SK8442000A3 - Hetorocyclic compounds, method for the preparation thereof, pharmaceutical composition comprising the same and their use - Google Patents

Abstract

The invention provides novel compounds, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.

Description

Technical field

The present invention relates to novel heterocyclic compounds, processes for their preparation, pharmaceutical compositions containing them, processes for the preparation of pharmaceutical compositions and their use in therapy.

BACKGROUND OF THE INVENTION

The P2X ₇ receptor (formerly known as the P2Z receptor), a ligand-closed ion channel, occurs in a variety of cell types, often those involved in the inflammatory / immune process, specifically in macrophages, mast cells and lymphocytes (T and B) . Activation of the P2X ₇ receptor by extracellular nucleotides, particularly adenosine triphosphate, results in the release of interleukin-β (IL 1β) and the formation of giant cells (macrophages / microglial cells), degranulation (mast cells) and L-selectin depletion (lymphocytes). P2X ₇ receptors are also found on antigen-presenting cells (APCs), keratinocytes, salivary lobe cells (parotid cells) and hepatocytes.

It is desirable to produce compounds acting as P2X ₇ receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases in which the aetiology of the P2X ₇ receptor may play a role.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula I (D wherein

R ¹

R ²

R ³

R ⁵

X is oxygen or

CH ₂ , CH ₂ CH ₂ or OCH ₂ ;

S or NH, a group _CH2 or C = O;

is pyridyl (in particular 3-pyridyl or;

4-pyridyl) or pyrimidinyl;

is phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen or amino, cyano, nitro, alkyl of up to 6 carbon atoms, haloalkyl of up to 6 atoms C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, (di) C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl C 1 -C 6 alkoxycarbonyl C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, -NR ³ SO ² R ⁴ or -SO ² NR ⁵ R ⁶ or -Z- (CH ₂ ) _p -Z- (CH ₂ ) _q -H, wherein each independently nitrogen or oxygen, p to 5 and q is 0 or ce wherein the number 1 hydroxyl containing 1 containing 1 carbon group, the part 1 group Z is an integer 2

R ⁴ are each independently a group containing from 1 to 5

R ⁶ are each, independently of one another, a hydrogen carbon atom; and hydrogen or alkyl or alkyl of up to 5;

a group containing from 1 to 6 carbon atoms or together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl group; or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present invention, unless otherwise indicated, the alkyl substituent or alkyl moiety in the substituent group may be straight or branched and also the alkyl groups in the dialkylamino substituents may be the same or different.

Further, when X is OCH 2, the oxygen atom is located next to the carbonyl group on the ring.

R ² is preferably a phenyl, pyridyl or pyrimidinyl group, each of which is optionally substituted with one, two, three or four substituents independently selected from the group consisting of a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom or an atom) iodine) or amino, cyano, hydroxyl, nitro, (C 1 -C 6) alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl), (C 1 -C 6) haloalkyl ( trifluoromethyl), (C1-C6) alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy), (C1-C6) alkylthio (e.g., methyl, ethyl, propyl, butyl, pentyl) or hexylthio), (di) alkylamino C 1 -C 6 alkyl group (e.g., methylamino, dimethylamino, ethylamino or diethylamino), (C 1 -C 6) alkylcarbonyl (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexylcarbonyl) ), alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxycarbonyl), alkylsulfinyl having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl-, butyl-, or hexylsulfinyl), carbon atoms containing 1 to propyl-, butyl-, -NR ³ SO ² R ⁴ Z- (CH ₂ ) _p Z- (CH ₂ ) _q -H, or an oxygen atom, numbers 1 to 5th

alkylsulfonyl (for example methyl-, hexylsulfonyl -SO ₂ NR ⁵ R ⁶ or pentyl- or a group wherein each Z is independently p is an integer from 2 to 5 and ac is 0 or the entire pentyl group ethyl- group), nitrogen

More preferably, R ^{2 is} phenyl, pyridyl or pyrimidinyl, each optionally substituted one, two or three times with substituents selected from the group consisting of halogen or amino, cyano, hydroxy, nitro, C 1-4 alkyl carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, (di) alkylamino of 1 to 4 carbon atoms, alkylcarbonyl of 1-alkyl part C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, -NR ³ SO ² R ⁴ or SO 2 NR ⁵ R ⁶ .

Even more preferably, R ^{2 is} phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen or amino, cyano, nitro, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or -SO ₂ NR ⁵ R ⁶ .

Most preferably, R ^{2 is} phenyl or pyridyl optionally substituted with one or two substituents selected from the group consisting of fluorine or chlorine or amino, cyano, nitro, trifluoromethyl, methoxy or -SO ₂ NR ⁵ R ⁶ .

R ³ and R ⁴ are preferably, independently of one another, a hydrogen atom or a C 1 -C 4 alkyl group (for example a methyl group or an ethyl group).

R ⁵ and R ⁶ are preferably, independently of one another, a hydrogen atom or a C 1 -C 4 alkyl group (for example a methyl or ethyl group), or together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidyl group, in particular pyrrolidinyl group.

Preferred compounds of the present invention include:

(+/-) - [N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (+ -) - N - [ 1- (3'-Methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione, (+/-) - N- [1- (Biphenyl-4-yloxy) ) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+/-) -N- [1- (3'-Chlorobiphenyl-4-yloxy) -4- (3- pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (+ -) - N - [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (+ -) - N - [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione (+ / -) -N- [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2R) -N- [ 1- (3'-Cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazole-2,4-dione, (2R) -N- [1- (3'- Nitrobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (2R) -N - [1- (3'-Cyanobiphenyl-4-yloxy) - 4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione, (+/-) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) - 2-Butyl] thiazolidin-2,4-dione, (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4- pyridyl) -2-butyl] pyrrolidine-2,5-dione, (+ -) - N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine -2,5-dione, (+ -) - N - [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidine-2,4-dione, ( +/-) - N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -oxazolidin-2-one, (2R) -N- [1- (3'- Chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (2R) -N- [1- (3'-Chloro-4 ') -fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (2R) -N- [1- (3 ', 5'-Dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+/-) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4- pyridyl) -2-butyl] oxazolidin-2-one, (2R) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4 -dione, (+ -) - N - [1- (3'- (Trifluoromethyl) biphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, ( + - -) -N- [1- (2'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl-2-butyl] thiazolidin-2,4-dione, (+ -) -N- [1] - (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridy) (l) -2-butyl] piperidine-2,6-dione, (+ -) - N- [1- (3'-Aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidine -2,4-dione, (+ -) - N - [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] - [1,3] oxazinane- 2-one, (2S) -N- [1- (3'-Cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2S) -N- [1- (3'-Aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2S) -N- [1- (3'-Methanesulfonamidobiphenyl-4)] -yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2S, 3S) -N- [1- (3'- (Pyrrolidine-1-sulfonyl) biphenyl-4- yloxy) -4- (3-pyridyl) -3-pentyl] pyrrolidin-2,5-dione, (2S, 3S) -N- [1- (3'-Cyano-4'-fluorobiphenyl-4-yloxy) - 4- (3-pyridyl) -3-pentyl] pyrrolidine-2,5-dione, (2S) -N- [1- (3'-Cyano-4'-fluorobiphenyl-4-yloxy) -4- (3 -pyridyl) -2-butyl] thiazolidin-2,4-dione, (+ -) - N - [1- (4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy) -4- (4-pyridyl) (2-Butyl) -oxazolidin-2-one, (+/-) - N- [1- (4- (6-Methoxypyridin-2-yl) phenoxy) -4- (4-pyridyl) -2-butyl] Oxazolidin-2-one, (+/-) - N- [1- (Biphenyls) 1- (4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+ -) - N - [1- (4'-Chlorobiphenyl-4-yloxy) -4- ( 4-pyridyl) -2-butyl] oxazolidin-2-one, (+/-) -N- [1- (4'-Methylbiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidine -2-one, (+ -) - N- [1- (4'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+ / -) -N- [1- (3 ', 4'-Dichlorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+/-) - N- [1- ( 4- (6-Methoxy-pyridin-2-yl) -phenoxy) -4- (4-pyridyl) -2-butyl] -piperidine-2,6-dione, (+ -) - N - [1- (3'- Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] imidazolidin-2,4-dione, (+ -) - N - [1- (3'-Nitrobiphenyl-4-yloxy) -4 - (4-Pyridyl) -2-butyl] piperidin-2-one and (+/-) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl pyrrolidin-2-one.

The present invention further provides a process for the preparation of a compound of formula I as defined above, comprising:

(a) reacting a compound of formula II

L

(II) wherein L is a leaving group (e.g., a hydroxyl group) and R ¹ and R ² are as defined above with a compound of formula III

wherein X and Y are as defined above except that when X is an oxygen atom or an OCH ₂ group, then Y is not a CH ₂ group; or (b) when X is oxygen and Y is CH ₂ , reacting a compound of formula IV

(IV) wherein R ¹ and R ² are the same as defined above with 2-chloroethyl chloroformate; or (c) when X is OCH ₂ and Y is CH ₂ , reacting a compound of formula IV as defined in (b) with

3-chloropropanol in the presence of phosgene; or (d) when X is CH ₂ and Y is CH ₂ , reacting a compound of formula IV as defined in (b) with

4-chlorobutyryl chloride; or (e) when X is CH ₂ CH ₂ and Y is CH ₂ , reacting a compound of formula IV as defined in (b) with

5-valeryl chloride; or (f) when X is O or OCH _2, reacting a compound of formula V

(V) wherein X is O or OCH ₂ and Y and R ¹ are as defined above, with a compound of formula VI, R ² -B (OH) ₂ , wherein R ² is as defined above; or (g) when X is oxygen or OCH ₂ , reacting a compound of formula VII

(VII) wherein X is O or OCH ₂ and Y and R ¹ are as defined above, with a compound of formula VIII, R ² -Br, wherein R ² is as defined above, and optionally after (a), (b), (c), (d), (e), (f) or (g) converting a compound of Formula I to another compound of Formula I and / or forming a pharmaceutically acceptable salt or solvate of a compound of Formula I.

Methods (a), (b), (c), (d), (e), (f) and (g) may conveniently be carried out in solvents (for example dichloromethane, chloroform, acetonitrile, dioxane or tetrahydrofuran), at a temperature of in the range of 0 to 100 ° C, preferably in the range of 10 to 80 ° C and in particular at room temperature (20 ° C). The compounds of the formula II are known from WO 97/20815 and WO 98/42670 or can be prepared by analogous methods as described in WO 97/20815 and WO 98/42670.

Compounds of formulas III, VI and VIII are known or commercially available compounds or can be prepared by methods known to those skilled in the art.

Compounds of formula IV may be prepared by methods known to those skilled in the art for the preparation of compounds of formula II.

Compounds of formula V and VII may be prepared by methods analogous to (a), (b) or (c) using the corresponding bromine or boron containing compounds of formula II or IV.

Those skilled in the art will recognize that in the process of the present invention, some functional groups (such as hydroxyl or amino) in intermediates may need to be protected with protecting groups. Therefore, the final step of preparing compounds of Formula I may involve the removal of one or more protecting groups.

The protection and deprotection of functional groups is described in Protective Groups in Organic Chemistry, ed. J.W.F. McOmie, Plenum Press (1973) and Protective Groups in Organic Synthesis, 2nd Ed., T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).

Compounds of formula I may be converted to other compounds of formula I using standard procedures. For example, compounds of formula I wherein R ² is nitrophenyl may be converted to compounds of formula I wherein R ² is aminophenyl by reduction using powdered iron and ammonium chloride in ethanol or in ethanol / water mixture under reflux conditions.

The compounds of formula I can be converted into pharmaceutically acceptable salts or solvates thereof, preferably acid addition salts such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate or alkali metal salts such as sodium or potassium salt.

Certain compounds of Formula I are capable of existing in stereoisomeric forms. The invention includes all geometric and optical isomers of a compound of Formula I and mixtures thereof including racemates. Tautomers and mixtures thereof are also aspects of the present invention.

The compounds of the present invention are preferred because they have pharmacological activity. Therefore, they appear to be pharmaceuticals for use in the treatment or prevention of diseases selected from the group consisting of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, airway hypersensitivity, septic shock, glomerulonephritis, irritable viscera, Crohn's disease, ulcerative colitis, and malignant cell metastases, myocardial ischemia, reperfusion heart damage, cerebral ischemia, stroke, myoblastic leukemia, diabetes, Alzheimer's disease, osteoporosis, burns, varicose veins and meningitis.

Accordingly, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In another aspect, the invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for the manufacture of a medicament for use in therapy.

The invention further provides a method of affecting immunosuppression (e.g., in the treatment of rheumatoid arthritis, irritable viscera, atherosclerosis or psoriasis), comprising administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof.

For the aforementioned therapeutic use, the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.

The compounds of formula I and their pharmaceutically acceptable salts and solvates may be used alone, but are generally administered in the form of a pharmaceutical composition wherein the compound of formula I or a salt or solvate thereof (active ingredient) is present in combination with a pharmaceutically acceptable excipient, diluent. or carrier. Depending on the route of administration, the pharmaceutical composition comprises from 0.05 to 99% by weight, more preferably from 0.10 to 70% by weight of the active ingredient and from 1 to 99.95% by weight, more preferably from 30 to 99.90% by weight of a pharmaceutically acceptable excipient. , a diluent or carrier; all percentages by weight are based on the total weight of the composition.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable excipient, diluent or carrier.

The invention provides a process for the preparation of a pharmaceutical composition which comprises admixing a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore described with a pharmaceutically acceptable excipient, diluent or carrier.

The pharmaceutical composition of the present invention may be administered topically (i.e. via the lungs / airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powders; or systemically, i.e. orally in the form of tablets, capsules, syrups, powders or granules, or parenterally in the form of solutions or suspensions, or subcutaneously or rectally in the form of suppositories or through the skin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is further described by means of the following illustrative examples wherein the abbreviations MS, NMR and DMSO refer to mass spectrum, nuclear magnetic resonance and dimethylsulfoxide.

Example 1 (+/-) - (N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl) pyrrolidine-2,5-dione

To a solution of 0.16 g of triphenylphosphine in 2 ml of tetrahydrofuran is added 0.1 ml of diethyl azodicarboxylate; a slightly exothermic reaction takes place. The resulting orange solution was stirred for 5 minutes, then 0.062 g of succinimide was added, stirring was continued for another 5 minutes, and then 0.10 g of (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) - was added. 2-butanol prepared as described in Example 25 of International Patent Application WO 97/20815. After stirring for 1.5 hours, the reaction mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography eluting with ethyl acetate to give 0.09 g of the title compound as a colorless solid.

Melting point: 150-151 ° C; MS (APCI + ve) 401 (M + H) ^{+ 1} H NMR (DMSO-d 6) δ 8.42-8.40 (2H, m), 7.64-7.55 (5H, m), 7, 43 (2H,

t), 7.33-7.28 (2H, m), 6.97 (2H, d), 4.45-4.33 (2H, m), 4.274.23 (1H, m), 2.62 -2.57 (6H, m), 2.32-2.24 (1H, m), 2.11-2.02 (1H, m).

Example 2 (+/-) -N- [1- (3'-Methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione

Following the procedure described in Example 1, from 0.30 g of succinimide a

0.25 g of (±) -1- (3'-methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, prepared according to the procedure of Example 42 of International Patent Application WO 97/20815, yields 0, 17 g of the title compound as a white solid.

Melting point: 92-94 ° C; MS (EI) 430 (M + H) ^{+ 1} H NMR (DMSO-d 6) δ 8.42-8.40 (2H, m), 7.61 (1H, m), 7.59 (2H, t) 7.33-7.28 (2H, m), 7.16 (1H, d), 7.12 (1H, t), 6.97 (2H, d),

6.88 (1H, dd), 4.44-4.33 (2H, m), 4.26-4.24 (1H, m), 3.81 (3H, s), 2.62-2, 57 (6H, m), 2.32-2.24 (1H, m), 2.11-2.02 (1H, m).

Example 3 (+/-) - N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione

From the procedure described in Example 1, from 0.32 g of (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, prepared according to the procedure of Example 25 of International Patent Application WO 97/20815 , and

2,4-thiazolinedione (0.23 g) affords 0.08 g of the title compound as a white solid.

Melting point: 125-126 ° C; MS (FAB) 419 (M + H) < ⁺ > ^.

1 H NMR (DMSO-d 6) δ 8.42-8.40 (2H, m), 7.55-7.49 (5H, m), 7.41 (2H, t), 7.33-7.28 (2H, m), 6.97 (2H, d), 4.76 (1H, m), 4.52 (1H, t), 4.16 (1H, dd), 3.83 (2H, s) 2.73-2.60 (2H, m), 2.55-2.49 (1H, m), 2.15-2.06 (1H, m).

Example 4 (+ -) - N- [1- (3'-Chlorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione

From the procedure described in Example 1, from 0.42 g of (±) -1- (3'-chlorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, prepared according to the procedure of Example 33 of the international patent application

WO 97/20815, and 0.24 g of succinimide gave 0.21 g of the title compound as a white solid.

Melting point: 154 ° C

MS (APCI + ve) 436/438 (M + H) < ⁺ > ^.

NMR (DMSO-d 6) δ 8.47-8.45 (2H, m), 7.53-7.23 (8H, m), 6.92 (2H, d), 4.63 (1H, m) 4.50 (1H, t), 4.16 (1H, dd), 2.73 (1H, m),

2.62-2.57 (6H, m); 2.11-2.02 (1H, m).

Example 5 (+/-) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione

From the procedure described in Example 1, from 0.05 g of (±) -1- (3'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, prepared according to the procedure of Example 43 of International Patent Application WO 97/20815, and 0.03 g of succinimide gave 0.06 g of the title compound as a white solid.

M.p .: 148 ° C

MS (APCI + ve) 419 (M + H) ^{+; H} NMR _(DMSO-d6) 5 8.42-8.40 (2H, m), 7.54-7.45 (3H, m), 7 , 38-

7.20 (4H, m), 7.01 (1H, m), 6.91 (2H, d), 4.62 (1H, m), 4.50 (1H, t), 4.16 (1H) , dd), 2.75-2.47 (2H, m), 2.56 (4H, s), 2.53 (1H, m), 2.11-2.02 (1H, m).

Example 6 (+ -) - N- [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione

a) (+/-) - 4-Bromo-phenyloxymethyl-oxirane

To a solution of 17 g of 4-bromophenol and 25 ml of epichlorohydrin in 50 ml of acetonitrile is added 24 g of cesium carbonate and the suspension obtained is refluxed for 4 hours. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between ether and water. The organic phase was separated, washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give a residue. Distillation of the residue in vacuo afforded 13 g of the subtitle compound as a colorless oil.

Boiling point: 140 ° C (oil pump)

MS (gcms) 228/230 M < ^{+ >.}

b) (+/-) -1- (4-Bromophenyloxy) -4- (4-pyridyl) -2-butanol

To a solution of 1.2 g of 4-methylpyridine in 10 ml of tetrahydrofuran cooled to -78 ° C was added 5.8 ml of a 2.5 M solution of n-butyllithium in hexane and the reaction mixture was warmed to 0 ° C. The mixture was slowly added via cannula to a solution of 3.0 g of 4-bromophenyloxymethyloxirane prepared as described in step a) in 5 ml of tetrahydrofuran cooled to 0 ° C. After stirring at room temperature for 1.5 hours, the reaction mixture is quenched by addition of aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic phase is then separated, washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give a residue. Purification of the residue by silica gel chromatography eluting with 5% methanol in dichloromethane gave 1.8 g of the subtitle compound as a yellow solid.

MS (APCI + ve) 322/324 (M + H) < ⁺ > ^.

c) (+ -) - 1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol

A mixture of 1.8 g of 1- (4-bromophenyloxy) -4- (4-pyridyl) -2-butanol prepared according to step b), 0.90 g of 3-methoxyphenylboronic acid, 0.16 g of tetrakis (triphenylphosphine) palladium (0), 3.5 ml of 2M aqueous sodium carbonate solution, 2 ml of ethanol and 7.5 ml of toluene were heated at reflux for 1.5 hours. The reaction mixture is partitioned between ethyl acetate and water and the organic phase is separated, washed with brine, dried over magnesium sulfate and then evaporated under reduced pressure to give a residue. Purification of the residue by silica gel chromatography eluting with 5% methanol in dichloromethane gave 1.0 g of the subtitle compound as a white solid.

M.p .: 74-76 ° C

MS (APCI + ve) 350 (M + H) < ⁺ > ^.

d) (+/-) -N- [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione

Using the procedure described in Example 1, from 0.42 g of (+ -) - 1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol prepared according to step c), and 0.30 g of succinimide gives 0.15 g of the title compound as a white solid.

Melting point: 111-113 ° C; MS (EI) 431 (M + H) ^{+; H} NMR (DMSO-d) delta 8.42 (2H, s), 7.48 (2H, d), 7.34 (1H, t), 7.15 (3H, m), 7.06 (1H, m), 6.88 (2H, d), 6.84 (1H, m), 4.61 (1H, m), 4.47 (1H, t) 4.16 (1H, dd), 3.83 (3H, s), 2.78 (1H, m), 2.61-

2.50 (2H, m), 2.46 (4H, s), 2.11-2.02 (1H, m).

Example 7 (+ -) - [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] 20 thiazolidin-2,4-dione

Using the procedure described in Example 1, from 0.10 g of (+ -) - 1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol, prepared according to the procedure described in Example 6c) , and 0.077 g of 2,4-thiazolinedione yields 0.07 g of the title compound as a colorless solid.

M.p .: 111-112 ° C;

MS (EI) 449 (M + H) < ⁺ > ^.

1 H NMR (DMSO-d 6) δ 8.46 (2H, d), 7.58 (2H, d) 7.34 (1 H, t), 7.23 (2H, d), 7.17 (2H, d), 7.12 (1H, d), 6.88 (2 H, d), 4.53 (LH, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (1H) 2H, s), 3.81 (3H, s), 2.62 (2H, t), 2.37-2.24 (1 H, m), 2.16-2.06 (1 H, m).

Example 8 (2R) -N- [1- (3'-Cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

Using the procedure described in Example 1, from 0.20 g of (2S) -1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure described in Example 38 of the international patent application WO 97/20815, and 0.13 g of 2,4-thiazolinedione yields 0.14 g of the title compound as a white solid.

Mp 110-112 ° C;

MS (EI) 444 (M + H) < ⁺ > ^.

^{Χ Η} NMR _(DMSO-d6) delta 8.43 1 2H, m), 8.10 (1H, s); 7.97 (1 H, d), 7.76 (1 H, d), 7.70-7.60 (4H , m), 7.32 (1 H, dd), 7.01 (2H, d) 4.56 (1 H, m), 4.46 (1H, t), 4.30 (1 H, dd), 4.19 (2H, s), 2.65 (2H,

t), 2.30 (1H, m), 2.09 (1H, m).

Example 9 (2R) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione

From the procedure described in Example 1, from 0.10 g of (2S) -1- (3'-nitrobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure described in Example 41 of the International Patent Application WO 97/20815, and 0.054 g of succinimide yield 0.03 g of the title compound as a white solid.

M.p .: 115-117 ° C

MS (EI) 446 (M + H) ^{+; H} NMR _(DMSO-d6) delta 8.40 (3H, m), 8.14 (2H, s), 7.72 (3H, m), 7. 63 (1H, d), 7.32 (1H, ddd), 7.03 (2H, d), 4.42 (2H, m), 4.28 (1H, dd), 2.61 (6H, m) 2.28 (1H, m), 2.07 (1H, m).

Example. 10 (2R) -N- [1- (3'-Cyanobi-phenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione

Using the procedure described in Example 1, from 0.15 g of (2S) -1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure described in Example 38 of the International Patent Application WO 97/20815, and 0.09 g of succinimide yields 0.09 g of the title compound as a white solid.

M.p .: 136-137 ° C

MS (EI) 426 (M + H) < ⁺ > ^.

^X H NMR _(DMSO-d6) delta 8.41 (2H, m), 8.11 (1H, s), 7.97 (1H, d), 7.77 (1H, d), 7.69-7.60 (4H, m), 7.32 (1H, dd), 6.99 (2H, d), 4.39 (2H, m), 4.28 (1H, dd), 2.60 (6H, m), 2.27 (1H, m), 2.02 (1 H,

m).

Example 11 (+ -) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

a) (+ -) - 1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol

Following the procedure described in Example 6c), 3.12 g of 1- (4-bromophenyloxy) -4- (4-pyridyl) -2-butanol prepared according to Example 6b) and 2.59 g of 3-nitrophenylboronic acid were obtained.

2.20 g of the subtitle compound as an orange oil.

MS (APCI + ve) 365 (M + H) < ⁺ > ^.

b) (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butylthiazolidine-2,4-dione

Using the procedure described in Example 1, from 0.14 g of (+/-) -1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol prepared as described in step a), and 0.09 g of 2,4-thiazolinedione, 0.11 g of the title compound is obtained as a pale yellow solid.

M.p .: 145-150 ° C

MS (EI) 446 (M + H) ^{+ 1} H NMR (DMSO-d 6) δ 8.47 (2H, d), 8.38 (1H, s), 8.17 (1H, d), 8.11 (1H, d), 7.75-7.70 (3H, m), 7.23 (2H, dd), 7.04 (2H, d), 4.604.44 (2H, m), 4.31 ( 1H, dd), 4.19 (2H, s), 2.65 (2H, t), 2.32 (1H, m), 2.09 (1H, m).

Example 12 (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione

N0 ₂

Using the procedure described in Example 1, from 0.09 g of (+/-) - 1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol, prepared according to the procedure of Example 11a), and 0.05 g of succinimide gave 0.03 g of the title compound as a yellow solid.

M.p .: 116-118 ° C

MS (EI) 426 (M + H) < ⁺ > ^.

NMR (DMSO-d ₆ ) δ 8.46 (2H, m), 8.38 (1H, s), 8.16 (1H, d), 8.11 (1H, d), 7.75-7, 70 (3H, m), 7.22 (2H, d), 7.03 (2H, d), 4.764.34 (2H, m), 4.28 (1H, dd), 2.65-2, 60 (6H, m), 2.29 (1H, m), 2.08 (1H, m).

Example 13 (+ -) - N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione

a) (+/-) -1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol

Following the procedure described in Example 6c), from 0.40 g of 1- (4-bromophenyloxy) -4- (4-pyridyl) -2-butanol prepared as described in Example 6b) and 0.28 g of 4-fluorophenylboronic acid, 0 was obtained. 23 g of the subtitle compound as a colorless solid.

MS (APCI + ve) 338 (M + H) < ⁺ > ^.

b) (+ -) - N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -pyrrolidine-2,5-dione

Using the procedure described in Example 1, from 0.10 g of (+/-) -1- (4'-fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol, prepared according to step a), and 0.06 g of succinimide affords 0.06 g of the title compound as a pale yellow solid.

Melting point: 113-114 ° C

MS (EI) 419 (M + H) ^{+ 1} H NMR (DMSO-d ₆ )? 8.46 (2H, d), 7.63 (2H, dd), 7.55 (2H, d),

7.28-7.21 (4H, m), 6.87 (2H, d), 4.45-4.33 (2H, m), 4.26 (1H,

m), 2.59 (6H, m), 2.28 (1H, m), 2.08 (1H, m).

Example 14 (+ -) - N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

Using the procedure described in Example 1, from 0.12 g of (+/-) -1- (4'-fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol, prepared according to the procedure of Example 13a), and 0.08 g of 2,4-thiazolinedione gives 0.06 g of the title compound as a light gray solid.

M.p .: 88-90 ° C

MS (EI) 437 (M + H) ^{+; H} NMR _(DMSO-d6) delta 8.46 (2H, d), 7.63 (2H, dd), 7.56 (2H, d), 7, 23 (4H, m), 6.97 (2H, d), 4.50 (1H, m), 4.44 (1H, t), 4.28 (1H, dd), 4.18 (2H, s) 2.65 (2H, t), 2.30 (1H, m), 2.12 (1H, m).

Example 15 (+/-) - N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] oxazolidin-2-one

a) (+/-) - N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] isoindole-1,3-dione

From the procedure described in Example 1, from 2.55 g of (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure of Example 25 of International Patent Application WO 97/20815 3.62 g of triphenylphosphine, 2.52 ml of diethyl azodicarboxylate and 2.36 g of phthalimide in tetrahydrofuran, after purification by flash column chromatography eluting with hexane: ethyl acetate (3: 2), yielded 3.9 g of the subtitle compound as colorless solid.

M.p .: 132-133 ° C

MS (EI) 448 (M + H) < ⁺ > ^.

NMR (DMSO-d ₆ ) δ 8.40 (1H, d), 8.25 (1H, d), 7.85 (4H, m), 7,62- 7.51 (5H, m), 7.41 (2H, t); 7.29 (1H, t), 7.23 (IH, dd), 6.93 (2H, d), 4.52 (2H, m), 4.38 (IH, dd), 2.70 (2H, t), 2.40 (IH,

m), 2.20 (1H, m).

b) (±) -1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butylamine

3.41 g of (+/-) - N- (1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl) isoindole-1,3-dione are dissolved in 100 ml of a 30% solution. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulphate, filtered and evaporated. elution with 10% methanol in dichloromethane gave

1.08 g of the subtitle compound as a cream solid.

52-53 ° C

MS (EI) 318 (M + H) < ⁺ > ^.

^X H NMR _(CDCl3) delta 8.51 (1 H, d), 8.45 (1 H, d), 7.56 -7.51 (5H, m) 7.42 (2 H, t), 7.32-7.31 (1 H, m), 7.24-7.22 (1 H, m), 6.96 (2 H, d), 4.00-3.96 (1H, m) 3.82 (1H, t), 3.25- 3.15 (1 H, m), 2,89- 2.82 (1 H, m), 2.78-2.72 (1H, m), 1.92-1.88 (1 H, m), 1.80-1.72

(3 H, m).

c) (+/–) - N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] oxazolidin-2-one

0.516 ml of 2-Chloroethyl chloroformate was added dropwise to the solution

0.318 g of (±) -1- (biphenyl-4-yloxy) -4- (3-pyridyl) -2-butylamine in ml of acetonitrile. The solution was stirred in the room. The solvent is removed under tetrahydrofuran and 0.12 g of the hydride solution is stirred and the mixture is added under reduced pressure for hours, the remainder ml of dimethylformamide.

sodium (60% dispersion for 1 hour at water temperature), the product is dissolved in 5 ml

To the solution was added in mineral oil), room was extracted to ethyl acetate and the organic extract was dried over magnesium sulfate and evaporated under reduced pressure. Purification by silica gel chromatography eluting with 3% methanol in dichloromethane followed by recrystallization from diethyl ether gave

0.093 g of the title compound

Mp .: 58-59 ° C

MS (FAB) 389 (M + H) ^{+ X} 1 HNMR (CDCl ₃₎ delta 8.50 to 8.49 (2H, m), t), 7.31 (1H, t), 7.29-7. 23 (1 H, (3H, m), 4.15 (2H, d), 3.73-3.60)

2.03 (2 H, m).

as a white solid. 7.58-7.52 (5 H, m), 7.42 (2H, m), 6.95 (2H, d), 4.43-4.26 (2H, m), 2.74 (2H, t), 2.16-

Example 16 (2R) -N- [1- (3'-Chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

The chiral

a) (2S) -1- (3'-Chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol

From the procedure described in Example 1, from 0.214 g of (223) -1- (4-bromophenoxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure of Example 40a) in the international patent application

WO 97/20815, and 0.18 g of 3-chloro-4-fluorophenylboronic acid 0.24 g of the subtitle compound as a yellow gum. MS (APCI + ve) 372/373 (M + H) *

b) (2R) -N- [1- (3'-Chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

Using the procedure described in Example 1, from 0.14 g of (2S) -1- (3'-Chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure of step a ), and 0.088 g of 2,4-thiazolinedione, after purification

by chromatography on silica for elution with 80% ethyl acetate in isohexane 0,077 g compound that in the name in the form of colorless rubber. MS (APCI + ve) 471/473 (M + H) < + > ^X H NMR _(DMSO-d6) delta 8.43-8.40 (2H, m), 7, 81 (1 H, dd), 7.65-7.60 (4H, m), 7.46 (1 H, t), 7.32 (1 H, dd), 6, 97 (2H, d) 4.50 (1 H, m), 4.45 (1 H, t), 4.28 (1 H, dd), 4.19 (2H, d), 2.64 (2 H, t),

2.39-2.26 (1 H, m), 2.18-2.03 (1 H, m).

Example 17 (2R) -N- [1- (3'-Chloro-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione

The chiral

From the procedure described in Example 7, from 0.10 g of (2S) -1- (3'-chloro-4'-fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol prepared according to the procedure of Example 16a. ), and 0.053 g of succinimide, after purification by chromatography on silica gel eluting with 50% acetone in isohexane, yielded 0.05 g of the title compound as a light brown foam.

MS (APCI + ve) 453/455 (M + H) < ⁺ > ^.

NMR (DMSO-d 6) δ 8.41 (1H, s), 8.39 (1 H, m), 7.81 (1 H, dd), 7 65-7.59 (4H, m), 7.56 (1H, t), 7.32 (1 H, dd), 6, 97 (2H, d) 4. 45-4.32 (2H, m), 4.26 (1H, m), 2.51 (6H, m), 2.25 (LH, m), 2 07 (1 H, m).

Example 18 (2R) -N- [1- (3 ', 5'-Dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione

a) (2S) -1- (4-Bromophenoxy) -4- (3-pyridyl) -2- (tert-butyldimethylsilyloxy) butane

A solution of 10 g of (2S) -4- (3-pyridyl) -1,2-butanediol, prepared according to the procedure of Example 26c) in International Patent Application WO 97/20815, and 12 g of 1,1-carbonyldiimidazole in 250 ml of chloroform are stirred at room temperature overnight. The mixture was partially evaporated under reduced pressure and then filtered through a silica gel column. Evaporation of the filtrate yielded a residue which was dissolved in 100 ml of dimethylformamide. Then 11.6 g is added

Of 4-bromophenol and 16.6 g of cesium carbonate, and the mixture is heated under reflux for 18 hours. The cooled reaction mixture was acidified with 2M hydrochloric acid and extracted three times with diethyl ether. The aqueous layer was separated and 2M sodium hydroxide solution was added until pH 9 was reached and extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a residue. 10 ml of dimethylformamide, then 6 g of imidazole and 8.4 g of tert-butyldimethylsilyl chloride are added to the residue, and the mixture is stirred at room temperature overnight. The reaction mixture was then poured into water and extracted twice with 1: 1 diethyl ether / hexane. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a residue. The residue was purified by silica gel chromatography eluting with 1: 1 diethyl ether / hexane to give 13.27 g of the subtitle compound as an oil.

MS (APCI + ve) 436/438 (M + H) < ⁺ > ^.

b) (2S) -4- [4- (3-pyridyl) -2- (tert-butyldimethylsilyloxy) butoxy] benzeneboronic acid

A solution of 15.0 ml of tert-butyllithium (1.7 M solution in hexane, caution pyrophoric) was added dropwise at -78 ° C to a stirring solution of 5.0 g of (2S) -1- (4-bromophenoxy) -4- ( 3-pyridyl) -2- (tert-butyldimethylsilyloxy) butane, prepared as described in step a), and

4.3 ml of triisopropylborate in 200 ml of tetrahydrofuran. After the addition was complete, the reaction mixture was stirred at -70 ° C for 1 hour. 200 ml of water and 200 ml of ethyl acetate are added. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by silica gel chromatography eluting with 5: 1 ethyl acetate / methanol to give 4.06 g of the sub-title compound as a foam.

MS (APCI + ve) 402 (M + H) < ⁺ > ^.

c) (2S) -1- (3 ', 5'-Dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol

A mixture of 0.479 g of (2S) -4- [4- (3-pyridyl) -2- (tert-butyldimethylsilyloxy) butoxy] benzeneboronic acid prepared according to the procedure described in step b), 0.371 g of 5-bromo-1,3-benzenedicarbonitrile (see Ref. J. Het. Chem. (1994), 31 (6), pp. 1417-1420, registration number 160892-07-9), 0.035 g tetrakis (triphenylphosphine) palladium (0), 0.9 ml A 2M aqueous solution of sodium carbonate, 10 ml of toluene and 4 ml of ethanol was heated at 100 ° C for 2 hours. The reaction mixture was partitioned between diethyl ether and 2N hydrochloric acid and the layers were separated. The aqueous layer was neutralized with 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a residue. The residue was dissolved in 25 ml of tetrahydrofuran and 0.163 g of tetrabutylammonium fluoride was added. The mixture was stirred at room temperature overnight, evaporated under reduced pressure and partitioned between diethyl ether and 2N hydrochloric acid. The layers were separated. The aqueous layer was neutralized with 2N sodium hydroxide solution and extracted dried over anhydrous reduced pressure and chromatography on dichloromethane / acetone and with ethyl acetate. magnesium sulphate,. to obtain a residue, silica gel recrystallizing from

The organic phase was separated, filtered and evaporated. Purification by elution with 2: 1 gave ethyl acetate / hexane to give the title compound as a white solid.

MS (APCI + ve) 370 (M + H) < ⁺ > ^.

d) (2R) -N- [1- (3 ', 5'-Dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

Using the procedure described in Example 1, from 0.05 g of (2S) -1- (3 ', 5'-dicyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to step c), and 0.032 g of 2,4-thiazolinedione, after purification by supercritical fluid chromatography eluting with 0 to 45% methanol in liquid carbon dioxide, afforded 0.015 g of the title compound as a glass.

MS (APCI + ve) 469 (M + H) < ⁺ > ^.

^T H NMR (DMSO-de)? 8.49 (2H, m) 8.41 (2 H, m), 8.36 (1H, s) 7.80 (2H, d), 7.63 (1H, d), 7.32 (1H, dd) 7.03 (2H, m), 4.47 (2H, m), 4.31 (1H, dd), 4.19 (2H, s), 2.65 (2H, t), 2.30 (1 H, m), 2.20 (1 H, m).

Example 19 (+ -) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

a) (+/-) - N-2- [1- (4-Bromophenoxy) -4- (4-pyridyl) -2-butyl] isoindole-1,3-dione

Following the procedure described in Example 15a), 10.13 g of 6.02 g of 1- (4-bromophenyloxy) -4- (4-pyridyl) -2-butanol prepared according to Example 6b) and 5.49 g of phthalimide are obtained. the title compound in the form of a golden oil.

MS (APCI) 451/453 (M + H) < ⁺ > ^.

b) (+/-) - N-2- (4-Bromophenoxy) -4- (4-pyridyl) butylamine

Following the procedure described in Example 15b), from 9.78 g of (+/-) - N-2- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] isoindole-1,3-dione to give 3.04 g of the subtitle compound as a yellow solid.

Melting point: 168-169 ° C

MS (APCI) 321/323 (M + H) < ⁺ > ^.

c) (+/–) - N - 2- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) butylamine

A mixture of 0.5 g of (+/-) - N-2- (4-bromophenoxy) -4- (4-pyridyl) butylamine prepared according to step b), 0.31 g of 3-nitrophenylboronic acid, 0.03 g tetrakis (triphenylphosphine) palladium (0), 0.93 ml of a 2M aqueous solution of sodium carbonate and 2 ml of ethanol are heated at reflux for 4 hours. After cooling to room temperature, the solvent was evaporated in vacuo.

Add diluted with diethyl ether. pH of bicarbonate with ethyl acetate. magnesium, aqueous sodium hydrochloric acid and the mixture was extracted with a little solid to alkaline and extracted with

The combined extracts were filtered and evaporated under reduced pressure.

dried over anhydrous

The residue was purified by column chromatography on neutral alumina eluting with dichloromethane: ethanol (98: 2) then ethanol to give 0.28 g of the sub-title compound as a yellow oil a.

MS (APCI) 364 (M + H) < ⁺ > ^.

d) (+/-) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

Following the procedure described in Example 15c), 0.025 g of the title compound was obtained as a yellow foam from 0.030 ml of 2-chloroethyl chloroformate, after purification of the product by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane.

M.p .: 67-69 ° C

MS (APCI) 434 (M + H) ^{@ +} @ 1 H NMR (DMSO-d6) .delta.4.46 (2H, dd), 8.39 (1H, t), 8.18-8.09 (2H, m) 7.76-7.70 (3H, m), 7.30 (2H, d), 7.09 (2H, d), 4.32-4.20 (2H, m), 4.16 (2H) d) 4.14 (1H, m), 3.63-3.47 (2H, m), 2.72-2.58 (2H, m), 1.95 (2H, kv).

Example 20 (2R) -N- (1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl) thiazolidin-2,4-dione

The chiral

a) (2S) -1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol

Following the procedure described in Example 18c), from 0.30 g of (2S) -4- [4- (3-pyridyl) -2- (tert-butyldimethylsilyloxy) butoxy] benzeneboronic acid, prepared according to the procedure of Example 18b), and 0.15 ml of 1-bromo-3-fluorobenzene gave 0.21 g of the subtitle compound as a colorless oil.

MS (APCI + ve) 338 (M + H) < ⁺ > ^.

b) (2R) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

Using the procedure described in Example 1, from 0, 205 g of (2S) -1- (3'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to step a), and 0 14 g of 2,4-thiazolinedione, after purification by normal phase HPLC eluting with 0-10% ethanol in dichloromethane and recrystallized from ethanol, yields 0.032 g of the title compound as a colorless solid.

Melting point: 117-118 ° C

MS (APCI + ve) 437 (M + H) ^{+; H} NMR (DMSO-d?) Delta 8.42 (2H, m), 7.63 (3H, m), 7.44 (3H, m), 7 33 (1H, dd), 7.13 (1H, m), 6.98 (2H, d), 4.54 (1H, m), 4.45 (1H, m,

t), 4.27 (1H, dd), 4.19 (2H, s), 2.62 (2H, t), s 2.30 (1H, m),

2.10 (1 H, m).

Example 21 (+ -) - N- [1- (3'- (Trifluoromethyl) biphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

a) (+/-) -1- (3 '- (Trifluoromethyl) biphenyl-4-yloxy) -4- (4-pyridyl) -

2-butanol

Following the procedure described in Example 6c), from 0.20 g of 1- (4-bromophenoxy) -4- (4-pyridyl) -2-butanol prepared according to Example 6b) and 0.13 g of 3-trifluoromethylphenylboronic acid were obtained. 18 g of the subtitle compound as a yellow oil.

MS (APCI + ve) 388 (M + H) < ⁺ > ^.

b) (+ -) - N- [1- (3'- (Trifluoromethyl) biphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

From the procedure described in Example 1, from 0.175 g of (+ -) - 1- (3'-trifluoromethylbiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol obtained according to step a), and 0.106 g. 2,4-thiazolinedione, after purification of the residue by chromatography on silica gel, eluting with 2% methanol in dichloromethane and supercritical fluid chromatography eluting with 0 to 45% methanol in liquid carbon dioxide and crystallizing from ethanol / ethyl acetate / isohexane yields 0, 10 g of the title compound as a colorless solid.

Melting point: 95-96 ° C

MS (APCI + ve) 487 (M + H) ^{+ 1} H NMR (DMSO-d ₆ ) δ 8.46 (2H, m), 7.92 (2H, m), 7.67 (4H, m), 7.23 (2H, d), 7.01 (2H, m), 4.56 (1H, m), 4.46 (1H, t), 4.30 (1H, dd), 4.18 (2H s), 2.65 (2H, t), 2.32 (1H, m), 2.10 (1H, m).

Example 22 (+ -) - N- [1- (2'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

a) (+ -) - 1- (2'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol

Following the procedure described in Example 6c), 0.18 g of 1- (4-bromophenoxy) -4- (4-pyridyl) -2-butanol prepared as described in Example 6b) and 0.104 g of 2-methoxyphenylboronic acid gave 0.18 g. g of the subtitle compound as a colorless solid.

MS (APCI + ve) 350 (M + H) < ⁺ > ^.

b) (+ -) - N- [1- (2'- (Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

Following the procedure described in Example 1, from (. + -) - 1- (3'-methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol prepared according to step a), 0.17 g. 0.114 g of 2,4-thiazolinedione, after purification by chromatography on silica gel eluting with 2% methanol in dichloromethane and supercritical fluid chromatography eluting with 0 to 45% methanol in liquid carbon dioxide, then after crystallization from ethanol / ethyl acetate / isohexane of the title compound as a colorless solid.

M.p .: 128-130 ° C

MS (APCI + ve) 487 (M + H) ^{+ 1} H NMR (DMSO-d 6) δ 8.46 (2H, d), 7.38 (2H, d), 7.33-7.22 (4H, m), 7.08 (1H, d), 6.99 (1H, m), 6.91 (2H, d), 4.55 (1H, m), 4.44 (1H, t), 4, 26 (1H, dd), 4.18 (2H, s), 3.75 (3H, s), 2.65 (2H, t), 2.31 (1H, m), 2.10 (1H, m) ).

Example 23 (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] piperidine-2,6-dione

Using the procedure described in Example 1, from 0.25 g of (+/-) -1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol prepared according to the procedure of Example 11a), and 0.16 g of glutarimide gives 0.11 g of the title compound as a light yellow foam.

Mp .: 53-55 ° C

MS (APCI) 460 (M + H) ^{+; H} NMR (DMSO-d)? 8.45 (2H, d), 8.38 (1 H, s), 8.17-8.09 (2H, m) 7.75-7.70 (3H, m), 7.21 (2H, d), 7.02 (2H, d), 5.10-5.00 (1H, m), 4.43-4 29 (2H, m), 2.57 (6H, t), 2.36-2.21 (1H, m), 2.162.01 (1H, m), 1.74 (2H, t).

Example 24 (+ -) - N- [1- (3'-Aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

Yellow suspension of 0.377 g of (+ -) - N- [1- (3'-nitrophenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidine-2,4-dione, prepared according to the procedure of Example 11b), 0.17 g of ammonium chloride and 0.18 g of iron powder in a 1: 1 ethanol / water mixture are heated under reflux for 1.5 hours. The cooled reaction mixture was filtered. The colorless filtrate was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by normal phase HPLC eluting with 0-10% ethanol in dichloromethane and then precipitated from the mixture. ethanol / ethyl acetate / isohexane, to give 0.34 g of the title compound as a colorless solid.

Melting point: 147-148 ° C

MS (APCI + ve) 434 (M + H) ^{+ 1} H NMR (DMSO-d ₆ ) δ 8.46 (2H, d), 7.46 (2H, d), 7.23 (2H, d), 7.05 (1H, t), 6.94 (2H, d), 6.77 (1H, s), 6.71 (1H, d), 6.50 (1H, d), 5.10 (2H s, 4.54 (1H, m), 4.43 (1H, t), 4.26 (1H, dd), 4.17 (2H, s), 2.62 (2H, t), 2 31 (1H, m); 2.12 (1H, m).

Example 25 (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] [1,3] oxyzinan-2-one

To a suspension of 0.31 ml of a 1.93 M solution of phosgene in toluene in 10 ml of toluene is added 0.20 g of (+ -) - N-2- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) of butylamine, prepared according to step 19c), and the reaction mixture is stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure and the residue was dissolved in 10 ml of dimethylformamide. This solution was slowly added to a suspension of 0.09 g of sodium hydride (60% dispersion in oil) in 1 ml of dimethylformamide. The mixture was heated at 70 ° C for 9 hours. After cooling to room temperature, the solvents were evaporated under reduced pressure. The pH of the residue was made alkaline with 2M aqueous sodium hydroxide solution and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a yellow oil (0.009 g).

MS (APCI) 448 (M + H) ^{+ Χ Η} NMR (DMSO-d) delta 8.46 (2H, dd), 8.39 (1H, t), 8.18-8.09 (2H, m) 7.75-7.70 (3H, m), 7.29 (2H, dd), 7.09 (2H, dd), 4.48-4.33 (1H, m), 4.20-4 12 (4H, m), 3.31-3.21 (2H, m), 2.65 (2H, t), 2.07-

1.86 (4 H, m).

Example 26 (2S) -N- [1- (3'-Cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

To 5 μπιοί (2R) -1- (3'-cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, prepared as described in Example 37 of WO 97/20815, add 50 μΐ 0.2 M solution of triphenylphosphine in tetrahydrofuran, then 50 μ 50 of a 0.2 M solution of 2,4-thiazolidinedione in tetrahydrofuran. 2 μΐ of diethyl azodicarboxylate are added and the reaction mixture is sealed and stirred at room temperature overnight. The mixture was evaporated under reduced pressure to give a residue. The residue was dissolved in dimethylsulfoxide to give the title compound as a 10 mM solution in dimethylsulfoxide and analyzed by HPLC on a Waters Symmetry C8 50 mm x 3.9 mm, 5 µm particle size, eluting with 0.1% aqueous solution. ammonium acetate.

MS (APCI + ve) 444 (M + H) < ⁺ > ^.

Example 27 (2S) -N- [1- (3'-Aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione

Following the procedure described in Example 26) from 5 µmol (2 R) -1- (3'-aminobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol prepared according to the procedure of Example 50 of the International Patent Application WO 97/20815, 50 μΐ of a 0.2 M solution of triphenylphosphine in tetrahydrofuran, 50 μΐ of a 0.2 M solution of 2,4-thiazolidinedione in tetrahydrofuran and 2 μΐ of diethyl azodicarboxylate gives the title compound as a 10 mM solution in dimethylsulfoxide and analyzed by HPLC for a Waters Symmetry C8 column 50 mm x 3.9 mm, particle size 5 μιη, eluting with 0.1% aqueous ammonium acetate.

MS (APCI + ve) 434 (M + H) < ⁺ > ^.

Example 28 (2S) -N- [1- (3'-Methanesulfonamidobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

Following the procedure described in Example 26), 5 µm of (2R) -1- (3'-methanesulfonamidobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, prepared according to the procedure of Example 98 of International Patent Application WO 97 / 20815, 50 μΐ of a 0.2M solution of triphenylphosphine in tetrahydrofuran, 50 μΐ of a 0.2M solution of 2,4-thiazolidinedione in tetrahydrofuran and 2 μΐ of diethyl azodicarboxylate gives the compound

title compound as a 10 mM solution in dimethylsulfoxide t and analyzed by HPLC on a Waters Symmetry C8 mm x 3.9 mm column, 5 µm particle size, eluting with 0.1% aqueous ammonium acetate.

MS (APCI + ve) 512 (M + H) < ⁺ > ^.

Example 29 (2S, 3S) -N- [1- {3'- (Pyrrolidine-1-sulfonyl) biphenyl-4-yloxy) -4- (3-pyridyl) -3-pentyl] pyrrolidine-2,5-dione

Following the procedure described in Example 26), from 6.67 μmηοΐ (3R, 4S ') -1-pyridin-3-yl-4- [3'- (pyrrolidine-1-sulfonyl) biphenyl-4-yloxy] pentane -3-ol, prepared according to the procedure of Example 72 of International Patent Application WO 98/42670, 50 μΐ of a 0.27M solution of triphenylphosphine in tetrahydrofuran, 50 μΐ of a 0.27M solution of succinimide in tetrahydrofuran and 3 μΐ of diethyl azodicarboxylate gives the title compound as 10 mM solution in dimethylsulfoxide and analyzed by HPLC on a Waters Symmetry C8 50 mm x 3.9 mm column, 5 µm particle size, eluting with 0.1% aqueous ammonium acetate.

MS (APCI + ve) 548 (M + H) < ⁺ > ^.

Example 30 (2S, 3S) -N- [1- (3'-Cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -3-pentyl] pyrrolidine-2,5-dione

Following the procedure described in Example 26), from 6.67 μmηοΐ (1S, 2R) -4-fluoro-4 '- (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile prepared by the procedure of according to Example 36 of International Patent Application WO 98/42670, 50 μΐ of a 0.27 M solution of triphenylphosphine in tetrahydrofuran, 50 μΐ of a 0.27 M solution of succinimide in tetrahydrofuran and 3 μΐ of diethyl azodicarboxylate gives the title compound as a 10 mM solution in dimethylsulfoxide and analyzed by HPLC on a Waters Symmetry C8 50 mm x 3.9 mm column, particle size 5 μιη, eluting with a mixture of 5 to 95¾ acetonitrile in ammonium acetate.

MS (APCI + ve) 458 (M + H) ⁺

Example 31 (2S) -N- [1- (3'-Cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione

Following the procedure described in Example 26) from 6.67 µ of (2 R) -1- (3'-cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butanol, µ, 0 A 27 M solution of triphenylphosphine in tetrahydrofuran, 50 μΐ of a 0.27 M solution of 2,4-thiazolidinedione in tetrahydrofuran and 3 μΐ of diethyl azodicarboxylate gives the title compound as a mM solution in dimethylsulfoxide and analyzed by HPLC on a Waters Symmetry C8 50 mm x 3 column. 9 mm, particle size 5 µm, eluting with a mixture of 5 to 95% acetonitrile in ammonium acetate.

MS (APCI + ve) 462 (M + H) < ⁺ > ^.

Example 32 (+ -) - N- [1- (4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

a) (+/-) - N- (1- (4-Bromophenoxy) -4- (4-pyridyl) -2-butyl) oxazolidin-2-one

Following the procedure described in Example 15c), starting from 1.08 g of (+/-) - N-2- (4-bromophenoxy) -4- (4-pyridyl) butylamine prepared according to the procedure of Example 19b), 0.521 ml

2-chloroethyl chloroformate and 0.408 g sodium hydride (60% dispersion in mineral oil). After 10 hours at 70 ° C, 100 ml of water are added and the product is extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography eluting with dichloromethane: ethanol (95: 5) to give 0.651 g of the subtitle compound as an oil.

MS (APCI + ve) 391/393 (M + H) ^{+; H} NMR (DMSO-d?) Delta 8.46 (2H, dd), 7.44 (2H, dd), 7.28 (2H, d) .

6.92 (2H, dd), 4.29-4.19 (2H, m), 4.07 (2H, d), 4.04-3.96 (1H,

m), 3.59-3.41 (2H, m), 2.70-2.56 (2H, m), 1.90 (2H, kv).

b) (+/-) - [4- (4-Pyridyl) -2- (oxazolidin-2-one-1-yl) butoxy] benzeneboronic acid

Following the procedure described in Example 18b), from 0.20 g (+/-) - N49

- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, prepared according to step a), 0.60 ml of a 1.7 M solution of tert-butyllithium in hexane and 0 17 ml of triisopropylborate are obtained

0.09 g of the subtitle compound as a foam.

MS (APCI + ve) 313 (MB (OH) ₂₎ ^{+; H} NMR _(DMSO-d6) delta 8.56 (2H, d), 7.82 (2H, d), 7.39 (2H, d 6.91 (2H, d), 4.25-4.15 (2H, m), 4.07 (2H, d), 4.05-3.94 (1H, m),

3.60-3.46 (2H, m), 2.74-2.62 (2H, m), 1.92 (2H, kv).

c) (+ -) - N- [1- (4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy) -4-

- (4-pyridyl) -2-butyl) oxazolidin-2-one

Following the procedure described in Example 6c), starting from 0.090 g of (+/-) - [4- (4-pyridyl) -2- (oxazolidin-2-one-1-yl) butoxy] benzeneboronic acid prepared according to the procedure of Example 6c). step b),

0.097 g of 5-bromo-2-fluorophenylsulfonamide prepared according to the procedure of Example 35a of the international patent application

WO 98/42670, 1 ml ethanol, 0.2 ml

2M aqueous sodium bicarbonate solution, 0.010 g tetrakis (triphenylphosphine) palladium (0). After work up, the residue was purified by column chromatography on silica gel eluting with dichloromethane: ethanol (95: 5) then dichloromethane: ethanol (90:10) to give 0.034 g of the title compound as a solid.

Melting point: 89: 91 ° C

MS (APCI + ve) 486 (M + H) < ⁺ > ^.

^X H NMR _(DMSO-d6) delta 8.46 (2H, d), 7.95 (1H, dd), 7.91-7.86 (LH, m), 7.72 (2H, s); 7.60 (2H, d); 7.48 (1H, t), 7.29 (2H, d), 7.07 (2H, d), 4.29-4.19 (2H, m), 4.14 (2H, d), 4.08-4.00 (LH, m), 3.63-3.47 (2 H, m), 2.72-2.60 (2H, m) 1.99-1.90 (2 H, m).

Example 33 (+ -) - N- [1- (4- (6-Methoxy-pyridin-2-yl) -phenoxy) -4- (4-pyridyl) -2-butyl] -oxazolidin-2-one

Following the procedure described in Example 6c), starting from 0.100 g of (+ -) - [4- (4-pyridyl) -2- (oxazolidin-2-on-1-yl) butoxy] benzeneboronic acid prepared according to the procedure of of Example 32b, 0.079 g of 2-bromo-6-methoxy-pyridine (J. Org. Chem.,

55, (1990), 69-73), 3 mL of ethanol, 0.2 mL of a 2M aqueous sodium bicarbonate solution, and 0.010 g of tetrakis (triphenylphosphine) palladium (0). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.082 g of the title compound as an oil.

MS (APCI + ve) 420 (M + H) ^{+ 1} H NMR (DMSO-d ₆ ) δ 8.46 (2H, dd), 8.04 (2H, d), 7.73 (1H, t), 7.48 (1H, d), 7.30 (2H, dd), 7.04 (2H, d), 6.70 (1H, d), 4.29-4.22 (2H, m), 4 15 (2H, d), 4.09-4.02 (1H, m), 3.94 (3H, s),

3.60-3.50 (2H, m), 2.73-2.59 (2H, m), 1.94 (2H, kv).

Example 34 (+/-) - N- [1- (Biphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl) oxazolidin-2-one

The procedure is as described in Example 6c), starting from 0.100 g of (+ -) - N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl) oxazolidin-2-one prepared by according to the procedure of Example 32a, 0.047 g of phenylboronic acid, 3 ml of ethanol, 0.2 ml of 2M aqueous sodium bicarbonate solution and 0.010 g of tetrakis (triphenylphosphine) palladium (0). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.012 g of the title compound as a solid.

M.p .: 116-117 ° C

MS (APCI + ve) 389 (M + H) ^{+ T} H NMR (DMSO-d) delta 8.46 (2H, d), 7.60 (4H, t), 7.43 (2H, t), 7 30 (3H, d), 7.03 (2H, d), 4.31-4.20 (2H, m), 4.13 (2H, d), 4.07-4.00 (1H, m) ), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, kv).

Example 35 (+ -) - N- [1- (4'-Chlorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

Following the procedure described in Example 6c), starting from 0.100 g of (+/-) - N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one prepared Procedure 0.060 g of 4-chlorobenzeneboronic acid, an aqueous solution of tetrakis (triphenylphosphine) palladium bicarbonate (0). After elution with a gradient

0.038 g of the compound of Example 32a), ml of ethanol, 0.2 ml of 2M sodium was purified by NPHPLC in dichloromethane, and worked up to a solid.

Melting point 103-105 ° C

10%

0.010 g of ethanol residue in

MS (APCI + ve) 423 (M + H) < ⁺ > ^.

^X H NMR (DMSO-d) 6 8.4 (2H, d), 7.62 (4H, qu), 7.47 (2H, d), 7.29 (2H, d) 7.03 (2H, d), 4,30-4,20 ( 2H, m), 4 , 13 (2H, d), 4.07-4.00 (1 H, m), 3, 62-3, 48 (2H, m); 2.70-2.58 (2H, m), 1, 94

(2H, kv).

Example 36 (+ -) - N- [1- (4'-Methylbiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

Following the procedure described in Example 6c), starting from 0.100 g of (+/-) - N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one prepared Procedure 0.052 g of 4-methylbenzeneboronic acid, an aqueous solution of tetrakis (triphenylphosphine) palladium bicarbonate (0). After elution with a gradient

0.033 g of the compound of Example 32a), ml of ethanol, 0.2 ml of 2M sodium is purified by NPHPLC in dichloromethane and the work up is carried out until

10%

0.010 g of ethanol residue as a solid.

M.p .: 109-110 ° C

MS (APCI + ve) 403 (M + H) < ⁺ >

7.29

d),

NMR (DMSO-d 6) δ 8.46 (2H,

d), 7.23 (2H, d); 7.01 (2H, d); 4.30-4.20 (2 H, m), d), 4.07-4.01 (1 H, m), 3.62-3.48 (2H, m), 2.72-2.59 1, 94 (2H, kv).

Example 37 (+ -) - N- [1- (4'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

The procedure is as described in Example 6c), starting from 0.100 g of (+/-) - N- [1- (4-bromophenoxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one prepared according to the procedure of Example 32a), 0.059 g of 4-methoxybenzeneboronic acid, 3 ml of ethanol, 0.2 ml of a 2M aqueous sodium hydrogen carbonate solution and 0.010 g of tetrakis (triphenylphosphine) palladium (0). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.026 g of the title compound as a solid.

M.p .: 114-115 ° C

MS (APCI + ve) 419 (M + H) ^{+; H} NMR (DMSO-d?) Delta 8.46 (2H, d), (4H, dd), 4.30-4.20 (2H, m),

3.32 (3H, s), 3.61-3.48 (2H,

7.53 (4H, dd), 7.29 (2H, d), 6.99

4.11 (2H, d), 4.06-4.01 (1H, m), m), 2.70-2.59 (2H, m), 1.94 (2H, kv).

Example 38 (+) - N- [1- (3 ', 4'-Dichlorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one

Following the procedure described in Example 6c), starting from 0.050 g of (+/-) - [4- (4-pyridyl) -2- (oxazolidin-2-on-1-yl) butoxy] benzeneboronic acid prepared according to the procedure of Example 32b), 0.048 g of 1-bromo-3,4-dichlorobenzene, 2 ml of ethanol,

0.1 ml of a 2M aqueous solution of sodium bicarbonate and 0.006 g of tetrakis (triphenylphosphine) palladium (0). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.010 g of the title compound as a solid.

Melting point: 92-93 ° C

MS (APCI + ve) 457/459/461 (M + H) < ⁺ > ^.

NMR (DMSO-d 6) δ 8.46 (2H, d), 7.89 (1H, d), 7.68-7.62 (4H, m),

7.29 (2H, d), 7.04 (2H, d), 4.30-4.20 (2H, m), 4.13 (2H, d), 4.07-4.01 (1H, m), 3.62-3.48 (2H, m), 2.72-2.59 (2H, m), 1.94 (2H, kv).

Example 39 (+/-) - N- [1- (4- (6-Methoxy-pyridin-2-yl) -phenoxy) -4- (4-pyridyl) -2-butyl] -piperidine-2,6-dione

a) (+/-) - I ^- (4-bromophenoxy) -4- (4-pyridyl) -2- (tert-butyldimethylsilyloxy) butane

20.53 g of tert-Butyldimethylsilyl chloride and 9.25 g of imidazole are added to a solution of 14.60 g of (+/-) - 1- (4-bromophenyloxy) -4- (4-pyridyl) -2-butanol prepared according to the procedure of of Example 6b) in 500 mL of dry dichloromethane. The solution was stirred at room temperature overnight. The solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane: ethyl acetate (5: 1) to give 19.34 g of the sub-title compound as a solid.

M.p .: 73-75 ° C

MS (APCI + ve) 436/438 (M + H) < + >

^X H NMR (DMSO-d₆) delta 8, 50 (2H, dd) 7.49 (2H, dd) 7.27 (2 H, d), 6.94 (2 H, dd), 4.13 -4.02 (2H, m), 3.93 -3.66 (1 H, m), 2.82-2.68 (2H, m), 1.97-1.79 (2H, m), 0.91 (9H, with) , 0.12 (3H, s) 0.09

(3 H, s).

b) (+/-) -4- [4- (4-Pyridyl) -2- (tert-butyldimethylsilyloxy) butoxy] benzeneboronic acid

Following the procedure described in Example 18b), starting from 10.0 g of (+/-) -1- (4-bromophenoxy) -4- (4-pyridyl) -2- (tert-butyldimethylsilyloxy) butane, prepared according to step a), 27 ml of a 1.7 M solution of tert-butyllithium in hexane and 6 ml of triisopropylborate in dry tetrahydrofuran 200 ml. After working up, the residue was purified by column chromatography on silica gel eluting with ethyl acetate: hexane (2: 1) then ethyl acetate to give 4.38 g of the sub-title compound as a foam.

MS (APCI + ve) 402 (M + H) ^{+ 1} HNMR (DMSO-d ₆ + D ₂ O) δ 8.45 (2H, dd), 7.71 (2H, d), 7.24 (2H, q);

6.87 (2H, d), 4.04-3.82 (3H, m), 2.79-2.66 (2H, m), 1.97-1.75 (2H, m), O, 87 (9H, s), 0.14 (3H, s), 0.08 (3H, s).

c) (+/-) -4- [4- (4-Pyridyl) -2-butoxy] benzeneboronic acid ml of 2M dilute hydrochloric acid is added to

4.38 g of (+) - 1- (4-bromophenoxy) -4- (4-pyridyl) -2- (tert-butyldimethylsilyloxy) butane, prepared according to step b), in 200 ml of methanol. The mixture was stirred at room temperature for 2 hours, then evaporated under reduced pressure. The residue was partitioned between diethyl ether and water. The pH of the aqueous mixture was adjusted to basic with aqueous sodium bicarbonate, then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give the subtitle compound as a powder.

MS (APCI + ve) 288 (M + H) ^{+; H} NMR (DMSO-d ₆ + D ₂ O) δ 8.43 (2H, d), 7.71 (2H, d), 7.31 (2H , d),

6.92 (2H, d), 3.92 (2H, d), 3.84-3.78 (1H, m), 2.87-2.64 (2H,

m), 1.89-1.74 (2 H, m).

d) (+ -) - 1- [4- (6-Methoxy-pyridin-2-yl) -phenoxy] -4- (4-pyridyl) -2-butanol

Following the procedure described in Example 6c), starting from 0.20 g of (+/-) - 4- [4- (4-pyridyl) -2-butoxy] benzeneboronic acid prepared according to step c), 0.26 g of 2-bromo-6-methoxypyridine (J. Org. Chem., 55, (1990), 69-73), 3 ml of ethanol, 0.7 ml of 2M aqueous sodium bicarbonate solution and 0.020 g of tetrakis (triphenylphosphine) palladium (0) ). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.15 g of the sub-title compound as an oil.

MS (APCI + ve) 351 (M + H) < ⁺ > ^.

³ H NMR (DMSO-d 6) δ 8.45 (2H, d), 8.03 (2H, dd), 7.73 (1 H, t), 7.47 (1 H, d), 7.26 (2H, dd), 7.03 (2H, dd), 6.70 (1H, d) 5.08 (1 H, d), 3, 95 (2H, d), 3.83-3.78 (1H, m), 3, 32 (3H, s) 2.85 -2.77 (1 H, m), 2.72-2.64 (1 H, m), 1.91- 1.83 (1 H, m), 1.78-1.70 (1 H,

m).

e) (+/-) - N- [1- (4- (6-Methoxy-pyridin-2-yl) -phenoxy) -4- (4-pyridyl) -2-butyl] -piperidine-2,6-dione

The procedure is as described in Example 1, starting with 0.15 g of (+ -) - 1- [4- (6-methoxy-pyridin-2-yl) -phenoxy] -4- (4-pyridyl) -2-butanol, prepared according to step d), 0.1 g of glutarimide, 0.22 g of triphenylphosphine and 0.14 ml of diethyl azodicarboxylate. After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.10 g of the title compound as an oil.

MS (APCI + ve) 446 (M + H) < ⁺ > ^.

NMR (DMSO-d ₆ ) δ 8.44 (2H, dd), 8.01 (2H, dd) 7.73 (1 H, t) / 7.47 (1 H, d), 7.21 (2 H, dd), 6.97 (2H, d), 6.70 (1 H, d), 5.07-5.02 (1 H, m), 4.42-4, 28 (2H, m); 3, 94 (3H, with) , 2,62- 2.51 (6H, m), 2.35-2.24 (1 H, m) , 2.12-2.01 (1 H, m), 1,78- 1.70 (2H,

m).

Example 40 (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] imidazolidine-2,4-dione

The procedure is as described in Example 1, starting from 0.20 g of (+/-) -N1- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butanol, prepared as described in Example 1. 15a), 0.11 g of hydantoin, 0.29 g of triphenylphosphine and 0.17 ml of diethyl azodicarboxylate in 10 ml of dry tetrahydrofuran and 2 ml of dimethylformamide. After work-up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.03 g of the title compound as a solid.

M.p .: 143-145 ° C

MS (APCI + ve) 447 (M + H) ^{+ 1} H NMR (DMSO-d 6) δ 8.45 (2H, d), 8.38 (1H, s), 8.17-8.07 (3H, m), 7.74-7.70 (3H, m), 7.24 (2H, d), 7.03 (2H, d), 4.51-4.45 (1H,

m), 4.38-4.23 (2H, m), 3.87 (2H, s), 2.69-2.60 (2H, m),

2.38-2.22 (1 H, m), 2.16-2.00 (1 H, m).

Example 41 (+/-) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] piperidin-2-one

0.07 ml of 5-Chlorvaleryl chloride is slowly added to a solution of 0.20 g of (+/-) - N-2- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) butylamine in the presence of 1 ml of triethylamine. prepared as described in Example 19c) in 10 mL of dry dichloromethane. The mixture was stirred at room temperature for 15 minutes, then evaporated under reduced pressure. To the residue dissolved in 10 ml of anhydrous tetrahydrofuran was added 1.5 ml of 1M potassium tert-butoxide solution. After 30 minutes at room temperature, the mixture was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.03 g of the title compound as an oil.

MS (APCI + ve) 446 (M + H) ^{+ 3} H NMR (DMSO-d ₆ ) δ 8.45 (2H, d), 8.38 (1H, t), 8.18-8.09 (2H , m), 7.75-7.69 (3H, m), 7.26 (2H, d), 7.07 (2H, d), 4.86-4.76 (1H,

m), 4.19-4.07 (2H, m), 3.25-3.14 (2H, m), 2.73 (2H, t),

2.28-2.22 (2H, m), 2.00-1.87 (2H, m), 1.64 (4H, br).

Example 42 (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl) pyrrolidin-2-one

Following the procedure described in Example 41, starting from 0.20 g of (+ -) - N - 2- (3'-nitrobiphenyl-4-yloxy) -4- (4-pyridyl) butylamine prepared according to the procedure of Example 19c. 1 ml of triethylamine, 0.06 ml of 4-chlorobutyryl chloride and 1.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran. After work up, the residue was purified by NPHPLC eluting with a gradient of 0 to 10% ethanol in dichloromethane to give 0.035 g of the title compound as an oil.

MS (APCI + ve) 432 (M + H) ^{+ 1} H NMR (DMSO-d ₆ ) δ 8.45 (2H, dd), 8.38 (1H, t), 8.18-8.09 (2H, m),

7.75-7.69 (3H, m), 7.28 (2H, dd), 7.07 (2H, dd), 4.34-4.27 (1H,

m), 4.11 (2H, d), 3.38-3.26 (2H, m), 2.61-2.55 (2H, m), 2.24 (2H, t), 1.97 -1.85 (4 H, m).

Example 43

Pharmacological analysis

Some compounds, such as benzoylbenzoyladenosine triphosphate (bbATP), are known for their antagonism against the P2X7 receptor, which acts on the formation of pores in the plasma membrane (Drug Development Research (1996), 37 (3), p. 126). Therefore, when the bbATP-activated receptor is in the presence of ethidium bromide (a fluorescent DNA probe), an increase in fluorescence occurs intracellularly through the DNA-bound ethidium bromide. The increase in fluorescence can be used as a measure of P2X7 receptor activation, thus quantifying the effect of the compound on the P2X7 receptor.

In this manner, the compound of Example 1 to 42 was tested for antagonist activity against the P2X7 receptor. The assay was performed on a 96-well microtiter plate. The wells were filled with 250 μΐ assay solution containing 200 μΐ suspension of THP-1 cells (2.5x10 ⁶ cells / ml) and 10 ^-4 M ethidium bromide, 25 μΐ potassium buffer solution containing 10 ^-5 M bbATP, and 25 μΐ potassium buffer solution containing 3x10 ^-5 M test compound. The microtiter plate is covered with a plastic cover and incubated at 37 ° C for one hour. Fluorescence measurements are then performed on a Perkin-Elmer instrument, excitation 520 nm, emission 595 nm, slit width: Ex 15 nm, Em 20 nm. BBATP (P2X7 receptor agonist) and pyridoxal-5-phosphate (P2X7 receptor agonist) were used as comparative experiment. From the values obtained, the pIC 50 value is calculated for each compound, which is the negative decimal logarithm of the concentration of test compound needed to reduce the bbATP agonist activity to 50%. Each compound of Examples 1 to 42 showed antagonistic

Claims (13)

PATENT CLAIMS (I) wherein X is O or S or NH, CH 2, CH 2 CH 2 or OCH 2; is CH2 or C = O; R 1 is pyridyl or pyrimidinyl; R 2 is phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen or amino, cyano, nitro, alkyl of up to 6 carbon atoms, haloalkyl of up to 6 atoms C 1 -C 6 alkoxy, C 1 -C 6 hydroxyl, C 1 -C 6 alkylthio, (di) C 1 -C 6 alkylamino, C 1 -C 6 alkylcarbonyl, Part 1 C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulphinyl, C 1 -C 6 alkylsulphonyl, -NR 3 SO 2 R 4 or -SO 2 NR 5 R 6 or -Z- (CH 2) P 2 - ) qH, each independently at m N or O, L to 5 and q is O or an integer of 1 Z is the integer 2 R 3 R 4 are each independently of the other hydrogen or alkyl having 1 to 6 carbon atoms; and up to 5; R 5 and R 6 are each independently hydrogen or C 1 -C 6 alkyl or together with the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl group; or a pharmaceutically acceptable salt or solvate thereof. 1, characterized in that (a) the reaction of a compound wherein L is as defined in formula (II), comprising a leaving group for the formula (II) as in (II) a compound of formula (III) wherein X and Y are as defined for formula (I) except that when. X is O or OCH ₂ , then Y is not CH ₂ ; or (b) when X is an oxygen atom and Y is a CH ₂ group, reacting a compound of formula IV (IV) wherein R ¹ and R ² are as defined for formula I with 2-chloroethyl chloroformate; or (c) when X is OCH ₂ and Y is CH ₂ , reacting a compound of formula IV as defined in (b) with 1-4 of the alkoxy moiety of 1-4 carbon atoms, alkylsulfinyl of 1-4 carbon atoms, alkylsulfonyl of 1-4 carbon atoms, -NR ³ SO ² R ⁴ or -SO ² NR ⁵ R ⁶ . 1-4 alkyl-containing atoms containing in the alkyl alkoxycarbonyl group consisting of a hydroxyl containing 1-4 containing 1 to 4 carbon atoms, carbon atoms, alkylthio containing (di) alkylamino group containing in each carbon atom, alkylcarbonyl groups 1 to 4 4 carbon atoms, cyano group 1 to 4 carbon, A compound according to claim 1, wherein X is a sulfur atom or a CH ₂ group. 3-chloropropanol in the presence of phosgene; or (d) when X is CH ₂ and Y is CH ₂ , reacting a compound of formula IV as defined in (b) with 3. Compound by any of the claims 1 or 2, wherein Y is a group C = 0. 4. Compound by any of the claims 1 to 3, wherein R ¹ is a pyridyl. 5. Compound by any of the claims 1 to 4, wherein R ² is a phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with one, two or three substituents independently selected from halogen or amino, a group, nitro, alkyl carbon atoms, haloalkyl alkoxy containing 4-chlorobutyryl chloride; or (e) when X is CH ₂ CH ₂ and Y is CH ₂ , reacting a compound of formula IV as defined in (b) with 5-valeryl chloride; or (f) when X is oxygen or OCH ₂ , reacting a compound of formula V (V) wherein X is oxygen or OCH ₂ and Y and R ¹ are as defined for formula I with a compound of formula VI, R ² -B (OH) ₂ wherein R ² is as defined for formula I; or (g) when X is oxygen or OCH ₂ , reacting a compound of formula VII (VII) wherein X is oxygen or OCH ₂ and Y and R ¹ are as defined above with a compound of formula VIII, R ² -Br wherein R ² is as defined for formula I, and optionally compounds of formula I and / or after (a), (b), (c), (d), (e), (f) or (g) of formula I converting a general solvate of the compound to a compound of formula I an acceptable salt; or A compound according to any one of claims 1 to 5, wherein R ² is phenyl, pyridyl or pyrimidinyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of halogen or amino, cyano, nitro , (1-4C) alkyl, (1-4C) haloalkyl, (1-4C) alkoxy, or -SO ² NR ⁵ R ⁶ . 7. A compound according to claim 1 which is: (+/-) - [N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (+ -) - N - [ 1- (3'-Methoxybiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] pyrrolidine-2,5-dione, (+/-) - N- [1- (Biphenyl-4-yloxy) ) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+ -) - N - [1- (3'-Chlorobiphenyl-4-yloxy) -4- (3- pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (+ -) - N - [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (+ -) - N - [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione (+/-) - N- [1- (3'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2R) -N- [ 1- (3'-Cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (2R) -N- [1- (3'-Nitrobiphenyl-4)] -yloxy) -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (2R) -N- [1- (3'-Cyanobiphenyl-4-yloxy) -4- (3- pyridyl) -2-butyl] pyrrolidine-2,5-dione, (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidine -2,4-dione, (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine n-2,5-dione, (+/-) -N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidine-2,5-dione, (+ -) - N- [1- (4'-Fluorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (+/-) - N- [1- (Biphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] -oxazolidin-2-one, (2R) -N- [1- (3'-Chloro-4'-fluorobiphenyl- 4-yloxy) -4- (3-pyridyl) -2-butyl] -thiazolidin-2,4-dione, (2R) -N- [1- (3'-Chloro-4'-fluorobiphenyl-4-yloxy)] -4- (3-pyridyl) -2-butyl] -pyrrolidine-2,5-dione, (2H) -N- [1- (3 ', 5'-Dicyanobiphenyl-4-yloxy) -4- (3- pyridyl) -2-butyl] -thiazolidin-2,4-dione, (+/-) -N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (2R) -N- [1- (3'-Fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione, (+/–) ) -N- [1- (3'- (Trifluoromethyl) biphenyl 1-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (+/-) -N- [1- (2'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl-2-butyl] thiazolidin-2,4-dione, (+ -) - N - [1- (3'-Nitrobiphenyl- 4-yloxy) -4- (4-pyridyl) -2-butyl] piperid n-2,6-dione, (+/-) -N- [1- (3'-Aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (+ -) - N- [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] - [1,3] oxazinan-2-one, (2S) -N- [1- (3'-Cyanobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2S) -N- [1- (3'- Aminobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] thiazolidin-2,4-dione, (2S) -N- [1- (3'-Methanesulfonamidobiphenyl-4-yloxy) -4- ( 3-pyridyl-2-butyl] thiazolidin-2,4-dione, (2S, 3S) -N- [1- (3'- (Pyrrolidine-1-sulfonyl) biphenyl-4-yloxy) -4- (3 (2S, 3S) -N- [1- (3'-Cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -pyridyl) -3-pentyl] pyrrolidine-2,5-dione -3-Pentyl] pyrrolidine-2,5-dione, (2S) -N- [1- (3'-Cyano-4'-fluorobiphenyl-4-yloxy) -4- (3-pyridyl) -2-butyl] Thiazolidin-2,4-dione, (+/-) - N- [1- (4'-Fluoro-3'-sulfonamidobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] -oxazolidine- 2-one, (+/-) - N- [1- (4- (6-Methoxypyridin-2-yl) phenoxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+ / -) - N- [1- (biphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+ -) - N- [1- (4'-Chlorobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one (+ / -) -N- [1- (4'-Methylbiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+ -) -N- [ 1- (4'-Methoxybiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+ -) - N - [1- (3 ', 4'-Dichlorobiphenyl) -4-yloxy) -4- (4-pyridyl) -2-butyl] oxazolidin-2-one, (+/-) - N- [1- (4- (6-Methoxy-pyridin-2-yl) -phenoxy) -4- (4-pyridyl) -2-butyl] piperidine-2,6-dione, (+ -) - N - [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl)] -2-butyl] imidazolidine-2,4-dione, (+ -) - N - [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] piperidin-2 -one or (+ -) - N - [1- (3'-Nitrobiphenyl-4-yloxy) -4- (4-pyridyl) -2-butyl] pyrrolidin-2-one. A process for the preparation of a compound of formula I according to claim 1 A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7 in association with a pharmaceutically acceptable additive, diluent or carrier. A process for the preparation of a pharmaceutical composition according to claim 9, which comprises admixing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7 with a pharmaceutically acceptable additive, diluent or carrier. A compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7 for use in therapy. Use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7 in the manufacture of a medicament for use in therapy. 13. A method of treating immunosuppression comprising administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7.