1H-benzo [1, 4]]Diazepine-2, 5-diones);
in another embodiment, R3Is a substituted or unsubstituted C fused to a substituted or unsubstituted aryl group3-C8Heterocycloalkyl (e.g. 1, 2,3, 4-tetrahydroquinoline, 1, 2,3, 4-tetrahydroquinoxaline, 2, 3-dehydrobenzo-1, 4-oxazine, 2, 3-dehydroindole or dihydrobenzo-pyrrolodiazepine))；
In another embodiment, R3Is a substituted or unsubstituted C fused to a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl3-C8Heterocycloalkyl (e.g. dihydrobenzopyrroldiazepine))；
In another embodiment, R3Is a substituted or unsubstituted alkyl group (e.g., isopropyl);
according to another embodiment, R2Or R3Wherein the substituents are selected from the group consisting of C1-C6Alkyl, alkoxy, cyano, amino and halogen (e.g. methyl, ethyl, butyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenoxy, chloro, fluoro); wherein alkyl, alkoxy or aryloxy is optionally substituted with halo (e.g., trifluoromethyl, trifluoromethoxy).
Another particular subgroup of formula (I) are compounds of formula (I'), wherein A, B, R2And R3Is as defined above, and each R1May independently be hydrogen or substituted or unsubstituted C1-C6-an alkyl group.
In a preferred embodiment, R1Is hydrogen.
A particular subgroup of formulae (I) and (I') are compounds of formula (Ia-Id), wherein A, R2And R3Is as defined above, and Z is O or S.
Pharmaceutically acceptable salts of compounds of formula I and compounds of sub-groups of formulae (Ia) to (Id) which contain a basic residue, e.g., a primary, secondary or tertiary amine or pyridyl group, are acid addition salts with pharmaceutically acceptable acids, e.g., the hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or bisulfate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate and p-toluenesulfonate salts.
Compounds of the invention which are particularly suitable for use as medicaments include:
| example numbering | Name of |
| 1 | N- {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamides |
| 2 | 2-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } -methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides |
| 3 | N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl]Phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide |
| 4 | 2-chloro-N- [3- (4- { [ methyl (phenyl) amino]Methyl } phenyl) pyrazin-2-yl]Benzenesulfonamides |
| 5 | 2-chloro-N- (3- {4- [ (2-naphthoxy) methyl group]Phenyl } pyrazin-2-yl) -benzenesulfonamides |
| 6 | 2-chloro-N- {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazin-2-yl } - + benzenesulfonamide |
| 7 | 2-chloro-N- (3- {4- [ (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) methyl]-phenyl } pyrazin-2-yl) benzenesulfonamides |
| 8 | 2-chloro-N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl]Phenyl } pyrazin-2-yl) benzenesulfonamides |
| 9 | N- (3- {4- [ (1, 3-benzodioxol-5-ylamino) methyl]Phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide |
| 10 | N- [3- (4- { [ (3-methoxybenzyl) oxy)]Methyl } phenyl) pyrazin-2-yl]-2- (trifluoromethyl) benzenesulfonamide |
| Example numbering | Name of |
| 11 | 3-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } -methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides |
| 12 | N- [3- (4- { [ (4-chlorophenyl) (methyl) amino]Methyl } phenyl) pyrazin-2-yl]-thiophene-2-sulfonamides |
| 13 | 4-phenoxy-N- {3- [4- (quinolin-2-ylmethyl) piperazin-1-yl]Pyrazin-2-yl } -benzenesulfonamides |
| 14 | 4-methyl-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } -methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides |
| 15 | 4-chloro-N- [3- (4- { [ methyl (phenyl) amino group]Methyl } phenyl) pyrazin-2-yl]-benzenesulfonamides |
| 16 | 4-cyano-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]-amino } -methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides |
| 17 | N- [3- (4- { [ (4-fluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethylPhenyl-sulfonamides |
| 18 | N- (3- {4- [ (methyl-phenyl-amino) -methyl)]-phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonAmides of carboxylic acids |
| 19 | N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethylPhenyl-sulfonamides |
| 20 | N- {3- [4- (4-fluoro-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 21 | N- (3- {4- [ (ethyl-phenyl-amino) -methyl)]-phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonAmides of carboxylic acids |
| Example numbering | Name of |
| 22 | N- {3- [4- (2, 3-dihydro-benzo [ b ], [2 ]1，4]Oxazin-4-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 23 | N- [3- (4- { [ (3-fluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethylPhenyl-sulfonamides |
| 24 | N- {3- [4- (6-chloro-pyridin-3-yloxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 25 | N- {3- [4- (2-pyridin-2-yl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 26 | N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulphonamide |
| 27 | N- [3- (4-phenoxymethyl-phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide |
| 28 | N- [3- (4- { [ (4-chloro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethylPhenyl-sulfonamides |
| 29 | 2-chloro-N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-benzenesulfonamides |
| 30 | N- [3- (4- { [ (3, 4-dichloro-phenyl) -methyl-amino]-methyl } -phenyl) -Pyrazin-2-yl radicals]-2-trifluoromethyl-benzenesulfonamide |
| 31 | N- {3- [4- (4-cyano-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 32 | N- {3- [4- (6-fluoro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulphonamide |
| Example numbering | Name of |
| 33 | 2-chloro-N- {3- [4- (5-methoxy-2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -benzeneSulfonamides |
| 34 | N- {3- [4- (4-methoxy-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulphonamide |
| 35 | N- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl]-phenyl } -pyrazin-2-yl) -2-chloro-benzenesulfonamide |
| 36 | N- {3- [4- (2, 3-dihydro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonic acidAmides of carboxylic acids |
| 37 | N- [3- (4- { [ (2, 4-dichloro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide |
| 38 | N- {3- [4- (3-chloro-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 39 | 2-chloro-N- [3- (4- { [ (2, 4-difluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-benzenesulfonamides |
| 40 | N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
| 41 | 2-chloro-N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -benzenesulfonamides |
| 42 | 2-chloro-N- [3- (4- { [ (2-fluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-benzene sulfonic acid amide |
| 43 | 2-chloro-N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -benzenesulfonamides |
| Example numbering | Name of |
| 44 | N- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl]-phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide |
| 45 | 2-chloro-N- (3- {4- [ (ethyl-pyridin-2-yl-amino) -methyl]-phenyl } -pyrazin-2-yl) -benzenesulfonamide |
| 46 | N- {3- [4- (5-chloro-2-methyl-indol-1-ylmethyl) -phenyl } -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide |
In a second aspect, the present invention provides a pharmaceutical composition comprising a 2, 3-substituted pyrazine sulfonamide according to formula (I) and a pharmaceutically acceptable excipient or carrier.
In a third aspect, the present invention provides the use of a 2, 3-substituted pyrazine sulfonamide according to formula (I) for the manufacture of a medicament for the treatment and/or prevention of a disease selected from allergic diseases (e.g. allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity) and inflammatory dermatoses (e.g. atopic dermatitis, eczema, allergic contact dermatitis and urticaria), myositis and other diseases with an inflammatory component (e.g. rheumatoid arthritis, osteoarthritis and Inflammatory Bowel Disease (IBD)) and other diseases associated with the activity of CTRH 2.
In a fourth aspect, the present invention provides a method of treating and/or preventing a disease selected from allergic diseases (e.g. allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity) and inflammatory dermatoses (e.g. atopic dermatitis, eczema, allergic contact dermatitis and urticaria), myositis, neurodegenerative diseases (e.g. neuropathic pain) and other inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, osteoarthritis and Inflammatory Bowel Disease (IBD)) and other diseases associated with the activity of CTRH2 by administering to a patient a 2, 3-substituted pyrazine sulfonamide according to formula (I).
The term "preventing" as used herein shall be understood to mean partially or completely preventing, inhibiting, alleviating or reversing one or more symptoms or causes of allergic disease or inflammatory dermatitis.
In a fifth aspect, the present invention provides the use of a 2, 3-substituted pyrazine sulfonamide of formula (I) for the preparation of a pharmaceutical composition useful in a variety of therapies, including the prevention and/or treatment of diseases selected from allergic diseases (e.g. allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity) and inflammatory dermatoses (e.g. atopic dermatitis, eczema, allergic contact dermatitis and urticaria), myositis, neurodegenerative diseases (e.g. neuropathic pain) and other inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, osteoarthritis and Inflammatory Bowel Disease (IBD)) as well as other diseases associated with CTRH2 activity.
The present invention further provides the use of a 2, 3-substituted pyrazine sulfonamide represented by formula (I) for the prevention and/or treatment of a disease selected from allergic diseases (e.g. allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity) and inflammatory dermatoses (e.g. atopic dermatitis, eczema, allergic contact dermatitis and urticaria), myositis, neurodegenerative diseases (e.g. neuropathic pain) and other inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis, osteoarthritis and Inflammatory Bowel Disease (IBD)) and other diseases associated with CTRH2 activity.
The compounds of the present invention may be incorporated in the dosage form of pharmaceutical compositions and unit dosage forms thereof, which may be in the form of oral solid (e.g., tablets or filled capsules) or liquid (e.g., solutions, suspensions, emulsions, elixirs, or capsules filled with these), together with conventional adjuvants, carriers, diluents, or excipients; or a sterile injectable solution for parenteral administration (including subcutaneous administration). Such pharmaceutical compositions and unit dosage forms may contain the ingredients in conventional proportions, with or without other active compounds or active ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
The compounds of formula (I) of the present invention are typically administered in the form of pharmaceutical compositions. The pharmaceutical compositions may be prepared by methods well known in the pharmaceutical industry and comprise at least one active compound. Typically, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response, severity of the patient's symptoms, and the like, of each patient.
The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Compositions for oral administration may take the form of large liquid solutions or suspensions, or large powders. More typically, however, the compositions will be presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable for use as unitary dosages by humans or other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-metered ampoules or injections of liquid compositions, or pills, tablets, capsules and the like of solid compositions. In such compositions, the substituted methylene amide (derivative) derivatives according to the present invention are generally a minor component (about 0.1 to 50% by weight or preferably about 1 to 40% by weight), the remainder being various excipients or carriers and processing aids to aid in the formation of the desired dosage form.
Liquid forms suitable for oral administration may include aqueous or non-aqueous vehicles containing buffers, suspending and dispersing agents, colors, flavors, and the like as appropriate. The solid form may include, for example, any of the following ingredients or compounds of similar nature: a binder (such as microcrystalline cellulose, tragacanth or gelatin), an excipient (such as starch or lactose), a disintegrant (such as alginic acid, Primogel, or corn starch), a lubricant (such as magnesium stearate), a glidant (such as colloidal silicon dioxide), a sweetening agent (such as sucrose or saccharin), or a flavoring agent (such as peppermint, methyl salicylate, or orange flavoring).
Injectable compositions are typically based on sterile injectable saline or phosphate buffered saline or other injectable carriers known in the art. As mentioned above, the substituted methylene amide derivatives of formula (I) are generally minor ingredients in such compositions, often in the range of 0.05 to 10% by weight, with the remainder being injectable carriers and the like.
The above ingredients for oral or injectable compositions are representative only. Further materials and processing techniques, etc., may be found in Remington's Pharmaceutical Sciences (20 th edition, 2000, Marck publishing company, Easton, Pa., USA), which is incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials is also provided above in Remington's pharmaceutical sciences.
In a sixth aspect, the present invention provides novel 2, 3-substituted pyrazinesulfonyl groups represented by the formulae (Ia) to (Id)Amines of which A, R2And R3The definition of (A) is as above. Novel compounds of the formulae (Ia) to (Id) are in particular the following:
n- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-naphthoxy) methyl ] phenyl } pyrazin-2-yl) -benzenesulfonamide,
2-chloro-N- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } - + benzenesulfonamide,
2-chloro-N- (3- {4- [ (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) methyl ] -phenyl } pyrazin-2-yl) benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) benzenesulfonamide,
n- (3- {4- [ (1, 3-benzodioxol-5-ylamino) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
n- [3- (4- { [ (3-methoxybenzyl) oxy ] methyl } phenyl) pyrazin-2-yl ] -2- (trifluoromethyl) benzenesulfonamide,
3-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-chlorophenyl) (methyl) amino ] methyl } phenyl) pyrazin-2-yl ] -thiophene-2-sulfonamide,
4-phenoxy-N- {3- [4- (quinolin-2-ylmethyl) piperazin-1-yl ] pyrazin-2-yl } -benzenesulfonamide,
4-methyl-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
4-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] -benzenesulfonamide,
4-cyano-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] -amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (methyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-fluoro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (ethyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-benzo [1, 4] oxazin-4-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (3-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-chloro-pyridin-3-yloxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2-pyridin-2-yl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4-phenoxymethyl-phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-chloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- [3- (4- { [ (3, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-cyano-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-methoxy-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- {3- [4- (4-methoxy-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-chloro-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (2, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (3-chloro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2, 4-difluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
2-chloro-N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- (3- {4- [ (ethyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -benzenesulfonamide, and
n- {3- [4- (5-chloro-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide.
In a seventh aspect, the invention provides a method of synthesizing a compound according to formulas (Ia) - (Id).
The 2, 3-substituted sulfonamides exemplified in this invention can be prepared from readily available starting materials using conventional methods and procedures. It should be recognized that while typical or preferred experimental conditions (i.e., reaction temperatures, times, moles of reagents, solvents, etc.) are given, other experimental conditions may be used unless otherwise indicated. Optimum reaction conditions will vary with the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures.
A general description of the process for preparing the compounds of formula (I) is given in WO 04/058265(PCT/GB 03/005668).
Scheme 1 depicts a general synthetic method to obtain compounds of formula (Ia) - (Id). The 2, 3-substituted pyrazine sulfamide derivative shown in the general formula I can be prepared from commercially available 2, 3-dichloropyrazine through 4-5 steps of chemical reaction. Schemes 1-10 outline the synthetic schemes.
Scheme 1
In a more specific method, the sulfonamide derivative XXI (wherein R is2The same as defined above) and 2, 3-dichloropyrazine II to obtain the corresponding 3-chloropyrazine sulfonamide compound III. The first reaction step can employ various reaction conditions, for example, using a sulfonamide derivative XXI in the presence of a base (e.g., cesium carbonate, potassium carbonate, etc.). Depending on the intrinsic reactivity of compounds XXI and II, the reaction can be carried out by conventional heating or microwave methods, using standard conditions well known to those skilled in the art, or as shown in scheme 2 below, in solvents (e.g., NMP, DMF or DMA) at various temperatures.
Scheme 2
Sulfonamide derivatives XXI are obtained commercially or can be prepared by treating the corresponding sulfonyl chlorides XX1 hours at room temperature with 2M ammonia EtOH or dioxane solution using standard conditions well known to those skilled in the art; or by conventional heating or using microwave techniques, according to the intrinsic reactivity of compound XXI, using standard conditions well known to those skilled in the art or at various temperatures as shown in scheme 3 below.
Scheme 3
The 2, 3-substituted pyrazine sulfonamide derivatives represented by the general formula Ia can be obtained by the following 3-step reaction according to the availability of starting materials and building blocks. Scheme 4 shows one synthetic route. In the first step, the 3-chloropyrazine sulfonamide compound III can be isolated after condensation with boronic acid XXII to give the 2, 3-substituted pyrazine sulfonamide derivative IVa. The reaction may be carried out in a solvent (e.g., dioxane, methanol, or a solution containing two solvents in various ratios) in the presence of a suitable palladium catalyst (e.g., palladium diacetate). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating or using microwave methods, using standard conditions well known to those skilled in the art, at various temperatures.
Next, after the intermediate compound IVa is chlorinated in the presence of thionyl chloride, 2, 3-substituted pyrazine sulfonamide derivative Va (wherein R of substituent is R) is isolated2As defined above). The reaction is generally carried out in a solvent (e.g., dichloromethane, dichloroethane or DMF) at room temperature using standard conditions well known to those skilled in the art.
Then, as shown in scheme 4, various nucleophiles can be used, such as amine XXIV or alcohol XXV (where R is4、R5、R6Independently selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl) or the mentioned fused ring systems to obtain the desired 2, 3-substituted pyrazine sulfonamide derivatives Va. Nucleophilic displacement of the chlorine atom at the benzyl position by the amine XXIV or alcohol XXV can be accomplished under anhydrous conditions with a suitable base (e.g., sodium hydride or potassium tert-butoxide) in a solvent (e.g., DMF, THF, or the like) in the presence or absence of a catalyst (sodium iodide or tetrabutylammonium iodide). Depending on the intrinsic reactivity of compounds Va, XXIV and XXV, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Scheme 4
r.t.: at room temperature
The 2, 3-substituted pyrazine sulfonamide derivatives represented by the general formula Ia can also be obtained by the following 3-step reaction, depending on the availability of starting materials and building blocks. Scheme 5 shows another synthetic route. In the first step, 3-chloropyrazine sulfonamide compound III is condensed with boronic acid XXIII to isolate 2, 3-substituted pyrazine sulfonamide derivative IVb. The reaction may be carried out in a solvent (e.g., dioxane, methanol, or a solution containing two solvents in various ratios) in the presence of a suitable palladium catalyst (e.g., palladium diacetate). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Next, after the intermediate compound IVb is chlorinated in the presence of oxalyl chloride or after the compound IVb is treated with a suitable coupling reagent (e.g., DCC, HATU or Mukayama reagent) in the presence of a base (e.g., DIPEA or triethylamine), the 2, 3-substituted pyrazine sulfonamide derivative Vb (wherein R of the substituent is R) is isolated2As defined above). These reactions are generally carried out in a solvent (e.g., dichloromethane, dichloroethane, or DMF) at room temperature using standard conditions well known to those skilled in the art.
Finally, as shown in scheme 5, the 2, 3-substituted pyrazine sulfonamide derivatives Vb can be treated with various nucleophiles (e.g., amines XXIV) to obtain the desired 2, 3-substituted pyrazine sulfonamide derivatives Ia. Formation of the amide bond can be accomplished by treatment with a suitable base (e.g., DIPEA or triethylamine) in a solvent (e.g., DMF, THF, or the like). Depending on the intrinsic reactivity of compounds Vb and XXIV, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Scheme 5
The 2, 3-substituted pyrazine sulfonamide derivatives of formula Ib can be obtained by the following 3-step reaction, depending on the availability of starting materials and building blocks. Scheme 6 shows one synthetic route. In the first step, 3-chloropyrazine sulfonamide compound III is condensed with boric acid XXVI and then separated into 2, 3-substituted pyrazine sulfonamide derivative VIa. The reaction may be carried out in a solvent (e.g., dioxane, methanol, or a solution containing two solvents in various ratios) in the presence of a suitable palladium catalyst (e.g., palladium diacetate). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Next, the intermediate compound VIa is chlorinated in the presence of thionyl chloride, and 2, 3-substituted pyrazine sulfonamide derivative VIIa (wherein R of substituent is2As defined above). The reaction is generally carried out in a solvent (e.g., dichloromethane, dichloroethane or DMF) at room temperature using standard conditions well known to those skilled in the art.
Then, as shown in scheme 6, the 2, 3-substituted pyrazine sulfonamide derivative VIIa can be treated with various nucleophiles (e.g., amine XXIV or alcohol XXV) to obtain the desired 2, 3-substituted pyrazine sulfonamide derivative Ib. Nucleophilic displacement of the chlorine atom at the benzyl position by the amine XXIV or alcohol XXV can be accomplished under anhydrous conditions with a suitable base (e.g., sodium hydride or potassium tert-butoxide) in a solvent (e.g., DMF, THF, or the like) in the presence or absence of a catalyst (sodium iodide or tetrabutylammonium iodide). Depending on the intrinsic reactivity of compounds VIIa, XXIV and XXV, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Scheme 6
Depending on the availability of starting materials and building blocks, 2, 3-substituted pyrazine sulfonamide derivatives of the general formula Ib can also be obtained by the following 3-step reaction. Scheme 7 shows another synthetic route. In the first step, 3-chloropyrazine sulfonamide compound III is condensed with boronic acid XXVII and then isolated as 2, 3-substituted pyrazine sulfonamide derivative VIb. The reaction may be carried out in a solvent (e.g., dioxane, methanol, or a solution containing two solvents in various ratios) in the presence of a suitable palladium catalyst (e.g., palladium diacetate). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Next, after chlorination of the intermediate compound VIb in the presence of oxalyl chloride or treatment of the compound VIb with a suitable coupling reagent (e.g., DCC, HATU or Mukayama reagent) in the presence of a base (e.g., DIPEA or triethylamine), the 2, 3-substituted pyrazine sulfonamide derivative VIIb (wherein R of the substituent is R) is isolated2As defined above). The reaction is generally carried out in a solvent (e.g., dichloromethane, dichloroethane or DMF) at room temperature using standard conditions well known to those skilled in the art.
Finally, as shown in scheme 7, the 2, 3-substituted pyrazine sulfonamide derivatives VIIb can be treated with various nucleophiles (e.g., amine XXIV) to obtain the desired 2, 3-substituted pyrazine sulfonamide derivatives Ib. Formation of the amide bond can be accomplished by using a suitable base (e.g., DIPEA or triethylamine) in a solvent (e.g., DMF, THF, or the like). Depending on the intrinsic reactivity of compounds VIIb and XXIV, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Scheme 7
Depending on the availability of starting materials and building blocks, 2, 3-substituted pyrazine sulfonamide derivatives of general formula Ic can be obtained by the following 3-step reaction. Scheme 8 shows one synthetic route. In the first step, 3-chloropyrazine sulfonamide compound III is condensed with acetylene XXVIII, and then 2, 3-substituted pyrazine sulfonamide derivative VIIIa is separated. The reaction can be carried out over a suitable palladium catalyst (e.g., tetrakis (triphenylphosphine) palladium or Pd (Ph)3)2Cl2) In the presence of cuprous iodide and potassium acetate in a solvent (e.g. dioxane, DMF or a solution containing both solvents in various ratios). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Next, the intermediate compound VIIIa is chlorinated in the presence of thionyl chloride and then isolated as a 2, 3-substituted pyrazine sulfonamide derivative IXa (wherein R of the substituent group is2As defined above). The reaction is generally carried out in a solvent (e.g., dichloromethane, dichloroethane or DMF) at room temperature using standard conditions well known to those skilled in the art.
Then, as shown in scheme 8, the 2, 3-substituted pyrazine sulfonamide derivative Ixa can be treated with various nucleophiles (e.g., amine XXIV or alcohol XXV) to obtain the desired 2, 3-substituted pyrazine sulfonamide derivative Ic. Nucleophilic displacement of the chlorine atom at the benzyl position by the amine XXIV or alcohol XXV can be accomplished under anhydrous conditions with a suitable base (e.g., sodium hydride or potassium tert-butoxide) in a solvent (e.g., DMF, THF, or the like), in the presence or absence of a catalyst (sodium iodide or tetrabutylammonium iodide). Depending on the intrinsic reactivity of the compounds IXa, XXIV and XXV, the reaction can be carried out by conventional heating methods or using microwave technology, using standard conditions well known to those skilled in the art, at various temperatures.
Scheme 8
Depending on the availability of starting materials and building blocks, 2, 3-substituted pyrazine sulfonamide derivatives of the general formula Ic can also be obtained by the following 3-step reaction. Scheme 9 shows another synthetic route. In the first step, 3-chloropyrazine sulfonamide compound III is condensed with acetylene XXIX, and then 2, 3-substituted pyrazine sulfonamide derivative VIIIb is isolated. The reaction can be carried out over a suitable palladium catalyst (e.g., tetrakis (triphenylphosphine) palladium or Pd (Ph)3)2Cl2) In the presence of cuprous iodide and potassium acetate in a solvent (e.g. dioxane, DMF or a solution containing both solvents in various ratios). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Next, after chlorination of the intermediate compound VIIIb in the presence of oxalyl chloride, or after treatment of compound VIIIb with a suitable coupling reagent (e.g., DCC, HATU or Mukayama reagent) in the presence of a base (e.g., DIPEA or triethylamine), the 2, 3-substituted pyrazine sulfonamide derivative IXb (wherein R of the substituent is R) is isolated2As defined above). The reaction is generally carried out in a solvent (e.g., dichloromethane, dichloroethane or DMF) at room temperature using standard conditions well known to those skilled in the art.
Finally, as shown in scheme 9, the 2, 3-substituted pyrazine sulfonamide derivatives Ixb can be treated with various nucleophiles (e.g., amines XXIV) to give the desired 2, 3-substituted pyrazine sulfonamide derivatives Ic. Formation of the amide bond can be accomplished by using a suitable base (e.g., DIPEA or triethylamine) in a solvent (e.g., DMF, THF, or the like). Depending on the intrinsic reactivity of the compounds IXb and XXIV, the reaction can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Scheme 9
The 2, 3-substituted pyrazine sulfonamide derivatives of the general formula Id can be obtained by the following 3-step reaction, depending on the availability of starting materials and building blocks. Scheme 10 illustrates one synthetic route. Firstly, condensing a 3-chloropyrazine sulfonamide compound III and piperazine-1-carboxylic acid tert-butyl ester XXX, and separating to obtain a 2, 3-substituted pyrazine sulfonamide derivative X. The reaction can be carried out in a solvent (e.g., NMP, DMF, or a solution containing both solvents in various ratios) in the presence of a suitable base (e.g., DIPEA or triethylamine). Depending on the intrinsic reactivity of compound III, the reaction can be carried out by conventional heating methods or microwave techniques, using standard conditions well known to those skilled in the art, at various temperatures.
Next, this gave the 2, 3-substituted pyrazine sulfonamide derivative XI: using TFA or HCl solutions of different concentrations, thereby leaving the group R2And the protection is carried out under the acidic condition. The reaction is generally carried out in a solvent (e.g., dichloromethane, dichloroethane or DMF) at room temperature using standard conditions well known to those skilled in the art.
Then, as shown in scheme 10, various electrophiles (e.g., alkyl halides XXXIIa) can be applied to a suitable base (e.g., Cs)2CO3DIPEA or triethylamine) or by treatment of the 2, 3-substituted pyrazine sulfonamide derivative X with a suitable coupling reagent (e.g. DCC, Mukayama reagent, PyBrop) pre-activated acid chloride or carboxylic acid XXXIb to obtain the desired 2, 3-substituted pyrazine sulfonamide derivative Id. Depending on the intrinsic reactivity of the compounds XI, XXXIIa or XXXIIb, nucleophilic displacement of halogen atoms or formation of amide bonds with alkyl halides XXXIIa or acid chlorides or carboxylic acids XXXIIb can be carried out by conventional heating methods or using microwave techniques, using standard conditions well known to those skilled in the art at various temperatures.
Scheme 10
The following abbreviations respectively represent the following definitions:
min (min), hr (h), g (g), MHz (megahertz), ml (ml), mmol (millimole), mM (millimole concentration), RT (room temperature), ATP (adenosine triphosphate), BSA (bovine serum albumin), DCM (dichloromethane), DCC (dicyclohexylcarbodiimide), DIPEA (diisopropylethylamine), DMSO (dimethyl sulfoxide), Mukayama reagent (1-methyl-2-chloropyridinium iodide), DMF (dimethylformamide), CsCO3(cesium carbonate), cHex (cyclohexane), Et3N (triethylamine), EtOAc (ethyl acetate), EtOH (ethanol), K2CO3(Potassium carbonate), NaI (sodium iodide), NaH (sodium hydride), NaHCO3(sodium bicarbonate), NH4Cl (ammonium chloride), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), Pd (PPh)3)4(tetrakis (triphenylphosphine) palladium), CuI (cuprous iodide), Pd (OAc)2(Palladium II acetate), Pd (PPh)3)2 Cl2(bis (triphenylphosphine) palladium II) chloride), CH3COOK (Potassium acetate), PPh3(triphenylphosphine), HATU (N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (uranium)), (CO)2Cl2(oxalyl chloride), SOCl2(thionyl chloride), tBuOK (potassium tert-butoxide), MeOH (methanol), MgSO4(magnesium sulfate), NMP (N-methylpyrrolidone), PetEther (petroleum ether), rt (room temperature), HPLC (high performance liquid chromatography), FC (silica gel flash chromatography), MS (mass spectrometry), NMR (nuclear magnetic resonance), PBS (phosphate buffered saline), SPA (scintillation Proximity Assay), TLC (thin layer chromatography), UV (ultraviolet).
If the general synthetic methods described above are not yet available to give compounds of formula (I) and/or intermediates required for the synthesis of compounds of formula (I), suitable preparative methods known to those skilled in the art should be used. In general, the synthetic route for each particular compound of formula (I) depends on the particular substituents per molecule and on whether the desired intermediate is readily available; these factors are well known to those skilled in the art. All protection and deprotection methods are described in J.Kocienski, "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994) and Greene and Peter G.M.Wuts, "Protecting Groups in Organic Synthesis" (Wiley Interscience, 3 rd edition, 1999).
The compounds of the invention associated with the solvent molecules can be isolated by crystallization from evaporation of a suitable solvent. Pharmaceutically acceptable acid addition salts of formula (I) containing a base centre may be prepared by conventional methods. For example, a solution of the free base can be treated with a suitable acid (either neat or dissolved in a suitable solvent) and the resulting salt isolated by filtration or evaporation of the reaction solvent in vacuo. Pharmaceutically acceptable base addition salts may likewise be obtained by treating a solution of a compound of formula (I) with a suitable base. The two types of salts may be formed or interconverted with ion exchange resins.
The invention will now be illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Experimental part
The HPLC, NMR and MS data in the following examples were obtained as follows: HPLC: column Waters symmetry C850X 4.6mm, conditions: MeCN/H2O, 5-100% (8min), maximum icon 230400 nm; mass spectrum: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: WatersZMD (ES);1H-NMR：Bruker DPX-300MHz。
preparative HPLC purification on a Pres Nova-Pak equipped columnHR C186μm 6040X 30mm (maximum column loading 100mg) or XTerraPrep MS C8, 10 μm, 50X 300mm (maximum loading 1g) on a preparative HPLC Waters Prep LC 4000 system. All purifications used gradient MeCN/H2O0.09% TFA. Semi-preparative reverse phase HPLC on a instrumented column SupelcosilTMABZ + Plus (25 cm. times.21.2 mm, 12 μm) on the Biotage parallel Flex system; ultraviolet detection wavelengths of 254nm and 220 nm; the flow rate was 20mL/min (maximum column loading 50 mg). TLC analysis was performed on Merck prep 60F 254 plates. Purification by flash chromatography on SiO2The procedure was carried out on a support with cyclohexane/EtOAc or DCM/MeOH mixtures as eluent.
Intermediate 1: 2- (trifluoromethyl) benzenesulfonamides
(see scheme 3, Compound XXI)
71ml of a 2M solution of ammonia in ethanol was added to a solution of 2- (trifluoromethyl) benzenesulfonyl chloride (5 g; 20.44 mmol; 1.00eq.) in anhydrous THF (5.00ml) at room temperature under a nitrogen atmosphere. The reaction mixture was shaken for 20h at room temperature. After concentration of the solvent, the residue was redissolved in EtOAc (150mL) and then treated with NH4Saturated aqueous Cl (50mL) and brine (50 mL). The organic layer was MgSO4Pure 2- (trifluoromethyl) benzenesulfonamide was obtained after drying, filtration and concentration of the solvent as a yellowish solid (4.6g, 89% yield, 98.6% HPLC purity). The compound was used as such in the next reaction.
1H NMR(300MHz，CDCl3)；5.0(m，2H)，7.6(m，2H)，7.8(m，1H)，8.3(m，1H)MS(ESI-)：224.1.
Intermediate 2: 2-chloro-N- (3-chloropyrazin-2-yl) benzenesulfonamides
(see scheme 2, Compound III)
2, 3-dichloropyrazine (1 g; 6.71 mmol; 1.00eq.) and 2-dichlorobenzenesulfonamide (1.29 g; 6.71 mmol; 1.00eq.) were stirred in NMP (9 ml). Cesium carbonate (2 g; 6 mmol; 0.90eq.) was added to the reaction mixture, stirred and heated to 130 ℃ for 20 h. Then cooled to room temperature, 98ml of water were added and washed with AcOEt (2X 30 ml). The aqueous phase was acidified with citric acid and extracted with AcOEt (3X 60 ml). The combined organic extracts were washed with brine (10ml) and MgSO4Drying and concentrating. The residue was purified by Flashmaster, gradient eluted with AcOEt/cHex 2: 8-AcOEt 100% over 45min, filtered and concentrated to isolate the title compound. The solid was recrystallized from a mixture of EtOAc: Chex (30: 70) to give pure 2-chloro-N- (3-chloropyrazin-2-yl) benzenesulfonamide as a yellowish solid 2-chloro-N- (3-chloropyrazin-2-yl) benzenesulfonamide (1g, 49% yield, 100% HPLC purity).
1H NMR(300MHz，CDCl3)；7.3-7.5(m，3H)，7.8-8.0(m，3H)，8.3(m，1H)。MS(ESI+)：304.1；MS(ESI-)：302.0。
Intermediate 3: n- (3-chloropyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide
(see scheme 2, Compound III)
Following the general procedure outlined for the preparation of intermediate 2, starting from 2, 3-dichloropyrazine and 2- (trifluoromethyl) benzenesulfonamide, the title compound was isolated after concentration and recrystallization as a yellowish solid in 63% yield (97% HPLC purity).
1H NMR(300MHz，CDCl3)；7.6-7.8(m，4H)，7.9-8.1(m，2H)，8.5(m，1H)。MS(ESI+)：338.0；MS(ESI-)：336.0。
Intermediate 4: 2-chloro-N- {3- [4- (hydroxymethyl) phenyl]Pyrazin-2-yl } benzenesulfonamides
(see scheme 4, Compound IVa)
2-chloro-N- (3-chloropyrazin-2-yl) benzenesulfonamide (2.2 g; 7.23 mmol; 1.00eq.) and 4-hydroxymethylphenylboronic acid (1.21 g; 7.96 mmol; 1.10eq.) were dissolved in 48mL of a pre-degassed mixture of dioxane: MeOH 1: 1. Potassium carbonate (2.75 g; 19.89 mmol; 2.75eq.) and triphenylphosphine (284.58 mg; 1.08 mmol; 0.15eq.) were added under nitrogen, followed by palladium II (81.19 mg; 0.36 mmol; 0.05 eq.). Reaction mixture in N2Heating at 110 deg.C for 30 min. It was then cooled to room temperature, diluted with ether (50mL) and water (25mL) and filtered through a layer of celite. The aqueous layer was separated, the organic layer was washed with water (50mL), the aqueous layers were combined and washed with diethyl ether (50mL), acidified with 5N HCl and extracted with AcOEt. The combined organic extracts were washed with brine (10ml) and MgSO4Drying and concentrating to obtain pure 2-chloro-N- {3- [4- (hydroxymethyl) phenyl]Pyrazin-2-yl } benzenesulfonamide as a yellowish solid (2.5g, 91% yield, 98% HPLC purity). The compound was used as such in the next reaction.
1H NMR(300MHz，CDCl3)；4.68(m，2H)，7.5-7.7(m，7H)，8.1-8.2(m，3H)，8.3(m，1H)。MS(ESI+)：376.1；MS(ESI-)：374.1。
Intermediate 5: 2-trifluoromethyl-N- {3- [4- (hydroxymethyl) phenyl]Pyrazin-2-yl } benzenesulfonamides
(see scheme 4, Compound IVa)
Following the general procedure outlined for the preparation of intermediate 4, starting from N- (3-chloropyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide and 4-hydroxymethylphenylboronic acid, the title compound was isolated after concentration and recrystallization as a yellowish solid in 85% yield (97% HPLC purity).
1H NMR(300MHz，CDCl3)；4.83(m，2H)，7.5-7.9(m，8H)，8.1(m，1H)，8.3(m，1H)，8.64(m，1H)。MS(ESI+)：410.3；MS(ESI-)：408.5。
Intermediate 6: 4- (3- { [ (2-chlorophenyl) sulfonyl]Amino-pyrazin-2-yl) benzoic acid
(see scheme 5, Compound IVb)
Following the general procedure outlined for the preparation of intermediate 4, starting from 2-chloro-N- (3-chloropyrazin-2-yl) benzenesulfonamide and 4-carboxyphenylboronic acid, the title compound was isolated after concentration and recrystallization as a yellowish solid in 83% yield (96% HPLC purity).
1H NMR(300MHz，CDCl3)；7.5-7.7(m，4H)，7.9-8.0(m，2H)，8.1-8.4(m，5H)。MS(ESI+)：390.8；MS(ESI-)：388.9。
Intermediate 7: 4- (3- { [ 2-trifluoromethylphenyl) sulfonyl group]Amino-pyrazin-2-yl) benzoic acid
(see scheme 5, Compound IVb)
Following the general procedure outlined for the preparation of intermediate 4, starting from N- (3-chloropyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide and 4-carboxyphenylboronic acid, the title compound was isolated after concentration and recrystallization as a yellowish solid in 80% yield (98% HPLC purity).
MS(ESI+)：424.4；MS(ESI-)：422.2。
Intermediate 8: 2-chloro-N- {3- [4- (chloromethyl) phenyl]Pyrazin-2-yl } benzene-sulfonamides
(see scheme 4, Compound Vb)
2-chloro-N- {3- [4- (hydroxymethyl) phenyl]Pyrazin-2-yl } benzenesulfonamide (3.15 g; 8.4 mmol; 1.00eq.) is dissolved in dichloromethane (80mL) and thionyl chloride (8.5mL, 117mmol, 14eq.) is added dropwise. The reaction mixture was stirred overnight and then carefully poured into ice/water (200mL) and stirred until the layers separated. Separating the mixture, and passing the organic layer through MgSO4Drying and concentrating to obtain a crude solid product, and recrystallizing in AcOEt/cyclohexane to obtain pure 2-chloro-N- {3- [4- (chloromethyl) phenyl]Pyrazin-2-yl } benzenesulfonamide as a white solid (3.02g, 95% yield, 99% HPLC purity).
1H NMR(300MHz，CDCl3)；4.69(m，2H)，7.45-7.6(m，3H)，7.65-7.7(m，5H)，8.0(m，1H)，8.3(m，1H)，8.38(m，1H)。MS(ESI+)：396.1；MS(ESI-)：393.1。
Intermediate 9: n- {3- [4- (chloromethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamides
(see scheme 4, Compound Vb)
Following the general procedure outlined for the preparation of intermediate 8, starting from 2-trifluoromethyl-N- {3- [4- (hydroxymethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide and thionyl chloride, the title compound was isolated after concentration and recrystallization as a white solid in 96% yield (97% HPLC purity).
MS(ESI+)：428.9；MS(ESI-)：426.7。
Intermediate 10: n- [3- (3-hydroxypropan-1-yn-1-yl) pyrazin-2-yl]-2- (trifluoromethyl) benzenesulfonamide
(see scheme 8, Compound VIIIa)
The method A comprises the following steps:
n- (3-Chloropyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide (1.35 g; 4.0 mmol; 1.00eq.) and 2-propyn-1-ol (336 mg; 6.0 mmol; 1.5eq.) were dissolved in 10mL of DMF under a nitrogen atmosphere. Adding CH under nitrogen atmosphere3COOK (588 mg; 6.0 mmol; 1.5eq.) and Pd (PPh)3)4(232 mg; 0.2 mmol). The reaction mixture was then heated at 100 ℃ for 2 hours under nitrogen. After removal of the solvent by distillation in vacuo, the residue was triturated with water (40mL) and extracted with ether (3X 30 mL). The organic layer was MgSO4Dried and concentrated. Purifying the crude product by silica gel column chromatography using hexane and AcOEt mixed solution as eluent to obtain pure N- [3- (3-hydroxypropane-1-alkyne-1-yl) pyrazine-2-yl]-2- (trifluoromethyl) benzenesulfonamide as a yellowish solid (686mg, 48% yield, 98% HPLC purity).
The method B comprises the following steps:
n- (3-Chloropyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide (1.35 g; 4.0 mmol; 1.00eq.) and 2-propyn-1-ol (336 mg; 6.0 mmol; 1.5eq.) were dissolved in 10mL of DMF under a nitrogen atmosphere. Adding CH under nitrogen atmosphere3COOK (588 mg; 6.0 mmol; 1.5eq.), CuI (40 mg; 0.2 mmol; 0.05eq.) and Pd (PPh)3)2Cl2(28 mg; 0.04 mmol). The reaction mixture was then heated at 100 ℃ for 2 hours under nitrogen. After removal of the solvent by distillation in vacuo, the residue was triturated with water (40mL) and extracted with ether (3X 30 mL). The organic layer was MgSO4Dried and concentrated. Purifying the crude product by silica gel column chromatography using hexane and AcOEt mixed solution as eluent to obtain pure N- [3- (3-hydroxypropane-1-alkyne-1-yl) pyrazine-2-yl]-2- (trifluoromethyl) benzenesulfonamide as a yellowish solid (702mg, 50% yield, 98% HPLC purity).
MS(ESI+)：358.6；MS(ESI-)：356.5。
Intermediate 11: n- (3-piperazin-1-ylpyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide
(see scheme 10, Compound XI)
Tert-butyl 4- [3- ({ [2- (trifluoromethyl) phenyl ] sulfonyl } amino) pyrazin-2-yl ] piperazine-1-carboxylate (1.46g, 3mmol) was dissolved in dichloromethane (50mL) and trifluoroacetic acid (4.5g, 40mmol) was added at 0 ℃. The reaction mixture was stirred for 2 h. The solvent was concentrated and the residue redissolved in dichloromethane (50ml) to afford the expected product N- (3-piperazin-1-ylpyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide as a yellow solid after evaporation to dryness (1.1g, 95% yield, 95% HPLC purity).
MS(ESI+)：388.4；MS(ESI-)：386.3。
Example 1: general procedure for the synthesis of 2, 3-substituted pyrazine sulfonamide derivatives of general formula I (a and Z are as defined above (schemes 1, 4, 5, 6, 7, 8, 9 and 10)): n- {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzene-sulphonamides
The method A comprises the following steps:
sodium hydride (80mg, 2mmol, 1eq) was added to a solution of 1H-indole (234mg, 2.0mmol, 1eq) in dimethylformamide (10 mL). After the hydrogen generation is finished, N- {3- [4- (chloromethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 26) (854mg, 2mmol, 1eq) in dimethylformamide (5mL) and the reaction mixture was heated at 80 ℃ for 3 hours. Cooled, diluted with 30mL of water and extracted with ether. The organic layer was MgSO4Drying, concentrating and purifying by silica gel flash chromatography (using AcOEt and cyclohexane as eluent) to obtain pure N- {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide as a yellow solid (630mg, 1.24mmol, yield: 62%, 97% purity by HPLC).
The method B comprises the following steps:
mixing N- {3- [4- (chloromethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 26) (854mg, 2mmol, 1eq) and 1H-indole (234mg, 2.0mmol, 1eq) were shaken in tetrahydrofuran (20mL) and heated at 50 ℃ for 10 min. Potassium tert-butoxide (4.5mL of a 1M solution in THF) was added. The reaction mixture was maintained at 50 ℃ for 5h and then cooled to room temperature. The reaction mixture was treated with 10mL aqueous citric acid (20g in 100mL water) and extracted with AcOEt. The organic layer was MgSO4Dried and concentrated. The crude product was purified in a manner analogous to Process A to give pure N- {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazine esters-2-yl } -2- (trifluoromethyl) benzenesulfonamide as a yellow solid (691mg, 1.36mmol, yield: 68%, 98% HPLC purity).
N {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide:
a yellow solid;1H NMR(300MHz，CDCl3)；5.50(m，2H)，6.5(m，1H)，7.0-7.2(m，2H)，7.4-7.65(m，8H)，7.65-7.7(m，2H)，8.0(m，2H)，8.3(m，1H)，8.38(m，1H).MS(ESI+)509.5，(ESI-)507.6。
example 2: 2-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } -methyl) -phenyl]Pyrazin-2-yl } benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and N-methyl-4- (trifluoromethoxy) aniline, the title compound was isolated as a yellow solid in 72% yield (99% HPLC purity).
MS(ESI+)：550.1；MS(ESI-)：547.8。
Example 3: n- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl]Phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2-ethylbenzimidazole, the title compound was isolated as a yellow solid in 63% yield (96% HPLC purity).
MS(ESI+)：538.6；MS(ESI-)：536.5。
Example 4: 2-chloro-N- [3- (4- { [ methyl (phenyl) amino]Methyl } phenyl) pyrazin-2-yl]-benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and N-methyl-aniline, the title compound was isolated as a yellow solid in 83% yield (99% HPLC purity).
MS(ESI+)：465.6；MS(ESI-)：463.8。
Example 5: 2-chloro-N- (3- {4- [ (2-naphthoxy) methyl group]Phenyl } pyrazin-2-yl) benzene-sulfonamides
Following the general procedure outlined in example 1 (method a), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 2-hydroxynaphthalene, the title compound was isolated as a yellow solid in 72% yield (99% HPLC purity).
MS(ESI+)：503.4；MS(ESI-)：501.2。
Example 6: 2-chloro-N- {3- [4- (1H-indol-1-ylmethyl) phenyl]Pyrazin-2-yl } benzene-sulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 1-H-indole, the title compound was isolated as a yellow solid in 71% yield (98% HPLC purity).
MS(ESI+)：475.9；MS(ESI-)：473.5。
Example 7: 2-chloro-N- (3- {4- [ (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) methyl]-phenyl } -pyrazin-2-yl) benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 6-hydroxy-1, 2,3, 4-tetrahydronaphthalene, the title compound was isolated as a yellow solid in 69% yield (99% HPLC purity).
MS(ESI+)：507.6；MS(ESI-)：505.2。
Example 8: 2-chloro-N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl]Phenyl } pyrazinyl) benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 2-ethylbenzimidazole, the title compound was isolated as a yellow solid in 65% yield (96% HPLC purity).
MS(ESI+)：505.4；MS(ESI-)：503.2。
Example 9: n- (3- {4- [ (1, 3-benzodioxol-5-ylamino) methyl]Phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 3, 4- (methylenedioxy) aniline, the title compound was isolated as a yellow solid in 69% yield (96% HPLC purity).
MS(ESI+)：529.7；MS(ESI-)：527.5。
Example 10: n- [3- (4- { [ (3-methoxybenzyl) oxy)]Methyl } phenyl) pyrazin-2-yl]-2- (trifluoromethyl) benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 3-anisic alcohol, the title compound was isolated as a yellow solid in 64% yield (92% HPLC purity).
MS(ESI+)：530.4；MS(ESI-)：528.8。
Example 11: 3-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 3-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide and N-methyl-4- (trifluoromethoxy) aniline, the title compound was isolated as a yellow solid in 69% yield (94% HPLC purity).
MS(ESI+)：550.2；MS(ESI-)：547.6。
Example 12: n- [3- (4- { [ (4-chlorophenyl) (methyl) amino]Methyl } phenyl) pyrazin-2-yl]-thiophene-2-sulfonamides
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } thiophene-2-sulfonamide and N-methyl-4-chloroaniline, the title compound was isolated as a yellow solid in 69% yield (94% HPLC purity).
MS(ESI+)：472.8；MS(ESI-)：470.7。
Example 13: 4-phenoxy-N- {3- [4- (quinolin-2-ylmethyl) piperazin-1-yl]Pyrazin-2-yl } -benzenesulfonamides
2- (chloromethyl) quinoline hydrochloride (214mg, 1mmol, 1eq) and DIPEA (322mg, 2.5mmol, 2.5eq) were added to a solution of 4-phenoxy-N- (3-piperazin-1-ylpyrazin-2-yl) benzenesulfonamide (411mg, 1.0mmol, 1eq) in dimethylformamide (10 mL). The reaction mixture was heated at 50 ℃ for 1 hour. Cooled, diluted with 30mL of water and extracted with ether. The organic layer was MgSO4Drying, concentrating and purifying by silica gel flash chromatography (using AcOEt and cyclohexane as eluent) to obtain pure 4-phenoxy-N- {3- [4- (quinoline-2-ylmethyl) piperazine-1-yl]Pyrazin-2-yl } benzenesulfonamide as a yellow solid (419mg, 0.76mmol, yield: 76%, 97% HPLC purity).
MS(ESI+)553.6，(ESI-)551.2。
Example 14: 4-methyl-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } -methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -4-methylbenzenesulfonamide and N-methyl-4- (trifluoromethoxy) aniline, the title compound was isolated as a yellow solid in 69% yield (94% HPLC purity).
MS(ESI+)：529.5；MS(ESI-)：526.6。
Example 15: 4-chloro-N- [3- (4- { [ methyl (phenyl) amino group]Methyl } phenyl) pyrazin-2-yl]-benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 4-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide and N-methyl-aniline, the title compound was isolated as a yellow solid in 76% yield (96% HPLC purity).
MS(ESI+)：465.6；MS(ESI-)：463.7。
Example 16: 4-cyano-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ]]Amino } -methyl) phenyl]Pyrazin-2-yl } benzenesulfonamides
Following the general procedure outlined in example 1 (method D), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -4-cyanobenzenesulfonamide and N-methyl-4- (trifluoromethoxy) aniline, the title compound was isolated as a yellow solid in 70% yield (92% HPLC purity).
MS(ESI+)：540.6；MS(ESI-)：538.5。
Example 17: n- [3- (4- { [ (4-fluoro-)Phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 4-fluoro-N-methylaniline, the title compound was isolated as a yellow solid in 78% yield (98% HPLC purity).
MS(ESI+)：517.9；MS(ESI-)：515.8。
Example 18: n- (3- {4- [ (methyl-phenyl-amino) -methyl)]-phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and N-methylaniline, the title compound was isolated as a yellow solid in 75% yield (99% HPLC purity).
MS(ESI+)：499.9；MS(ESI-)：497.8。
Example 19: n- [3- (4- { [ (4-cyano-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 4- (N-methylamino) benzonitrile, the title compound was isolated as a yellow solid in 71% yield (94% HPLC purity).
MS(ESI+)：524.6；MS(ESI-)：522.4。
Example 20: n- {3- [4- (4-fluoro-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 4-fluorophenol, the title compound was isolated as a yellow solid in 67% yield (95% HPLC purity).
MS(ESI+)：504.6；MS(ESI-)：502.6。
Example 21: n- (3- {4- [ (ethyl-phenyl-amino) -methyl)]-phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and N-ethylaniline, the title compound was isolated as a yellow solid in 70% yield (96% HPLC purity).
MS(ESI+)：513.6；MS(ESI-)：511.7。
Example 22: n- {3- [4- (2, 3-dihydro-benzo [1, 4]]Oxazin-4-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 3, 4-dihydro-2H-1, 4-benzoxazine, the title compound was isolated as a yellow solid in 65% yield (97% HPLC purity).
MS(ESI+)：527.7；MS(ESI-)：525.5。
Example 23: n- [3- (4- { [ (3-fluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 3-fluoro-N-methylaniline, the title compound was isolated as a yellow solid in 69% yield (92% HPLC purity).
MS(ESI+)：517.7；MS(ESI-)：515.6。
Example 24: n- {3- [4- (6-chloro-pyridin-3-yloxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2-chloro-5-hydroxy-pyridine, the title compound was isolated as a yellow solid in 73% yield (98% HPLC purity).
MS(ESI+)：522.1；MS(ESI-)：520.1。
Example 25: n- {3- [4- (2-pyridin-2-yl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2-pyridin-2-yl-1H-indole, the title compound was isolated as a yellow solid in 56% yield (92% HPLC purity).
MS(ESI+)：586.8；MS(ESI-)：584.6。
Example 26: n- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 5-fluoro-indole, the title compound was isolated as a yellow solid in 69% yield (99% HPLC purity).
MS(ESI+)：527.6；MS(ESI-)：525.7。
Example 27: n- [3- (4-phenoxymethyl-phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and phenol, the title compound was isolated as a yellow solid in 75% yield (98% HPLC purity).
MS(ESI+)：486.8；MS(ESI-)：484.7。
Example 28: n- [3- (4- { [ (4-chloro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 4-chloro-N-methylaniline, the title compound was isolated as a yellow solid in 72% yield (94% HPLC purity).
MS(ESI+)：534.1；MS(ESI-)：532.1。
Example 29: 2-chloro-N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (chloro) benzenesulfonamide (intermediate 8) and 4- (N-methylamino) -benzonitrile, the title compound was isolated as a yellow solid in 52% yield (99% HPLC purity).
MS(ESI+)：491.0；MS(ESI-)：489.0。
Example 30: n- [3- (4- { [ (3, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 3, 4-dichloro-N-methylaniline, the title compound was isolated as a yellow solid in 63% yield (91% HPLC purity).
MS(ESI+)：569.6；MS(ESI-)：565.1。
Example 31: n- {3- [4- (4-cyano-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 4-cyanophenol, the title compound was isolated as a yellow solid in 73% yield (93% HPLC purity).
MS(ESI+)：511.6；MS(ESI-)：509.6。
Example 32: n- {3- [4- (6-fluoro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 6-fluoro-1H-indole, the title compound was isolated as a yellow solid in 77% yield (97% HPLC purity).
MS(ESI+)：527.8；MS(ESI-)：525.6。
Example 33: 2-chloro-N- {3-[4- (5-methoxy-2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (chloro) benzenesulfonamide (intermediate 8) and 2-methyl-5-methoxyindole, the title compound was isolated as a yellow solid in 72% yield (98% HPLC purity).
MS(ESI+)：520.2；MS(ESI-)：518.3。
Example 34: n- {3- [4- (4-methoxy-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 4-hydroxyanisole, the title compound was isolated as a yellow solid in 48% yield (91% HPLC purity).
MS(ESI+)：516.6；MS(ESI-)：514.5。
Example 35: n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl]-phenyl } -pyrazin-2-yl) -2-chloro-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (chloro) benzenesulfonamide (intermediate 8) and 2-benzylaminopyridine, the title compound was isolated as a yellow solid in 35% yield (94% HPLC purity).
MS(ESI+)：543.3；MS(ESI-)：541.3。
Example 36: n- {3- [4- (2, 3-dihydro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2, 3-dihydro-1H-indole, the title compound was isolated as a yellow solid in 66% yield (94% HPLC purity).
MS(ESI+)：511.6；MS(ESI-)：509.4。
Example 37: n- [3- (4- { [ (2, 4-dichloro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2, 4-dichloro-N-methylaniline, the title compound was isolated as a yellow solid in 69% yield (96% HPLC purity).
MS(ESI+)：569.6；MS(ESI-)：566.8。
Example 38: n- {3- [4- (3-chloro-phenoxymethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 3-chlorophenol, the title compound was isolated as a yellow solid in 70% yield (98% HPLC purity).
MS(ESI+)：521.0；MS(ESI-)：519.0。
Example 39: 2-chloro-N- [3- (4- { [ (2, 4-difluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (chloro) benzenesulfonamide (intermediate 8) and 2, 4-difluoro-N-methylaniline, the title compound was isolated as a yellow solid in 77% yield (92% HPLC purity).
MS(ESI+)：502.0；MS(ESI-)：500.0。
Example 40: n- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2-methyl-1-H-indole, the title compound was isolated as a yellow solid in 70% yield (98% HPLC purity).
MS(ESI+)：523.5；MS(ESI-)：521.5。
Example 41: 2-chloro-N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 5-fluoroindole, the title compound was isolated as a yellow solid in 72% yield (96% HPLC purity).
MS(ESI+)：493.9；MS(ESI-)：491.9。
Example 42: 2-chloro-N- [3- (4- { [ (2-fluoro-phenyl) -methyl-amino]-methyl } -phenyl) -pyrazin-2-yl]-benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 2-fluoro-N-methyl-aniline, the title compound was isolated as a yellow solid in 79% yield (99% HPLC purity).
MS(ESI+)：484.1；MS(ESI-)：482.1。
Example 43: 2-chloro-N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 2-methyl-1-H-indole, the title compound was isolated as a yellow solid in 81% yield (96% HPLC purity).
MS(ESI+)：490.0；MS(ESI-)：488.1。
Example 44: n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl]-phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and N- (2-pyridine) -benzylamine, the title compound was isolated as a yellow solid in 79% yield (98% HPLC purity).
MS(ESI+)：576.6；MS(ESI-)：574.6。
Example 45: 2-chloro-N- (3- {4- [ (ethyl-pyridin-2-yl-amino) -methyl]-phenyl } -pyrazin-2-yl) -benzenesulfonamides
Following the general procedure outlined in example 1 (method B), starting from 2-chloro-N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide (intermediate 8) and 2- (ethylamino) -pyridine, the title compound was isolated as a yellow solid in 64% yield (96% HPLC purity).
MS(ESI+)：481.0；MS(ESI-)：478.1。
Example 46: n- {3- [4- (5-chloro-2-methyl-indol-1-ylmethyl) -phenyl]-pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide
Following the general procedure outlined in example 1 (method a), starting from N- {3- [4- (chloromethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide (intermediate 9) and 2-methyl-5-chloroindole, the title compound was isolated as a yellow solid in 71% yield (95% HPLC purity).
MS(ESI+)：558.3；MS(ESI-)：556.4。
Example 47: preparation of pharmaceutical formulations
The following formulation examples illustrate representative pharmaceutical compositions of the present invention, and the invention is not limited thereto.
Formulation 1-tablet
2, 3-substituted pyrazine sulfonamide derivative dry powder of formula I is mixed with dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was tableted using a tablet press to form 240-270mg tablets (each containing 80-90mg of the active 2, 3-substituted pyrazine sulfonamide compound).
Preparation 2-capsule
The 2, 3-substituted pyrazine sulfonamide dry powder of formula I is mixed with a starch diluent in a weight ratio of about 1: 1. The mixture was filled into 250mg capsules (each capsule containing 125mg of the active 2, 3-substituted pyrazine sulfonamide compound).
Formulation 3-liquid
The 2, 3-substituted pyrazine sulfonamide represented by formula I (1250mg), sucrose (1.75g) and xanthan gum (4mg) were mixed, passed through a U.S. sieve having No. 10 mesh, and then mixed with an aqueous solution of previously prepared microcrystalline cellulose and sodium carboxymethylcellulose (11: 89, 50 mg). Sodium benzoate (10mg), perfume and pigment were diluted with water and added to the solution with stirring. Sufficient water was then added to bring the total volume to 5 ml.
Formulation 4-tablet
2, 3-substituted pyrazine sulfonamide derivative dry powder of formula I is mixed with dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was tableted using a tablet press to form 450-900mg tablets (each containing 150-300mg of the active 2, 3-substituted pyrazine sulfonamide compound).
Preparation 5-injection
The 2, 3-substituted pyrazine sulfonamide derivatives of formula I were dissolved in buffered sterile saline injectable medium at a concentration of about 5 mg/ml.
Biological identification
Example 48: construction of pCEP4-hCRTH2 mammalian expression vector
The CRTH2 cDNA was amplified by PCR using a human bladder cDNA library as a template and cloned into the pCEP4 vector (Invitrogen) using specific primers containing HindIII and BamHI restriction sites. The construction of this vector is described in detail in Sawyer et al, British journal of pharmacy (Br. J. Pharmocol)2002, 137, 1163-72. The nucleotide sequence of the cloned cDNA was identical to the previously reported sequence of hRTH 2 (Nagata et al, 1999, J.Immunol.)162, 1278-1286).
Example 49: establishment of pCEP4-hCRTH2-HEK293(EBNA) cell line
HEK293(EBNA) cells were transfected with the pCEP4-hCRTH2 construct using calcium phosphate technology. Cells at 37 ℃ and 5% CO2Cultured under an atmosphere in Dulbecco's modified Eagle's F12 medium (Invitrogen) containing heat-inactivated fetal bovine serum (TerraCell International, Canada), 2mM glutamine, 100U/ml penicillin and 100. mu.g/ml streptomycin (Invitrogen). 48 hours after transfection, cells were grown in the presence of 300. mu.g/ml hygromycin B (Invitrogen) for 4 hours and antibiotic resistant cells grown for cell membrane preparation.
Example 50: preparation of hCRTH2 expression membrane
At 225cm2Adherent HEK293(EBNA) cells expressing hCRTH2 were cultured in 30ml of medium in cell culture flasks (Corning, usa). After rinsing twice with Phosphate Buffered Saline (PBS), the solution was rinsed withThe cells were collected in 10ml PBS containing 1mM EDTA, centrifuged at 500Xg for 5min at 4 ℃ and frozen at-80 ℃. The pellet was resuspended in 50mM Tris-HCl buffer (Tris) -HCl (pH7.4), 2mM EDTA, 250mM sucrose, tablets containing protease inhibitor cocktail (complete absence of EDTA, Roche, Germany) and incubated at 4 ℃ for 30 min. Cells were disrupted by nitrogen cavitation (Pasteur Instruments, USA) (800 pounds per square inch (p.s.i.), 30min) at 4 ℃ and centrifugation at 500Xg for 10min at 4 ℃. The pellet containing nuclei and cell debris was discarded and the supernatant was centrifuged at 45000Xg for 60min at 4 ℃. The membrane pellet was resuspended in stock buffer (10mM HEPES/KOH (pH7.4), 1mM EDTA, 250mM sucrose, protease inhibitor cocktail tablets) using a Dounce homogenizer, frozen with liquid nitrogen, and stored at-80 ℃.
Example 51: radioligand binding assays
The mixtures of the invention inhibit the binding of PGD2 to its receptor CRTH 2. The inhibitory activity can be studied using the radioligand binding assay (Sawyer et al, British journal of pharmacy (Br. J. Pharmocol)2002, 137, 1163-72). Radioligand binding assay A final volume of 100 μ l of a 96 well plate (Corning, USA) containing 1.5nM [2 ]3H]PGD2(Amersham, 156 Western angstroms per millimole (Cie/mmol)) and 10. mu.g of binding buffer for hCRTH2HEK293(EBNA) cell membrane protein (10mM HEPES/KOH pH7.4, 10mM mNCl)2Protease inhibitor cocktail tablets) at room temperature. Competing pyrazine sulfonamides were diluted with dimethyl sulfoxide to keep the total volume of dimethyl sulfoxide constant at 1% dimethyl sulfoxide (Me)2SO). Add 10. mu.l pyrazine sulfonamide. The culture (60 min at room temperature) was terminated by rapid filtration through GF/C Unifilter plates (Whatman, USA). The filter was washed with 250. mu.l Tris-HCl (pH7.4), 10mM MnCl2The binding activity was determined by washing twice, mixing the residual radioligand bound to the filter with 100 μ l scintillation cocktail and counting the residual radioligand with a 1450 μ β scintillation counter (Wallac, uk). The results of the binding assay are shown in table 1.
TABLE 1
Example 52: measurement of Ki (radioligand binding assay)
Using pair of t 23H]PGD2The equilibrium competition binding assay of (2) determines the Ki value. Ki values are calculated using the following formula and represent the average of at least three independent dose-response assays. Ki values give inhibition of 3[ H ]]PGD2The concentration of ligand necessary to bind 50% of CRTH 2.
Ki＝IC50/((1 + [ concentration of ligand))]/Kd)]
All assays were performed in 96-well plates, following the filtration assay described above, with a final volume of 100. mu.l. Membranes and 3[ H ]]PGD2The concentrations of (c), and the positive and negative controls were the same as described above.
In one embodiment, the pyrazine sulfonamides of the present invention inhibit CRTH2 at concentrations < 100 μ M. In another embodiment, the pyrazine sulfonamides of the present invention inhibit CRTH2 at concentrations < 10 μ M. In a preferred embodiment, the pyrazine sulfonamides of the invention inhibit CRTH2 at concentrations < 5 μ M. In a more preferred embodiment, the pyrazine sulfonamides of the present invention inhibit CRTH2 at concentrations < 1 μ M.
Ki values are shown in Table 2. It can be seen that the compounds of formula I show a significant inhibitory effect on the binding of PGD2 to CRTH 2.
TABLE 2
| Compound numbering | Ki[μM] | Compound No. | Ki[μM] | Compound No. | Ki[μM] |
| 1 | 1.01 | 17 | 0.38 | 33 | 2.21 |
| 2 | 1.26 | 18 | 0.40 | 34 | 2.60 |
| 3 | 0.45 | 19 | 0.47 | 35 | 2.64 |
| 4 | 1.57 | 20 | 0.48 | 36 | 2.69 |
| 5 | 2.32 | 21 | 0.59 | 37 | 2.82 |
| 6 | 2.12 | 22 | 0.62 | 38 | 2.90 |
| 7 | 2.59 | 23 | 0.70 | 39 | 2.95 |
| 8 | 1.42 | 24 | 0.72 | 40 | 3.06 |
| 9 | 2.98 | 25 | 0.85 | 41 | 3.90 |
| 10 | 1.40 | 26 | 0.95 | 42 | 3.90 |
| 11 | 5.16 | 27 | 1.32 | 43 | 4.11 |
| 12 | 8.43 | 28 | 1.47 | 44 | 4.44 |
| 13 | 4.03 | 29 | 1.49 | 45 | 4.51 |
| 14 | 5.85 | 30 | 1.58 | 46 | 4.65 |
| 15 | 5.38 | 31 | 1.59 | ||
| 16 | 5.71 | 32 | 1.93 |
Example 53: [35S]GTP γ S binding assay
[35S]The GTP γ S assay measures the increase in guanylate exchange on cell membrane G-proteins resulting from the binding of an agonist (PGD2) to CRTH 2. This process can be performed by contacting a cell membrane containing the G-protein and CRTH2 with GDP and [2 ]35S]GTP gamma S (radiolabeled GTP water resistanceAnalog) in vitro culture was monitored (see Harrison et al, Life Sciences 74, 489-. The addition of pyrazine sulfonamide results in binding to CRTH2, thereby inhibiting agonist binding, which can be monitored as inhibition of the stimulation of GTP/GDP exchange.
The assay conditions were the same as for the radioligand binding assay described in example 21. [35S]GTP γ S binding assays were performed at 30 ℃ on 96-well white polystyrene scintillation plates (Perkin Elmer, USA) in a final volume of 200 μ l containing 2% dimethylsulfoxide (Me)2SO). 2, 3-substituted pyrazine sulfonamides at 20mM HEPES/KOH (pH7.4), 10mM MgCl210 μ g/ml Saponin, 3 μ M GDP, 150mM NaCl, 10 μ g hRTH 2 receptor expressing membrane (Euroscreen, Belgium) for 10 min. Nonspecific binding was determined in the presence of 10. mu.M of GTP. gamma.S. Samples in PGD2At increasing concentrations or at 80nM PGD2In the case of (2), incubation is carried out for 30min, and the agonist activity and antagonist activity are measured, respectively. Next, 0.15nM [2 ] is added to the sample35S]GTP γ S was cultured for 30min, and then centrifuged at 1000Xg at 4 ℃ for 10min to terminate the reaction. The supernatant was taken out and measured with a 1450 Micro-. beta.scintillation counter35S]GTP γ S binding, data was analyzed using "Prism" (GraphPad Software, inc. Determination of the IC50 value (i.e.the amount required for binding to achieve 50% inhibition (. mu.M)) was performed on 96-well plates at a final concentration of 100. mu.l according to the filtration assay described above. The membrane and radioligand concentrations, and the positive and negative controls were the same as those used and described in examples 21 and 22 above.
The compound IC50 value of example 1 was 1.9. mu.M, the compound IC50 value of example 2 was 4.6. mu.M, and the compound IC50 value of example 3 was 1.4. mu.M.
Example 54: CHS model
A contact hypersensitivity model can be used to assess the therapeutic effect of 2, 3-substituted pyrazine sulfonamides on T cell mediated skin inflammation. The present model is suitably established for the identification of dermatological indications such as psoriasis and allergic contact dermatitis (Xu et al. J Exp Med.183, 1001-12, 1996). It is involved in the sensitisation phase and subsequent challenge with an antigen (DNFB, 2, 4-dinitrofluorobenzene). This leads to skin inflammation, formation of skin edema and cellular infiltration. The degree of edema can be measured at the challenge site (mouse ear) using calipers. Intravenous administration of the compounds of the invention 30 minutes prior to DNFB challenge resulted in a reduction in swelling and thus reduced skin inflammation compared to the positive control group treated with vehicle alone prior to antigen challenge. The negative control mice were not sensitized but challenged with DNFB, and thus did not develop T phase-dependent inflammatory responses nor edema. Balb/c mice were obtained from Charles river (Calcco, Italy). The animals were placed in conventional animal facilities. Treatment started at an average week age of 8-12 weeks.
DNFB (2, 4-dinitrofluorobenzene) was purchased from Sigma-Aldrich (St. Louis, Mo., USA).
Sensitization and CHS challenge with DNFB
Sensitization and challenge to mice resulted in CHS to DNFB. The allergic phase is followed by the challenge phase. The DNFB was diluted with acetone/olive oil (4/1) before use. Mice were shaved on the back and sensitized to DNFB by applying 25 μ l of 0.5% DNFB solution to the skin. After 5 days, 10 μ l of 0.2% DNFB (challenge) was administered bilaterally in the right ear. Ear thickness was measured on day 6 (1 day after challenge) with a caliper (Mitutoyo, milan, italy). Calculation of ear swelling: ((Tn-T5) right ear- (Tn-T5) left ear), where Tn and T5 represent the ear thickness on day n of study and day 5 before challenge, respectively.
List of references
Cosmi et al (2000) European journal of immunology (Eur. J. Immunol.)30, 2972-2979
Bush, r.k., Georgitis j.w., manual of asthma and rhinitis, 1 st edition (Handbook of asthama and rhinitis. lst ed.) (1997), Abingdon: blackwell science.270
Harrison et al (2003) Life Sciences (Life Sciences)74, 489-
Hirai et al (2001) J exp. Med.193, 255-
Lewis et al (1982) J.Immunol.129, 1627
Matsuoka et al (2000) Science 287, 2013-
Nagata et al (1999) J.Immunol.162, 1278-1286
Sawyer et al (2002) Br.J. Pharmacol.137, 1163-
Woodward et al (1990) invest, Ophtalomol Vis, Sci.31, 138-
Woodward et al (1993) Eur.J.Pharmacol.230, 327-333
Xu et al (1996) J Exp Med.183, 1001-12
WO 04/106302
WO 04/096777
WO 04/035543
WO 04/032848
WO 05/007094
WO 04/108692
WO 04/108717
WO 04/058265
WO 05/102338
Claims (11)
1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier:
wherein:
a is selected from the group consisting of:
wherein n is an integer independently selected from 0, 1, 2,3 or 4;
m is 1 or 2;
b is selected from phenyl or piperazinyl;
R1is hydrogen;
R2is phenyl, wherein R2Optionally substituted by one or more groups selected from halogen, cyano, C1-C6-substituent substitution of alkyl;
R3is selected from C1-C6Alkyl, aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl and C3-C8-heterocycloalkyl, wherein said C1-C6Alkyl, aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl and C3-C8-heterocycloalkyl each of which may be optionally substituted by one or more groups chosen from halogen, cyano, C1-C6Alkyl radical, C1-C6-substituent substitution of alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or wherein said aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl or C3-C8Heterocycloalkyl radical which may be substituted with one or more aryl, heteroaryl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl fused and optionally substituted by one or more groups chosen from C1-C6-substituted with alkyl, alkoxy, aryl, heteroaryl, carboxy, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulfoxy, sulfonyl, sulfonamide, and trihaloalkyl; r7Selected from hydrogen, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl radical、C3-C8-heterocycloalkyl, carboxyl, cyano, amino and hydroxyl;
R8selected from hydrogen, C1-C6-alkyl, aryl and heteroaryl;
the aryl is selected from phenyl or naphthyl;
the heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl and quinolyl.
2. The pharmaceutical composition of claim 1, wherein B is selected from phenyl.
3. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier:
wherein:
a is selected from the group consisting of:
wherein n is an integer independently selected from 0, 1, 2,3 or 4;
m is 1 or 2;
b is selected from phenyl or piperazinyl;
R1is hydrogen;
R2is phenyl;
R3is selected from C1-C6Alkyl, aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl and C3-C8-heterocycloalkyl, wherein said aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl or C3-C8Heterocycloalkyl radical which may be substituted with one or more aryl, heteroaryl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl fused;
R2and R3Each independently by 1-3 substituents selected from C1-C6-alkyl, alkoxy, cyano, amino or halogen, wherein said C is1-C6Alkyl or alkoxy groups which may be substituted by halogen
R7Selected from hydrogen, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, carboxyl, cyano, amino and hydroxyl;
R8selected from hydrogen, C1-C6-alkyl, aryl and heteroaryl;
the aryl is selected from phenyl or naphthyl;
the heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl and quinolyl.
4. A pharmaceutical composition comprising a compound selected from the group consisting of:
n- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-naphthoxy) methyl ] phenyl } pyrazin-2-yl) benzenesulfonamide,
2-chloro-N- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
2-chloro-N- (3- {4- [ (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) methyl ] -phenyl } pyrazin-2-yl) benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) benzenesulfonamide,
n- (3- {4- [ (1, 3-benzodioxol-5-ylamino) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
n- [3- (4- { [ (3-methoxybenzyl) oxy ] methyl } phenyl) pyrazin-2-yl ] -2- (trifluoromethyl) benzenesulfonamide,
3-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-chlorophenyl) (methyl) amino ] methyl } phenyl) pyrazin-2-yl ] -thiophene-2-sulfonamide,
4-phenoxy-N- {3- [4- (quinolin-2-ylmethyl) piperazin-1-yl ] pyrazin-2-yl } -benzenesulfonamide,
4-methyl-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
4-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] -benzenesulfonamide,
4-cyano-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] -amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (methyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-fluoro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (ethyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-benzo [1, 4] oxazin-4-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (3-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-chloro-pyridin-3-yloxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2-pyridin-2-yl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4-phenoxymethyl-phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-chloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- [3- (4- { [ (3, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-cyano-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-methoxy-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- {3- [4- (4-methoxy-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-chloro-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (2, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (3-chloro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2, 4-difluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
2-chloro-N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- (3- {4- [ (ethyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -benzenesulfonamide, and
n- {3- [4- (5-chloro-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide.
5. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of allergic diseases, inflammatory skin diseases and neuropathic pain, all mediated by CRTH2 activity,
wherein:
a is selected from the group consisting of:
wherein n is an integer independently selected from 0, 1, 2,3 or 4;
m is 1 or 2;
b is selected from phenyl or piperazinyl;
R1is hydrogen;
R2is phenyl, wherein R2Optionally substituted by a group selected from halogen, cyano, C1-C6-one or several substituents of alkyl;
R3is selected from C1-C6Alkyl, aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl and C3-C8-heterocycloalkyl, wherein said C1-C6Alkyl, aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl and C3-C8-heterocycloalkyl each of which may be optionally substituted by one or more substituents chosen from halogen, cyano, C1-C6Alkyl radical, C1-C6-alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or wherein said aryl, heteroaryl, C1-C6Alkyl aryl radical, C1-C6-alkylheteroaryl, C3-C8-cycloalkyl or C3-C8Heterocycloalkyl radical which may be substituted with one or more aryl, heteroaryl, C3-C8-cycloalkyl or C3-C8-heterocycloalkyl fused and possibly substituted with C1-C6-one or several substituents of alkyl, alkoxy, aryl, heteroaryl, carboxy, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulfoxy, sulfonyl, sulfonamido and trihaloalkyl;
R7selected from hydrogen, C1-C6Alkyl radical, C2-C6-alkenyl, C2-C6-alkynyl, aryl, heteroaryl, C3-C8-cycloalkyl, C3-C8-heterocycloalkyl, carboxyl, cyano, amino and hydroxyl; and
R8selected from hydrogen, C1-C6-alkyl, aryl and heteroaryl;
the aryl is selected from phenyl or naphthyl;
the heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl and quinolyl.
6. Use according to claim 5, wherein the allergic disease is selected from allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity.
7. The use according to claim 5, wherein the inflammatory dermatosis is selected from atopic dermatitis, eczema, allergic contact dermatitis, urticaria and myositis.
8. The use according to claim 5, wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, osteoarthritis and Inflammatory Bowel Disease (IBD).
9. The use according to any one of claims 5 to 8, wherein the compound is an inhibitor of CRTH2 activity.
10. The use according to any one of claims 5 to 8, wherein the compound is selected from:
n- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-naphthoxy) methyl ] phenyl } pyrazin-2-yl) -benzenesulfonamide,
2-chloro-N- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } - + benzenesulfonamide,
2-chloro-N- (3- {4- [ (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) methyl ] -phenyl } pyrazin-2-yl) benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) benzenesulfonamide,
n- (3- {4- [ (1, 3-benzodioxol-5-ylamino) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
n- [3- (4- { [ (3-methoxybenzyl) oxy ] methyl } phenyl) pyrazin-2-yl ] -2- (trifluoromethyl) benzenesulfonamide,
3-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-chlorophenyl) (methyl) amino ] methyl } phenyl) pyrazin-2-yl ] -thiophene-2-sulfonamide,
4-phenoxy-N- {3- [4- (quinolin-2-ylmethyl) piperazin-1-yl ] pyrazin-2-yl } -benzenesulfonamide,
4-methyl-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
4-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] -benzenesulfonamide,
4-cyano-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] -amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (methyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-fluoro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (ethyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-benzo [1, 4] oxazin-4-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (3-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-chloro-pyridin-3-yloxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2-pyridin-2-yl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4-phenoxymethyl-phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-chloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- [3- (4- { [ (3, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-cyano-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-methoxy-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- {3- [4- (4-methoxy-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-chloro-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (2, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (3-chloro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2, 4-difluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
2-chloro-N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- (3- {4- [ (ethyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -benzenesulfonamide, and
n- {3- [4- (5-chloro-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide.
A 2, 3-substituted pyrazine sulfonamide selected from:
n- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
2-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-naphthoxy) methyl ] phenyl } pyrazin-2-yl) -benzenesulfonamide,
2-chloro-N- {3- [4- (1H-indol-1-ylmethyl) phenyl ] pyrazin-2-yl } - + benzenesulfonamide,
2-chloro-N- (3- {4- [ (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) methyl ] -phenyl } pyrazin-2-yl) benzenesulfonamide,
2-chloro-N- (3- {4- [ (2-ethyl-1H-benzimidazol-1-yl) methyl ] phenyl } pyrazin-2-yl) benzenesulfonamide,
n- (3- {4- [ (1, 3-benzodioxol-5-ylamino) methyl ] phenyl } pyrazin-2-yl) -2- (trifluoromethyl) benzenesulfonamide,
n- [3- (4- { [ (3-methoxybenzyl) oxy ] methyl } phenyl) pyrazin-2-yl ] -2- (trifluoromethyl) benzenesulfonamide,
3-chloro-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-chlorophenyl) (methyl) amino ] methyl } phenyl) pyrazin-2-yl ] -thiophene-2-sulfonamide,
4-phenoxy-N- {3- [4- (quinolin-2-ylmethyl) piperazin-1-yl ] pyrazin-2-yl } -benzenesulfonamide,
4-methyl-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
4-chloro-N- [3- (4- { [ methyl (phenyl) amino ] methyl } phenyl) pyrazin-2-yl ] -benzenesulfonamide,
4-cyano-N- {3- [4- ({ methyl [4- (trifluoromethoxy) phenyl ] -amino } -methyl) phenyl ] pyrazin-2-yl } benzenesulfonamide,
n- [3- (4- { [ (4-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (methyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-fluoro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (ethyl-phenyl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-benzo [1, 4] oxazin-4-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (3-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-chloro-pyridin-3-yloxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (2-pyridin-2-yl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4-phenoxymethyl-phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (4-chloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (4-cyano-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- [3- (4- { [ (3, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (4-cyano-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (6-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-methoxy-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- {3- [4- (4-methoxy-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-chloro-benzenesulfonamide,
n- {3- [4- (2, 3-dihydro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
n- [3- (4- { [ (2, 4-dichloro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -2-trifluoromethyl-benzenesulfonamide,
n- {3- [4- (3-chloro-phenoxymethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2, 4-difluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
n- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- {3- [4- (5-fluoro-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
2-chloro-N- [3- (4- { [ (2-fluoro-phenyl) -methyl-amino ] -methyl } -phenyl) -pyrazin-2-yl ] -benzenesulfonamide,
2-chloro-N- {3- [4- (2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -benzenesulfonamide,
n- (3- {4- [ (benzyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -2-trifluoromethyl-benzenesulfonamide,
2-chloro-N- (3- {4- [ (ethyl-pyridin-2-yl-amino) -methyl ] -phenyl } -pyrazin-2-yl) -benzenesulfonamide, and
n- {3- [4- (5-chloro-2-methyl-indol-1-ylmethyl) -phenyl ] -pyrazin-2-yl } -2-trifluoromethyl-benzenesulfonamide.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05103254 | 2005-04-21 | ||
| EP05103254.8 | 2005-04-21 | ||
| US67538105P | 2005-04-27 | 2005-04-27 | |
| US60/675,381 | 2005-04-27 | ||
| PCT/EP2006/061706 WO2006111560A2 (en) | 2005-04-21 | 2006-04-20 | 2,3 substituted pyrazine sulfonamides as inhibitors of crth2 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1119080A1 HK1119080A1 (en) | 2009-02-27 |
| HK1119080B true HK1119080B (en) | 2012-09-21 |
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