JP3465825B2 - Triarylethane derivatives as PDE IV IV inhibitors - Google Patents

Description

BACKGROUND OF THE INVENTION The present invention inhibits phosphodiesterase IV (PDE IV) to induce cyclic adenosine-3 ', 5'-monophosphate (cA
It relates to compounds and pharmaceutical compositions for treating diseases by increasing the level of MP).

Many hormones and neurotransmitters are adenosine-
It regulates tissue function by increasing intracellular levels of 3 ', 5'-cyclic monophosphate (cAMP). cAMP
Intracellular levels of are regulated by mechanisms that control synthesis and degradation. cAMP is synthesized by adenyl cyclase, which is directly activated by substances such as forskolin.
Alternatively, a specific agonist is regulated by adenyl cyclase, which can be indirectly activated by binding to a cell surface receptor that is coupled to adenyl cyclase.
Degradation of cAMP is controlled by the phosphodiesterase (PDE) isoenzyme family, which also controls the degradation of guanosine-3 ', 5'-cyclic monophosphate (cGMP). Regarding the family, seven members (PDE I-VII) whose distributions differ from one tissue to another have been described so far. This suggests that specific inhibitors of PDE isoenzymes may increase cAMP in different tissues at different levels [Review of PDE distribution, structure, function and regulation by Beavo & Reifsnyder (1990). See TIPS, 11 : 150-155; and Nicholson et al. (1991) TIPS, 12 : 19-27].

By utilizing PDE isotype selective inhibitors,
It has made it possible to study the role of PDEs in different cell types. In particular, PDE IV is associated with many inflammatory cells such as basophils [PT Peachell et al., (1992) J. Immunol. 148 2503-25.
10] and eosinophils [G. Dent et al., (1991) Br. J. Pharmacol. 103.
1339-1346] and that inhibition of this isotype also inhibits cell activation. In addition, an increase in cAMP in airway smooth muscle causes an antispasmodic effect. As a result, PDE IV inhibitors are currently being used due to their anti-inflammatory and bronchodilator effects.
In particular, it is being developed as a potential anti-inflammatory drug for the prevention and treatment of asthma.

Applying molecular cloning techniques to the study of PDEs revealed that there could be more than one isoform for each isotype. There are four isoforms (A, B, C and D) in PDE IV, and each isoform is
Rodents [JV Swinnen et al., (1989) Proc. Natl. Acad.
Sci. USA 86 5325-5329], human [G. Bolger
Et al. (1993) Mol. Cell Biol. 13 6558-6581] were also shown to be encoded by separate genes.

The presence of large numbers of PDE IVs holds the hope that inhibitors that are selective for individual isoforms may be obtained, and thus the specificity of action of such inhibitors may be enhanced. This builds on the hypothesis that the various PDE IV isoforms are functionally different. Indirect evidence supporting this hypothesis is the selective distribution of the isoform in various tissues [Swinnen et al., 1989; Bolger et al., 1993; R. Obernolte.
(1993) Gene 129 239-247, supra] and a high degree of sequence conservation between isoforms of different species.

To date, full-length cDNAs of human PDE IV A, B and D capable of producing functional recombinant enzymes by expressing the cDNA in a suitable host cell [Bolger et al., 1993 supra; Obernolt.
e, 1993, supra; M. Mclaughlin et al., (1993) J. Biol. Chem.2.
68 6470-6476] and rat PDE IV A, B and D full-length cDNAs [R. Davis et al. (1991) Proc. Natl. Acad. Sci. USA
86 3604-3609; jVSwinnen, (1991) J. Biol. Chem. 266.
18370-18377] have been reported. These cDNAs were isolated by conventional hybridization methods. However, using this method, the cDNA of human or rat PDE IV C
[Bolger et al., Supra, 1993 and Swinn
en et al., supra, 1989 and international patent application WO 91/16457].

Attempts to synthesize PED IV inhibitors for treating inflammatory diseases such as asthma have so far been less successful. Many of the PDE IV inhibitors synthesized have poor potency and / or only non-selectively inhibit one or more PDE isoenzymes. PDE IV inhibitors that are relatively potent and selective for PDE IV are also reported to be emetic. Indeed, this side effect is so common that experts have published the idea that the vomiting that occurs when a PDE IV inhibitor is administered may be mechanism-based.

The present inventor has now found a series of novel tri-substituted phenyl derivatives. Members of the derivative are potent inhibitors of PDE IV at concentrations that have little or no inhibitory effect on other PDE isoenzymes as compared to structurally similar known compounds. These compounds are human recombinant PDE
Not only inhibits the IV enzyme, but also increases cAMP in isolated leukocytes. Certain compounds include carrageenan, platelet activating factor (PAF), interleukin-5
Prevents lung inflammation induced by (IL-5) or antigen challenge. The compounds further suppress the airway smooth muscle hyperresponsiveness seen in lung inflammation. Advantageously, the compounds of the invention have good oral activity and show little or no side effects associated with known PDE IV inhibitors such as rolipram at orally effective dosages. . Accordingly, the compounds of the present invention are
It is useful in medicine, especially in the prevention and treatment of asthma and other inflammatory conditions.

SUMMARY OF THE INVENTION The present invention provides Formula I, which is useful in treating diseases by inhibiting PDE IV and increasing cAMP. Of the novel compounds of

The present invention also includes certain pharmaceutical compositions and methods of treating disorders by inhibiting PDE IV and increasing cAMP, including using compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION The present invention is of formula I, useful in the treatment of diseases by inhibiting PDE IV and increasing cAMP. [Wherein R is selected from (a) hydrogen, (b) C _1-6 alkyl, (c) halo, and (d) CF ₃ ; R ¹ is — (CH ₂ ) _m —CO—N _{^{(R 4) -S (O)}} 2 -R 5 ( wherein, m is 0, 1 or _{2), - (CH 2)} m -CO-N (R 4) -S (O) 2 -NR _{^{6 R 7, - (CH 2}} ) m -S (O) 2 -N (R 4) -CO-R 4, - (CH 2) m -S (O) 2 -N (R 4) -CO-NR ⁶ R ⁷ , —C (OH) (C _1-6 haloalkyl) ₂ ; R ² and R ³ are independently (a) C _1-7 alkyl, (b) substituted C _1-7 alkyl (here And the substituents are F, C
l, Br or I), (c) optionally mono- or di-substituted 2-phenethyl or 2-indanyl (wherein the substituents on the benzene ring are independently (1) halo, (2) C _C1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5 ) CF 3, (6) C 1-6 alkyl, (7) N _3, the group consisting of (8) -CO ₂ H R ⁴ is (a) hydrogen, (b) C _1-6 alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl (wherein benzene Substituents on the ring are independently (1) halo, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _{1-6 alkyl, (7) N 3, (} 8) is selected from -CO ₂ is selected from the group consisting of H); R ^5, R ⁸ and R ¹¹ are each independently, (a) CF _3, (b) C _1-6 alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl (wherein the substituents on the benzene ring is independently (1) halo, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _1-6 alkyl, (7) N ₃ , (8) -CO ₂ Selected from the group consisting of H); R ⁶ , R ⁷ , R ⁹ and R ¹⁰ are each independently selected from (a) hydrogen and (b) C _1-6 alkyl; or R ⁶ And R ⁷ together form a saturated 5-, 6- or 7-membered heterocycle (wherein the heterocycle contains a heteroatom nitrogen and optionally an additional heteroatom which is an O or S atom or NR ⁴
And optionally a carbonyl group) can be formed; HET is optionally mono- or di-substituted pyridyl and imidazolyl, wherein the substituents are independently halo, C _1-6.
Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁸ , NR ⁹ R ¹⁰ , NHS (O)
₂ R ¹¹ , OH, CN or CF ₃ ) and their N-oxides; X is selected from N, N → O or CH] Includes the above acceptable salts.

This embodiment includes compounds where R ² is cyclopentyl and R ³ is methyl.

For the above species, R is selected from (a) hydrogen, (b) C _1-4 alkyl, (c) halo, and (d) CF ₃ ; R ¹ is — (CH ₂ ) _m —CO— _{^{N (R 4) -S (O}} ) 2 -R 5 ( wherein, m is 0, 1 or _{2), - (CH 2)} m -CO-N (R 4) -S (O) 2 - ^{NR 6 R 7, - (CH} 2) m -S (O) 2 -N (R 4) -CO-R 4, - (CH 2) m -S (O) 2 -N (R 4) -CO- NR ⁶ R ⁷ , selected from —C (OH) (C _1-6 haloalkyl) ₂ ; R ² is cyclopentyl; R ³ is methyl; R ⁴ is (a) hydrogen, (b) C _{1 -6} alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl (wherein the substituents on the benzene ring are independently (1) halo, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _1-6 alkyl, (7) N ₃ , (8) selected from the group consisting of —CO ₂ H); R ⁵ , R ⁸ and R ¹¹ are each independently (a) —CF ₃ , (B) C _1-6 alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl (wherein the substituents on the benzene ring are independently (1) halo, (2) C _C1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5 ) CF 3, (6) C 1-6 alkyl, (7) N _3, the group consisting of (8) -CO ₂ H is selected from to) selected from; to R ^6, R ^7, R ⁹ and R ¹⁰ are each independently selected from (a) hydrogen, and (b) C _1-6 alkyl; or R ⁶ and R ⁷ Taken together, a saturated 5-, 6-, or 7-membered heterocycle (wherein the heterocycle contains a heteroatom nitrogen and optionally an additional heteroatom or O or S atom) NR ⁴
HET is optionally mono- or di-substituted pyridyl and imidazolyl, wherein the substituents are independently halo, C _1-6.
Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁸ , NR ⁹ R ¹⁰ , NHS (O)
₂ R ¹¹ , OH, CN or CF ₃ ) and its N-oxides; X includes a group of compounds selected from N, N → O or CH.

The above groups, R is, (a) hydrogen, (b) C _1-3 alkyl is selected from (c) halo, and (d) CF _3; and there against the R ¹ in the ortho position; R ¹ _{but, - (CH 2) m -CO} -N (R 4) -S (O) 2 -R 5 ( wherein, m is 0, 1 or _{2), - (CH 2)} m -CO-N _{^{(R 4) -S (O)}} 2 -NR 6 R 7, - (CH 2) m -S (O) 2 -N (R 4) -CO-R 4, - (CH 2) m -S (O ^{_{) 2 -N (R 4) -CO}} -NR 6 R 7, is selected from -C (OH) (C _{1-6 haloalkyl) 2;} R ² is cyclopentyl; R ³ is methyl; R ⁴ is , (A) hydrogen, (b) C _1-6 alkyl; R ⁵ , R ⁸ and R ¹¹ are each independently selected from (a) —CF ₃ , (b) C _1-6 alkyl, It is; to R ^6, R ^7, R ⁹ and R ¹⁰ are each independently, from (a) hydrogen, and (b) C _1-6 alkyl Is-option; or R ⁶ and R ⁷ together form a saturated 5-membered, 6-membered or 7-membered heterocyclic ring (the heterocyclic ring contains a hetero atom of nitrogen, optionally additional heteroatoms is O or S atom Atom or NR ⁴
HET is optionally mono- or di-substituted pyridyl, wherein the substituents are independently halo, C _1-6 alkyl, C _1-6.
Alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁸ , NR ⁹ R ¹⁰ , NHS (O) ₂ R ¹¹ , OH, CN or CF ₃
Selected from the group consisting of) and its N-oxides; and compounds of the subclass wherein X is CH.

As will be appreciated by those in the art, halo is meant to include F, Cl, Br and I.

As used herein, alkyl includes straight chain, branched chain and cyclic structures, C _1-6 alkyl includes methyl, ethyl, propyl, 2-propyl, s-butyl, t-butyl, butyl, pentyl, Defined to include hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C _1-6 alkoxy is intended to include alkoxy groups of 1 to 6 carbon atoms having a straight chain, branched chain or cyclic structure. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. In addition, C _1-6 alkylthio includes an alkylthio group having 1 to 6 carbon atoms having a straight chain, branched chain or cyclic structure. Examples of alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio and the like. For example, a propylthio group is represented by -SCH ₂ CH ₂ CH _3. C _1-6 haloalkyl means an alkyl group in which two or more hydrogen atoms are replaced with halogen atoms.

The present invention is exemplified by the following compounds: (a) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} methane Sulfonamide, (b) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} benzenesulfonamide, (c) N- {(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} trifluoromethanesulfonamide, (d) N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} o-toluenesulfonamide, (e) N-{(R) -4- [ 1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetyl} benzenesulfonamide, (f) N-{(R) -4- [1- (3-cyclopentyloxy) -4-Methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetyl} trifluoromethanesulfonamide, (g) (R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (1,1,1,3,3,
3-hexafluoro-2-hydroxypropan-2-yl) ethyl} pyridine, and (h) N- (o-toluoyl) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2-
(4-Pyridyl) ethyl] benzenesulfonamide.

Some of the compounds described herein contain one or more asymmetric centers and are thus capable of producing diastereomers and optical isomers. The present invention is meant to include such diastereomers that may be formed as well as their racemic and isolated enantiomerically pure forms and pharmaceutically acceptable salts thereof.

Some of the compounds described herein contain an olefinic double bond. Unless otherwise noted
The compounds are intended to include E and Z geometric isomers.

The present invention comprises in a second embodiment a pharmaceutical composition for treating a disease by inhibiting PDE IV as disclosed herein, wherein said composition is pharmaceutically acceptable. It contains a possible carrier and a non-toxic therapeutically effective amount of a compound of formula I as described above.

The present invention, in the above embodiment, comprises a pharmaceutical composition for treating a disease by inhibiting PDE IV and increasing cAMP as disclosed herein, wherein the composition comprises It contains a pharmaceutically acceptable carrier and a non-toxic, therapeutically effective amount of a compound of formula I as described above.

As used herein, a compound selectively inhibits PDE IV in preference to other PDEs if the IC ₅₀ concentration ratio of inhibition of all other PDEs to PDE IV is 100 or more.

The pharmaceutical composition of the present invention contains a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may further contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic salts include salts of aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, ferric manganese, ferrous manganese, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, naturally substituted amines, substituted amines including cyclic amines, basic ion exchange resins such as arginine. , Betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, Hydrabamine, isopropylamine,
Lysine, methylglucamine, morpholine, piperazine,
Examples include piperidine, polyamine resins, procaine, purines, theobromine, tritylamine, trimethylamine, tripropylamine, tromethamine and the like.

It will be understood that, in the description of treatment methods provided below, when referring to a compound of formula I, the compound also includes pharmaceutically acceptable salts thereof. The compounds of the invention are selective and potent PDE IV inhibitors. The ability of the compound to act in this way can be readily quantified with the tests described in the Examples below.

Thus, the compounds of the present invention may be associated with undesirable inflammatory responses or muscle spasms (eg, bladder or gastrointestinal smooth muscle spasms).
Is present and increasing cAMP levels are particularly useful in the prevention and treatment of human diseases in which the inflammation may be prevented or reduced, or muscle relaxation may be expected.

Particular uses to which the compounds of the invention may be applied include asthma,
In particular, lung inflammation with asthma, prevention and treatment of cystic fibrosis, or inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and other benign and malignant proliferative skin diseases, endotoxic shock, Septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury
y), inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring catarrh, arterial restenosis and arteriosclerosis Treatment of is included.

The compounds of the invention further suppress neurodegenerative inflammation by increasing cAMP in sensory neurons. Thus, the compounds are analgesics, antitussives and antihyperalgesics in hypersensitivity and pain-related inflammatory diseases. Furthermore, the compounds of the present invention increase cAMP in lymphocytes, thereby causing unwanted lymphocyte activation in immune disorders such as rheumatoid arthritis, ankylosing spondylitis, graft rejection and graft versus host disease. Can also be suppressed.

The compounds of the invention have also been found to reduce gastric acid secretion and therefore may be used in the treatment of conditions associated with gastric acid hypersecretion.

The compounds of the invention inhibit cytokine synthesis by inflammatory cells in response to immune or infectious stimuli. Therefore, the compounds are useful in the treatment of sepsis induced by bacteria, fungi or viruses and septic shock in which cytokines such as tumor necrosis factor (TNF) are the major mediators. The compounds of the present invention also suppress inflammation and fever caused by cytokines, and are therefore useful for treating inflammation and cytokine-mediated chronic tissue degeneration that occur in diseases such as rheumatoid arthritis and osteoarthritis.

Overproduction of cytokines such as TNF in diseases such as bacterial, fungal or viral infections or cancer results in cachexia and muscle wasting. The compounds of the invention ameliorate these symptoms and, consequently, the quality of life.

Furthermore, the compounds of the invention increase cAMP in specific areas of the brain, thereby preventing depression and memory deficits.

The compounds of the present invention inhibit cell proliferation in specific tumor cells and can therefore be used to prevent tumor growth or normal tissue invasion.

The compound of the present invention can be administered as a pharmaceutical composition for preventing or treating a disease. The invention provides, according to another aspect, a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.

In any of the above treatments, the compound of formula I may be administered orally, topically, parenterally, in a unit dosage form containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
It may be given by enteral administration or by inhalation spray. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection or digestion methods. The compounds of the present invention are effective for treating humans in addition to treating warm-blooded animals such as mice, rats, horses, cows, sheep, dogs and cats.

The pharmaceutical composition containing the active ingredient is, for example, oral tablets such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. It may be in a dosage form suitable for administration. The composition for oral administration may be manufactured according to any method for manufacturing a pharmaceutical composition known in the art. Such a composition has a sweetening agent, a corrigent and
1 selected from the group consisting of flavoring agents, coloring agents and preservatives
It may include more than one substance. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin. Or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated according to known methods to delay disintegration and absorption in the gastrointestinal tract and to prolong the action over an extended period of time. For example, an aging substance such as glyceryl monostearate or glyceryl distearate may be used. The tablets may be coated according to the methods described in US Pat. Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Oral formulations are prepared by mixing the active ingredient with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a hard gelatin capsule, or by mixing the active ingredient with water or an oil medium such as peanut oil, liquid paraffin or olive oil. It can also be presented as a soft gelatin capsule mixed with.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose,
Methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; the dispersant or wetting agent is a natural phosphatide (eg lecithin),
Condensates of alkylene oxides and fatty acids (eg polyoxyethylene stearate), condensates of ethylene oxide and long chain aliphatic alcohols (eg heptadecaethylene-oxycetanol), or ethylene oxide and partial esters derived from fatty acids and hexitols. Condensate of (eg polyoxyethylene sorbitol monooleate)
Alternatively, it may be a condensate of ethylene oxide with a fatty acid and a partial ester derived from hexitol anhydride (eg polyethylene sorbitan monooleate). Aqueous suspensions further include one or more preservatives such as ethyl, n-
It may contain propyl or p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (for example, peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (for example, liquid paraffin). The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. A delicious oral preparation can be obtained by adding the above-mentioned sweetening agent and taste-masking / flavoring agent. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for the addition of water to prepare an aqueous suspension include the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. In addition, excipients such as sweetening agents, flavoring agents and coloring agents may be added.

The pharmaceutical composition of the present invention may be in the form of oil-in-water emulsion. The oily phase may be a vegetable oil (eg olive oil or peanut oil) or a mineral oil (eg liquid paraffin), or mixtures thereof. Suitable emulsifiers include natural phosphatides (eg soybean and lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (eg sorbitan monooleate), and condensates of said partial esters with ethylene oxide (eg polyoxyethylene). Ethylene sorbitan monooleate). The emulsion may further contain sweetening and flavoring agents.

Syrups and elixirs include sweetening agents, for example
Glycerol, propylene glycol, sorbitol or sucrose may be included. Such formulations may additionally contain a demulcent, a preservative, flavoring and coloring agents. The pharmaceutical compositions of the invention may be in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Sterile injectable formulations include, for example, 1,3-
It may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fatty oils are conventionally used as solvents or suspending media. For this purpose any bland fatty oil may be used including synthetic mono- or diglycerides. Fatty acids such as oleic acid are also used in the production of injectables.

The compounds of formula I can also be administered in the form of suppositories for rectal administration of the drug. These compositions provide the drug
It is solid at room temperature but liquid at intestinal temperature and therefore may be prepared by mixing with a suitable non-irritating excipient that melts in the rectum and releases the drug. Such substances are cocoa butter and polyethylene glycol.

For topical administration, creams, ointments, jellies, solutions or suspensions containing the compound of formula I are used. (Topical formulations include mouthwashes and mouthwashes for this purpose.) Treatment of the above conditions is about 0.0 per kg of body weight per day.
1 to about 140 mg, or about 0 per patient per day.
Dosage levels of 5 mg to about 7 g are useful. For example, inflammation is about 0.01-50 mg of compound per kg of body weight per day,
Alternatively, about 0.5 mg to about 3.5 g per patient per day
Can be effectively treated by administering a compound of

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. For example, an oral formulation for humans may contain from 0.5 mg to 5 g of active ingredient combined with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total composition.
Unit dosage forms are generally about 1 to about 500 mg, typically 25 m
g, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600m
Contains g, 800 mg or 1,000 mg of active ingredient.

However, a particular dosage level for a particular patient is
Subject to various factors including age, weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination and severity of the particular disease being treated It will be understood.

Synthetic Methods The compounds of the present invention are disclosed in WO94 / 14742 published Jul. 7, 1994.
Or WO95 / 17386 published June 29, 1995 (both of which are incorporated herein by reference) or the methods described below. Using a similar method,
It will be apparent to those skilled in the art that it is possible to prepare enantiomers or racemates of the exemplified compounds.

Chemical Scheme 1 A carboxylic acid derivative was prepared according to the method shown in Scheme 1. Appropriate Bromoaryl-1,3-dioxolane derived Grignard reagents were added diastereoselectively to the acylsultam Michael acceptor II to give the triarylpropanoylsultam intermediate. Then
Sequential treatment with a suitable lithium thiolate, saponification with aqueous hydroxide, followed by aqueous acidic treatment to remove chiral auxiliaries followed by decarboxylation and aldehyde depletion in a one-pot process. Protected. In this way, a carboxaldehyde intermediate was obtained. The intermediate was oxidized with sodium chlorite to give carboxylic acid intermediates 1 and 2. Acids 1 and 2 were treated with sulfonamides in the presence of the appropriate carbodiimide and 4-dimethylaminopyridine to prepare acyl sulfonamides.

Scheme 2 Scheme 2 shows a method for producing a (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) arene derivative. The appropriate dihaloarene was monolithiated, then hexafluoroacetone was added to give the corresponding bis (trifluoromethyl) carbinol intermediate, which was then protected as its trimethylsilylethoxymethyl ether. The Grignard reagent derived from the intermediate was diastereoselectively added to the acylsultam Michael receptor II to give the trialalpropanoylsultam intermediate. Successive treatments with the appropriate lithium thiolate, saponification with aqueous hydroxide and then aqueous acidic treatment were then carried out to remove the chiral complement and then decarboxylate in a one-pot procedure. Finally, it is treated with tetrabutylammonium fluoride to deprotect the tertiary alcohol, and the desired (1,1,1,3,3,3-hexafluoro-2-
A hydroxypropan-2-yl) arene derivative was obtained.

Scheme 3 The arene sulfonamide derivatives were prepared according to the method shown in Scheme 3. Suitable arene carboxaldehyde and diphenyl di-1-chloro-1- (heteroaryl) methanephosphonate (J.Org.Chem., 1992,57,1622)
Was condensed with and the corresponding diaryl alkyne was obtained. Acid-catalyzed addition of hydrogen iodide followed by palladium-catalyzed stannylation afforded the vinyltin intermediate. The intermediate was coupled with N, N-bis- (p-methoxybenzyl) -4-bromobenzenesulfonamide by palladium catalysis to give the corresponding triarylethylene derivative. Sodium borohydride and nickel chloride (I
I) reacting with hexahydrate to reduce the double bond, then
The sulfonamide moiety was deprotected by treatment with trifluoroacetic acid to give a benzenesulfonamide intermediate. The intermediate was reacted with a carboxylic acid in the presence of the appropriate carbodiimide and 4-dimethylaminopyridine to give the acylbenzenesulfonamide intermediate.

The compounds of Schemes 4-6 were prepared as racemic mixtures as described below.

Scheme 4 Using DMF as a solvent in the presence of potassium carbonate, 85
Coupling of 3,4-dihydroxybenzaldehyde with chlorodifluoromethane at [deg.] C gave 3,4-bis- (difluoromethoxy) benzaldehyde X. this,
Condensation with the lithium anion of protected 4-bromohenylbis-trifluoromethylcarbinol Xa of Example 7 afforded the tertiary alcohol XI, which was thionyl chloride in the presence of Hunig's base in toluene solution. Was converted to the corresponding chloride XII using. The chloride XII is condensed with the a-anion of ethyl 4-pyridylacetate to give an intermediate ester derivative.
XIII was obtained, which was hydrolyzed with lithium hydroxide in THF-methanol-water medium and then acidified with aqueous ammonium chloride to give decarboxylated intermediate XIV. T
The TBEM in HF was used to remove the SEM protecting group and the final compound XV
Got

Scheme 5 Compound XV was oxidized with m-chloroperoxybenzoic acid to give N-oxide XVI.

Scheme 6 A 3,4-dichloropyridine analog was prepared as follows: Chloride XII was condensed with the lithium anion of 3,4-dichloropicoline produced using LDA to give intermediate XVII in THF solution. The SEM protecting group was removed using TBAF in to give the final product XVIII.

Representative compounds are shown in Tables 1-3.

Physiological activity quantitative assay Establishment of CHO-K1 cell line stably expressing PDE IVa enzyme CHO stably expressing prostacyclin receptor
-K1 cells were previously described (Y. Boie et al., J. Biol. Chem .: 269,12.
173-12178, 1994) and grown under G418 selection to give 1.7
Α-MEM medium at a density of 5 × 10 ⁶ cells / 175 cm ² , 10% heat-inactivated fetal bovine serum (FBS); 1% (v / v) penicillin / streptomycin; 25 mM Hepes, pH 7.4; and 500 μg / ml G418
T-175 flask containing (complete medium) (Gibco, Burli
ngton, YT). Cells were maintained in an incubator for 24 hours at 37 ° C., 5% CO ₂ . The cells were then washed with warm sterile sterile phosphate buffered saline (PBS), 2 μg / ml
DNA, and 9 μg / ml Lipofectamine reagent in Opti-MEM were incubated at 37 ° C., 5% CO ₂ for 7 hours. Incubate the solution with Opti-M containing 20% FBS.
Diluted 1: 2 with EM and incubated overnight. After overnight incubation, the medium was replaced with complete medium containing 500 μg / ml hygromycin B. Colonies were identified and grown in T-175 flasks for further characterization.

Measurement of total cell cAMP content CHO-K1 cells were cultured in complete medium containing 500 μg / ml hygromycin at a density of 10 ⁶ cells / 175 cm ² . The flask was kept in an incubator at 37 ° C. and 5.0% CO ₂ for 72 hours. The medium was changed and the cells were grown overnight. Cells were washed and detached from plates with PBS containing 0.5 mM EDTA.
The cell suspension was centrifuged at 150 g × 10 minutes to measure the cAMP content of the cells. The cells were then resuspended in Hank's buffered salt solution at a density of 0.2 × 10 ⁶ cells / ml. Cells at room temperature 15
It was preincubated for 10 minutes and then incubated with 10 μM prostaglandin I ₂ (PGI ₂ ) and the indicator compound for a further 10 minutes. Basal cAMP levels were quantified by incubating cells in 0.1% DMSO. HCl (final concentration
The incubation was stopped by the addition of 0.1 N) and the cells were measured for cAMP as described below.

18 in ScintiStrip ^™ wells (final volume 300 μl) at room temperature
Time, reconstituted rabbit anti-succinyl cAMP serum (100 μ
l) is a whole cell reaction product or a known cAMP standard solution (100 μl)
And incubated with ¹²⁵ I-cAMP TME (30 pmol) to quantify total cell cAMP content. Total cpm (B ₀ ) was quantified in the absence of cAMP standard solution sample. The reaction mixture was then aspirated from the wells and individual wells were counted in a Beckman LS 600SC with windows open for 10-999 minutes.
Data are% B / B ₀ = [(standard or sample cpm-nonspecific c
pm) / (B ₀ cpm-nonspecific cpm)] × 100. S
Non-specific cpm were quantified in cintiStrip ^™ wells by incubating only ¹²⁵ I-cAMP TME with assay buffer (50 nM acetate; pH 5.8). The quantification was performed 3 times in each case.

Hosphodiesterase Scintillation Proximity Assea
y) 50% in ice-cold solution containing 50 mM Tris, pH 7.5; 1 mM EDTA; and 200 μM b-mercaptoethanol (Braunsonic
Model 2000) sonicated for 10 seconds at CHO-K
1 dissolved. Sonicate strips at 4 ° C for 90 minutes at 100,0
Centrifugation at 00 × g gave a soluble granular fraction of cells.
50 mM Tris, pH 7.5; 10 mM in the presence of varying concentrations of inhibitor
PDE activity was measured in a solution containing MgCl ₂ ; 1 mM EDTA; and 100 nM (or the designated) ³ H-cAMP (final volume 100 μl). The reaction mixture containing the enzyme was added to a 96-well View Plates (Packa
rd) incubated at 30 ° C for 10 min in Phosphodiesterase Scintillation Proximity Assa containing 18 mM ZnSO _4.
The incubation was stopped by adding 50 μl of y (SPA) Beads (Amersham). Plates were counted in a Wallac 1450 mBeta LSC counter to quantify ³ H-cAMP hydrolysis.

Increase in cAMP in leukocytes Intracellular cAMP using human neutrophils or guinea pig eosinophils
The effect of the compounds of the present invention on the was investigated. Human neutrophils were isolated from peripheral blood and incubated with dihydrocytochalasin B and test compound for 10 minutes, then EMLP
I was stimulated by. Guinea pig eosinophils were collected by peritoneal perfusion of animals pretreated by intraperitoneal injection of human serum.
Eosinophils were separated from peritoneal exudates and incubated with isoprenaline and test compound. For both cell types, the suspension was centrifuged after incubation, the cell pellet was resuspended in buffer, boiled for 10 minutes and then subjected to specific radioimmunoassay (DuPont) to measure cAMP.

The most potent compounds described in the examples are 0.
CAMP of neutrophils and / or eosinophils at a concentration of 1 nM to 1 μM
Induced a concentration-dependent increase in

Inhibition of leukocyte function The compounds of the invention were investigated for their effect on superoxide production, chemotaxis, and neutrophil and eosinophil adhesion. Isolated leukocytes were incubated with dihydrocytochalasin B (only for superoxide production) and test compounds before stimulation with EMLP. The most potent compounds in the examples are 0.1 nM-1 μM
At a concentration of 10 μm caused a concentration-dependent inhibition of superoxide formation, chemotaxis and adhesion.

Lipopolysaccharide (LPS) -induced synthesis of tumor necrosis factor (TNF) by human peripheral blood monocytes (PBM) is inhibited by the compounds of the Examples at concentrations of 0.01 nM-10 μM.

Relaxation of contractile airway smooth muscle in vitro The effect of the compounds of the invention on tracheal smooth muscle isolated from guinea pigs was investigated. The isolated airway ring was suspended in an organ bath and immersed in an oxygenated Krebs solution. Smooth muscle was contracted with submaximal concentrations of histamine or carbachol before increasing concentrations of test compound were added to the organ bath. The most potent compounds in the examples at concentrations of 1 nM to 100 μM reversed both histamine and carbachol-induced contraction in a concentration-dependent manner. The compounds are generally more potent in histamine-induced tone than in carbachol-induced tone.

In Vitro Effects on Myocardium The effects of the compounds of the invention on isolated myocardium were tested. The right atrial and papillary muscles are severed from the guinea pig heart to produce a spontaneously beating atribe.
Suspended in an organ bath to measure the (metaperiodic) velocity of a) and the (inotropic) force of the electrically stimulated papillary muscles. In these specimens, selective PDE IV inhibitors such as rolipram have no direct effect, but milrinone (milrin)
Selective PDE III inhibitors such as one) have positive rhythmic and inotropic effects. Theophylline, a non-selective PDE inhibitor used for asthma as a bronchodilator, also causes significant cardiovascular changes such as tachycardia. Therefore, selective PDE IV inhibitors are advantageous over theophylline due to less cardiovascular side effects. The most potent and selective compounds in the examples had no direct effects on atrial and papillary muscles in vitro at concentrations below 10 μM, but the inhibitors were combined with PDE III inhibitors. And increased the rhythm and inotropic activity typical of selective type IV inhibitors.

In vivo anti-inflammatory activity Rat interleukin-5 (IL-5) -induced pleural eosinophils (Lisle et al., 1993, Br.J.Pharmacl. 108 , p. 230)
Is inhibited by the compounds of the Examples administered orally at a dosage of 0.0001-10.0 mg / kg. The most potent compound is
Dose-dependent reduction of eosinophil migration with an ED ₅₀ of 0.003-0.03 mg / kg (oral).

The compounds of the present invention further include platelet activating factor (PAF)
Also reduces the inflammatory response induced in rats.

In Vivo Antiallergic Activity Compounds of the invention were tested for their effect on IgE-mediated allergic lung inflammation induced by inhaling antigen in sensitized guinea pigs. First, guinea pigs were sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression by intraperitoneal injection of antigen in combination with aluminum hydroxide and pertussis vaccine. Two and four weeks later, booster doses of antigen were administered and at six weeks
Challenge was performed with ovalbumin aerosolized under the protection of a histamine drug (mepyramine) administered intraperitoneally. After a further 48 hours, bronchoalveolar (BAL) was washed and
The number of eosinophils and other white blood cells in AL fluid was counted. The lungs were also removed for histological examination of inflammatory damage. Administration of the compounds of the Examples up to three times within 48 hours after antigen challenge [0.001-10 mg / kg (intraperitoneal or oral)] significantly reduced the deposition of eosinophils and other inflammatory leukocytes. Also,
Inflammatory damage to the lungs of animals treated with the compounds of the Examples was also reduced.

Effect on Pulmonary Kinetics Compounds of the invention (0.00 via oral or other routes of administration)
1-10 mg / kg) reduces antigen-induced allergic bronchoconstriction in sensitized guinea pigs.

The compounds of the invention were tested for their effect on the airway ozone-induced hyperreactivity of guinea pigs. After inhaling ozone, guinea pigs are much more sensitive than insensitive animals to the bronchoconstrictor effects of inhaled histamine (Yeadon et al., 1992, Pulmonary Pha.
rm., 5 , 39). There is a significant leftward shift (10-30 fold) in the dose response curve to histamine and a very significant increase in the maximum increase in lung resistance. Compounds of the Examples administered one hour prior to intraperitoneal or oral administration of ozone (0.001-10 mg / kg) caused a dose-dependent inhibition of ozone-induced hyperreactivity.

Adverse Effects The compounds of the present invention show no adverse effects even after repeated overdose in rats and dogs. For example, administration of an excess of 125 mg / kg per day of the active compounds of the Examples to the rats for 30 days does not cause harmful toxicity.

The most potent compounds of the invention are 20-30 times less active than rolipram in inducing behavioral modulation, sedation or emesis in rats, ferrets or dogs.

SPA-based PDE activity assay protocol for type IV cAMP-specific phosphodiesterase for cAMP
Compounds that inhibit the hydrolysis to AMP are
Screened in well plate format: 96 well plate at 30 ° C. with test compound (2 μl
Those dissolved in DMSO), [2,8- ³ H] adenosine 3 ',
5'-cyclic phosphate (cAMP, 100nM-50μ
M), 10 mM MgCl ₂ , 1 mM EDTA, 50 mM Tris, pH 7.5, 188 ml of substrate buffer was added. 10 ml human recombinant PDE
The reaction was initiated by the addition of -IV (adjusted volume to form ~ 10% product in 10 minutes at 30 ° C). 10 minutes later, 1 mg
The reaction was stopped by adding PDE-SPA beads (Amersham). The generated AMP was quantified with a Microbeta 96 well plate counter. The signal in the absence of enzyme was defined as background. The signal detected in the presence of enzyme and DMSO minus background was 10
It was defined as 0% activity. Percentage inhibition was calculated accordingly. 1
IC ₅₀ values were predicted from 0-point titers by non-linear regression fit of the standard 4-parameter / multiple binding site equation.

Purified GS of human recombinant phosphodiesterase IVa (met-248) produced from baculovirus / Sf-9 expression system
The IC ₅₀ values shown in Table 4 for 100 nM cAMP were quantified using the T fusion protein.

The invention is illustrated by the following non-limiting examples. In the examples, unless otherwise indicated: (i) All operations are at room or ambient temperature, ie 18-25
It was carried out at temperatures in the range of ° C; evaporation of the solvent was carried out under reduced pressure (600
~ 4000 pascals: 4.5-30 mmHg) using a rotary evaporator under a bath temperature of 60 ℃ or less; the reaction progress was followed by thin layer chromatography (TLC), the reaction time is for illustration only. Shown; melting points are uncalibrated, "d" indicates decomposition; melting points shown are
Obtained for materials prepared as described; polymorphism may be due to isolation of materials with different melting points in several preparations; structure and purity of all final products
Confirmed using one or more of C, mass spectroscopy, nuclear magnetic resonance (NMR) analysis or microanalysis data; yields are shown for illustration only; when NMR data is shown , The data are given in ppm for tetramethylsilane (TMS) as an internal standard, using the indicated solvents.
It is in the form of delta (δ) values of the major diagnostic protons quantified at 300MHz or 400MHz; the conventional abbreviations used for signal shape are: s = singlet, d = doublet, t = triplet, m = multiple lines, br = wide width, etc .; also “Ar”
Represents an aromatic signal; the chemical symbols have their usual meanings; the following abbreviations: v (volume), w (weight), b.
p. (boiling point), mp (melting point), L (liter), ml (milliliter), g (gram), mg (milligram), mol
(Mole), mmol (mmol), eq (equivalent) are also used.

  The following abbreviations have the indicated meanings: Ac = acetyl Bn = benzyl cAMP = cyclic adenosine-3 ', 5'-monophosphate DBU = 1,8-diazabicyclo [5.4.0] undec-7-d
The DIBAL = diisobutyl aluminum hydride DMAP = 4- (dimethylamino) pyridine DMF = N, N-dimethylformamide Et₃N = triethylamine GST = glutathione transferase LDA = lithium diisopropylamide m-CPBA = metachloroperbenzoic acid MMPP = monoperoxyphthalic acid MPPM = monoperoxyphthalic acid magnesium salt 6H₂O Ms = methanesulfonyl = mesyl = SO₂Me Ms0 = methanesulfonate = mesylate NSAID = non-steroidal anti-inflammatory drug o-Tol = o-tolyl OXONE = 2KHSO_Five・ KHSO_Four・ K₂SO_Four PCC = pyridinium chlorochromate PDC = pyridinium dichromate PDE = phosphodiesterase Ph = phenyl Phe = benzenediyl PMB = p-methoxybenzyl Pye = Pyridindiyl r.t. = room temperature rac. = racemic compound SAM = aminosulfonyl or sulfonamide or SO₂NH₂ SEM = 2- (trimethylsilyl) ethoxymethoxy SPA = scintillation proximity assay TBAF = tetra-n-butylammonium fluoride Th = 2- or 3-thienyl TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran Thi = thiophenediyl TLC = thin layer chromatography TMS-CN = trimethylsilyl cyanide Tz = 1H (or 2) -tetrazol-5-yl C₃H_Five= Allyl.

Abbreviation of alkyl group Me = methyl Et = ethyl n-Pr = positive propyl i-Pr = isopropyl n-Bu = positive butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr = cyclopropyl c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl.

Example 1 N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} methanesulfonamide CH ₂ Cl ₂ (3 ml). Carboxylic acid intermediate 1 (100mg, 0.24m
mol), methanesulfonamide (27 mg, 0.29 mmol), 1-
A solution of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (35 mg, 0.29 mmol) was added at room temperature to 1
It was stirred for 9 hours. Then glacial acetic acid (0.2 ml) was added, and after 10 minutes, CH ₂ Cl ₂ was added. The organic phase of 25% aqueous NH ₄ OAc, water and brine, dried (MgSO _4), and concentrated. Column chromatography of the residue on silica (CH ₂ Cl ₂ / MeOH 9
2: 8) and the title compound (63m
g, 53%) was obtained. ¹ H NMR (400 MHz, acetone-d ₆ ): δ1.55 (m, 2H), 1.7
5 (m, 6H), 2.95 (wide s, 3H), 3.40 (d, 2H), 3.70 (s, 3
H), 4.40 (t, 1H), 4.75 (m, 1H), 6.80 (m, 2H), 6.90
(S, 1H), 7.15 (d, 2H), 7.35 (d, 2H), 7.95 (d, 2H), 8.
35 (d, 2H).

Example 2 N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} benzenesulfonamide According to the procedure described in Example 1, However, methanesulfonamide was replaced with benzenesulfonamide to obtain the title compound (79%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ): δ1.55 (m, 2H), 1.7
0 (m, 6H), 3.40 (d, 2H), 3.70 (s, 3H), 4.40 (t, 1H),
4.75 (m, 1H), 6.80 (s, 2H), 6.90 (s, 1H), 7.15 (d, 2
H), 7.25-7.45 (m, 5H), 7.95 (m, 4H), 8.35 (d, 2H).

Example 3 N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} trifluoromethanesulfonamide Following the procedure described in Example 1. However, the methanesulfonamide was replaced with trifluoromethanesulfonamide to obtain the title compound (68%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ): δ1.55 (m, 2H), 1.7
0 (m, 6H), 3.40 (d, 2H), 3.70 (s, 3H), 4.40 (t, 1H),
4.75 (m, 1H), 6.80 (s, 2H), 6.90 (s, 1H), 7.15 (d, 2
H), 7.35 (d, 2H), 8.00 (d, 2H), 8.35 (d, 2H).

Example 4 N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} o-toluenesulfonamide The procedure described in Example 1. Following, but substituting o-toluenesulfonamide for methanesulfonamide, the title compound (83%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ1.50-1.70 (m, 6H),
1.80 (m, 2H), 2.55 (s, 3H), 3.40 (d, 2H), 3.65 (s, 3
H), 4.40 (t, 1H), 4.70 (m, 1H), 6.80 (s, 2H), 6.90
(S, 1H), 7.20 (d, 2H), 7.30-7.45 (m, 4H), 7.55 (t, 1
H), 7.75 (d, 2H), 8.00 (d, 1H), 8.35 (d, 2H).

Example 5 N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetyl} benzenesulfonamide Following the procedure described in Example 1. However, the carboxylic acid intermediate 1 was replaced with the carboxylic acid intermediate 2, and the methanesulfonamide was replaced with benzenesulfonamide to obtain the title compound (43%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ): δ1.50-1.62 (m, 2
H), 1.63-1.87 (m, 6H), 3.37 (d, 2H), 3.57 (s, 2H),
3.70 (s, 3H), 4.31 (t, J = 8Hz, 1H), 4.74 (m, 1H), 6.78
(M, 2H), 6.88 (s, 1H), 7.07 (d, J = 8Hz, 2H), 7.13 (d,
J = 6Hz, 2H), 7.25 (d, J = 8Hz, 2H), 7.54 (m, 2H), 7.66
(M, 1H), 7.94 (d, J = 7Hz, 2H), 8.33 (d, J = 6Hz, 2H).

Example 6 N-{(R) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetyl} trifluoromethanesulfonamide According to the procedure of Example 1, However, the carboxylic acid intermediate 1 was replaced with the carboxylic acid intermediate 2, and the methanesulfonamide was replaced with trifluoromethanesulfonamide to obtain the title compound (80%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ1.51-1.63 (m, 2
H), 1.64-1.90 (m, 6H), 3.39 (m, 4H), 3.70 (s, 3H),
4.30 (t, 1H), 4.76 (m, 1H), 6.79 (m, 2H), 6.92 (s, 1
H), 7.15 (m, 4H), 7.25 (d, J = 8Hz, 2H), 8.33 (m, 2
H).

Example 7 (R) -4- {2- (3-cyclopentyloxy-4-)
Methoxyphenyl) -2- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl] ethyl} pyridine Step 1: 2- (4-bromophenyl) -1,1,1,3,3,3-
Hexafluoro-2-propanol n-butyllithium (2.4 M solution in hexane; 92.7 ml, 0.
222 mol) was added dropwise (20 min) to a solution of p-dibromobenzene (50.0 g, 0.212 mol) in Et ₂ O (1.2 L) at -60 ° C. After the addition was complete, the reaction mixture was left at -50 ° C for 30 minutes,
Hexafluoroacetone (4
2.2 g, 0.254 mol) was blown in. The resulting solution was warmed to −30 ° C. over 30 minutes and then saturated aqueous NH ₄ Cl was added. The aqueous layer was extracted twice with EtOAc and the combined organic extracts were 25%
It was washed successively with aqueous NH ₄ Cl buffer, water and brine, dried (MgSO ₄ ) and concentrated. Vacuum distillation of the residue (bp 85-90
℃ / 12mmHg), and the title compound (53.5
g, 78%) was obtained.

Step 2: 2- (4-Bromophenyl) -2- [2-
(Trimethylsilyl) ethoxymethoxy] -1,1,1,3,3,
A solution of 2- (trimethylsilyl) ethoxymethyl chloride (25.9 g, 0.155 mol) in 3-hexafluoropropane CH ₂ Cl ₂ (50 ml) was added to CH ₂ Cl ₂
To a solution of the product of step 1 2- (4-bromophenyl) -1,1,1,3,3,3-hexafluoro-2-propanol (38.6g, 0.120mol) in (500ml) at 0 ° C. Dropped. After the addition was complete, warm the mixture to room temperature and stir for 3 hours before adding CH
Diluted with Cl ₃ (500 ml). The obtained solution is 1N HCl
(2 times), saturated aqueous NaHCO ₃ , water and brine successively, dried (Na ₂ SO ₄ ) and concentrated. Distill the residue under vacuum (bp
128 ° C./0.9 mmHg) to give the title compound (50.0 g, 92%) as a colorless liquid.

Step 3: (1R, 5S) -N-{(3R) -3- (3-cyclopentyloxy-4-methoxyphenyl) -3- [4
-(2- (2- (trimethylsilyl) ethoxymethoxy) -1,1,1,3,3,3-hexafluoropropan-2-yl) phenyl] -2- (4-pyridyl) propanoyl}
-10,10-Dimethyl-3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane-3,3-dioxide The product of Step 2 2- (4-bromophenyl) -2 in THF (15 ml). A solution of-[2- (trimethylsilyl) ethoxymethoxy] -1,1,1,3,3,3-hexafluoropropane (30.4g, 67.1mmol) was added to magnesium shavings in THF (40ml) (1.71g, 70.4 mmol). After adding a few iodine crystals and stirring the mixture at reflux temperature for 1 hour,
Acyl sultam I ^aa (12.0 g, 22.4 mmo in THF (200 ml)
The solution of l) was added dropwise at 0 ° C. The reaction mixture was stirred for 16 hours at room temperature and quenched by addition of saturated aqueous NH ₄ Cl. The organic phase was concentrated, diluted with EtOAc and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were, 25% aqueous NH ₄ OAc buffer, water and successively washed with brine, dried (MgSO _4), and evaporated. The residue was recrystallized in EtOH and further purified by column chromatography on silica (acetone / CHCl ₃ 5:95) to give the primary product of the title compound as a white solid. The EtOH filtrate was concentrated and purified by successive column chromatography (Id.) And recrystallization (EtOH) to give a secondary product, giving a total mass of 9.48 g (46%).

Step 4: (R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (2- (2
-(Trimethylsilyl) ethoxymethoxy) -1,1,1,3,
3,3-hexafluoropropan-2-yl) phenyl]
Ethyl} pyridine n-butyllithium (2.4M solution in hexane; 7.76 ml, 1
8.6 mmol) was added dropwise to a solution of 1-propanethiol (2.06 ml, 22.8 mmol) in THF (100 ml) at 0 ° C. After 1.5 hours the product of step 3 (1R, 5S) -N in THF (25 ml)
-{(3R) -3- (3-Cyclopentyloxy-4-methoxyphenyl) -3- [4- (2- (2- (trimethylsilyl) ethoxymethoxy) -11,1,3,3,3-hexafluoro Propan-2-yl) phenyl] -2- (4-pyridyl) propanoyl} -10,10-dimethyl-3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane-3,3-dioxide (9.43 g , 10.4 mmol) solution was added dropwise at 0 ° C. and the reaction mixture was stirred at room temperature for 3 hours. Then 25% aqueous NH
_The reaction was quenched by the addition of ₄ OAc buffer. EtOA aqueous layer
Extracted twice with c and the combined organic extracts were extracted with 25% aqueous NH ₄ OA.
c buffer and successively washed with brine, dried (MgSO _4), and concentrated. The residue was dissolved in EtOH (170 ml) and water (57 ml), lithium hydroxide monohydrate (2.20 g, 52.0 mmol) was added and the mixture was heated to reflux for 2.5 hours. After cooling the reaction mixture to room temperature, AcOH (3.56 ml, 62.1 mmol) was added. 3
After 0 minutes, 25% aqueous NH ₄ OAc buffer was added and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with 25% aqueous NH ₄ OAc.
Buffer and successively washed with brine, dried (MgSO _4), and concentrated. The residue was purified by column chromatography on silica (EtOAc / hexane 1: 1) to give the title compound (4.08g, 58%) as a colorless gum.

Step 5: (R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (1,1,1,3,
3,3-hexafluoro-2-hydroxypropane-2-
Ill) phenyl] ethyl} pyridine tetrabutylammonium fluoride (1.0M solution in THF; 3
0.4 ml, 30.4 mmol) was added to the product of step 4 (R) -4- {2- (3-cyclopentyloxy-) in THF (50 ml).
4-methoxyphenyl) -2- [4- (2- (2- (trimethylsilyl) ethoxymethoxy) -1,1,1,3,3,3-
Hexafluoropropan-2-yl) phenyl] ethyl} pyridine (4.08 g, 6.09 mmol) was added dropwise at room temperature, and the resulting solution was heated to reflux temperature for 2.5 hours, cooled, and
5% aqueous NH ₄ OAc buffer was added. The aqueous layer was extracted 3 times with EtOAc and the combined organic extracts were extracted with 25% aqueous NH ₄ OAc buffer,
Successively washed with water and brine, dried (MgSO _4), and concentrated. Column chromatography of the residue on silica (Et
Purify over OAc / Hexane 1: 1) to give a white solid,
This was triturated with 1: 4 Et ₂ O / hexane to give the title compound (2.87 g, 87%). ¹ H NMR (400 MHz, acetone-d ₆ ) δ1.50-1.62 (m, 2
H), 1.63-1.88 (m, 6H), 3.44 (m, 2H), 3.71 (s, 3H),
4.43 (t, J = 8Hz, 1H), 4.75 (m, 1H), 6.81 (m, 2H), 6.89
(S, 1H), 7.14 (d, J = 6Hz, 2H), 7.44 (s, 1H), 7.51 (d,
J = 8Hz, 2H), 7.67 (d, J = 8Hz, 2H), 8.33 (d, J = 6Hz, 2
H).

Example 8 N- (o-toluoyl) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzenesulfonamide Step 1: (3-Cyclopentyloxy-4 -Methoxyphenyl) (4-pyridyl) acetylene 3-Cyclopentyloxy-4-methoxybenzaldehyde (6.07g, 27.6mmol) and 1-chloro-1- (4-pyridyl) methanephosphonate diphenyl (J) in dioxane (150ml). .Org.Chem., 1992,57,1622) (9.03g, 52.1
mmol) in a suspension of potassium t-butoxide (7.03 g, 6
2.8 mmol) was added in small portions. The mixture was stirred at room temperature for 1 hour and then refluxed. After 3.5 hours, 7 g of potassium t-butoxide was further added, and the reflux was continued for 18 hours. After cooling, the mixture was diluted with water (1 L) and extracted 3 times with EtOAc. The extracts are washed 3 times with water, dried, evaporated and the residue is chromatographed on silica gel (EtOAc / hexane).
Purification by 1: 2) gave the title acetylene (4.72 g, 64%) as a cream colored solid.

Step 2: 1- (3-Cyclopentyloxy-4-methoxyphenyl) -1-iodo-2- (4-pyridyl) ethylene A solution of the acetylene of Step 1 (8.79 g, 30 mmol) in dichloromethane (600 ml) at room temperature. At that time, a solid mixture of sodium iodide (18 g, 120 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol) was added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with aqueous 1N NaOH (600 ml) and stirred vigorously for 15 minutes. The organic phase was collected, washed 3 times with water, dried, evaporated and the residue was stirred in a 2: 1 mixture of hexane and ether (100 ml) for 2 hours, filtered and obtained as a light brown solid. Vinyl iodide (8.46g, 67
%), Which was assayed by NMR and found to be a 4: 1 mixture of Z and E isomers.

Step 3: 1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) -1- (trimethylstannyl) ethylene vinyl iodide (1.
9g, 4.5mmol) and hexamethylditin (2.15g, 6.6mmol)
The mixture was placed under N ₂ atmosphere. Tetrakis (triphenylphosphine) palladium (0) (180mg, 0.12mmol)
Was added and the mixture was heated at 90 ° C. for 18 hours. After cooling, the mixture was diluted with EtOAc, washed 3 times with water, dried and evaporated. The crude product was chromatographed on silica gel (hexane / EtOAc 1: 1) to give the title vinylstannane (1.28 g, 62%) as a thick syrup which was assayed by NMR to determine the Z and E isomers. It was found to be a 10: 1 mixture of.

Step 4: N, N-bis- (p-methoxybenzyl) -4
-[1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethenyl] benzenesulfonamide 1,3-dioxane (15 ml) vinyltin intermediate of step 3 (2.03 g, 4.4 mmol) ), N, N-bis- (p-methoxybenzyl) -4-bromobenzenesulfonamide (1.
A solution of 30 g, 2.7 mmol), tetrakis (triphenylphosphine) palladium (0) (0.26 g, 0.22 mmol) and lithium chloride (0.8 g, 19 mml) was refluxed for 5 days. Then EtOAc was added and the organic phase was washed with 25% aqueous NH ₄ OAc buffer,
Successively washed with water and brine, dried (MgSO _4), and concentrated. The residue was purified by flash chromatography (silica gel, hexane / EtOAc 65: 35 → 40: 60),
The title compound (0.81 g, 43%) was obtained as a yellow solid.

Step 5: N, N-bis- (p-methoxybenzyl) -4
-[1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzenesulfonamide alkene of step 4 (452 mg, 0.65 mmol) in MeOH (4 ml) and THF (2 ml) and Sodium borohydride (80 mg, 2.1 mmol) was added in small portions to a 0 ° C. solution of nickel (II) chloride hexahydrate (30 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 70 minutes, then cooled to 0 ° C. and additional portions of nickel (II) chloride hexahydrate (75 mg, 0.32 mmol) and sodium borohydride (60 mg, 1.6 mmol) were added. After 18 hours at room temperature, further sodium borohydride (5 x 50 mg, 6.6 mmol)
Was added over 6 hours to completely convert the starting material.
The reaction mixture was then filtered through Celite, the cake washed with MeOH and the filtrate evaporated. The residue was dissolved in EtOAc, the organic phase, 25% aqueous NH ₄ OAc buffer, water and successively washed with brine, dried (MgSO _4), and concentrated. Flash chromatography of the residue (silica gel, hexane
/ EtOAc 40: 60 → 25: 75) to give the title compound (236 mg, 52%) as a colorless gum.

Step 6: 4- [1- (3-cyclopentyloxy-4
-Methoxyphenyl) -2- (4-pyridyl) ethyl]
Trifluoroacetic acid (0.5 ml) was added to a 0 ° C. solution of the protected sulfonamide of Step 5 in benzenesulfonamide CH ₂ Cl ₂ (3 ml) and the reaction mixture was stirred at room temperature for 24 hours. Then EtOAc was added and the organic phase was washed successively with 25% aq. NH ₄ OAc buffer, water and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc) to give the title compound as an off-white solid (46
mg, 72%) was obtained.

Step 7: N- (o-toluoyl) -4- [1- (3-
Cyclopentyloxy-4-methoxyphenyl) -2-
(4-Pyridyl) ethyl] benzenesulfonamide Example 9 4- {2- (3,4-difluoromethoxy) phenyl-2
-[4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl] ethyl} pyridine Step 1: 3,4-bis (difluoromethoxy) benzaldehyde N, N -A suspension of 3,4-dihydroxybenzaldehyde (6.9g, 50mmol) and potassium carbonate powder (13.8g, 100mmol) in dimethylformamide (400ml) was cooled to -45 ° C. The mixture was bubbled with chlorodifluoromethane until 19 g had dissolved (219 mmol). Attach a dry ice cooler and gradually raise the temperature to 85 ° C for 16 hours
Maintained at 0 ° C. After cooling to room temperature, the mixture is washed with water (600 m
Carefully diluted with l), extracted 4 times with ether, washed the extract 3 times with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with a 1: 3 mixture of ethyl acetate and hexane to give the desired product (4.7g, 39.5%) as a colorless liquid. ¹ H NMR (400MHz, acetone-d ₆ ) δ 7.13 (t, large J, 1
H), 7.20 (t, large J, 1H), 7.58 (d, 1H), 7.87 (s, 1
H), 7.93 (d, 1H), 10.04 (s, 1H).

Step 2: [3,4-bis (difluoromethoxy) phenyl]-{4- [2- (2-trimethylsilylethoxy)]
Methoxy] -1,1,1,3,3,3-hexafluoropropane-
2-ylphenyl} methanol The product of step 2 of Example 2-in THF (15 ml) 2-
To a solution of (4-bromophenyl) -2- [2- (trimethylsilyl) ethoxymethoxy] -1,1,1,3,3,3-hexafluoropropane (2.44g, 5.4mmol) at -78 ° C. N-Butyllithium in hexane (1.25M; 4ml, 5mmol) was added and the resulting solution was kept at -78 ° C for 20 minutes. This solution was added via cannula to a solution of the product of Step 1, 3,4-bis (difluoromethoxy) benzaldehyde (1.31 g, 5.5 mmol) in THF (10 ml). The resulting yellow solution was stirred at -78 ° C for 1 hour, then quenched by the addition of saturated aqueous ammonium chloride, warmed and partitioned between ether and water. The crude organic product was chromatographed on silica gel eluting with a 1:19 mixture of ethyl acetate and toluene to give the desired secondary alcohol (1.86g, 55%) as a colorless syrup. ¹ H NMR (400 MHz, acetone-d ₆ ) δ0.05 (s, 9H), 0.98
(T, 2H), 3.86 (t, 2H), 4.93 (s, 2H), 5.28 (d, 1H, O
H), 5.95 (d, 1H), 6.92 (t, large J, 1H), 6.96 (t, large J, 1H), 7.30 (d, 1H), 7.36 (d, 1H), 7.50 (s, 1H) , 7.
64 (s, 4H).

Step 3: [3,4-bis (difluoromethoxy) phenyl]-{4- [2- (2-trimethylsilylethoxy)]
Methoxy] -1,1,1,3,3,3-hexafluoropropane-
2-ylphenyl} chloromethane To a solution of the secondary alcohol from step 2 (918 mg, 1.5 mmol) and N, N-diisopropylethylamine (275 mg, 1.65 mmol) in toluene (15 ml) thionyl chloride (357 mg,
3 mmol) was added. The mixture was stirred at room temperature for 1 hour, concentrated and chromatographed on silica gel eluting with a 1: 5 mixture of ethyl acetate and hexane to give the desired chloride (762 mg, 81%) as a colorless syrup. ¹ H NMR (400 MHz, acetone-d ₆ ) δ0.05 (s, 9H), 0.98
(T, 2H), 3.86 (t, 2H), 4.94 (s, 2H), 6.55 (s, 1H), 7.
02 (t, large J, 2H), 7.39 (d, 1H), 7.48 (d, 1H), 7.55
(S, 1H), 7.72 (s, 4H).

Step 4: 4- {1-carbetoxy-2- [3,4-bis (difluoromethoxy) phenyl] -2- [4- (2-
(2-Trimethylsilyl) ethoxymethoxy) -1,1,1,
3,3,3-Hexafluoropropan-2-ylphenyl]
Ethyl} pyridine Ethyl 4-pyridine ethyl acetate in THF (8 ml) (236 mg, 1.43
mmol) and hexamethylphosphoramide (256 mg, 1.43 mm
to a solution of 0.85M potassium bis (trimethylsilyl) amide in THF (1.56ml, 1.33mmol) at -78 ° C. The resulting red-orange solution was stirred at -78 ° C for 1 hour,
A cold (-78 ° C) solution of the chloride of step 3 in THF (8ml) was then added via cannula. The mixture was warmed to room temperature and stirred overnight. After quenching by adding saturated aqueous ammonium chloride, the mixture was partitioned between ethyl acetate and water. The crude organic product was used as such in the next step.

Step 5: 4- {2- [3,4-bis (difluoromethoxy) -2- [4- (2- (2-trimethylsilyl) ethoxymethoxy) -1,1,1,3,3,3-hexafluoro Propan-2-ylphenyl] ethyl} pyridine The crude product of Step 4 was treated with lithium hydroxide hydrate (16
The mixture was refluxed for 1.5 hours in a mixture of methanol (10 ml) containing 8 mg, 4 mmol), THF (10 ml) and water (5 ml). After cooling
Saturated aqueous ammonium chloride (25 ml) was added and heated for 20 minutes. The cooled mixture was partitioned between ethyl acetate and water and the crude organic product was chromatographed on silica gel eluting with a 2: 1 mixture of ethyl acetate and hexane to give the desired compound as a colorless syrup (327mg, 50%). Got ¹ H NMR (400 MHz, acetone-d ₆ ) δ0.05 (s, 9H), 0.97
(T, 2H), 3.50 (m, 2H), 3.85 (t, 2H), 4.62 (t, 1H), 4.
89 (s, 2H), 6.91 (t, large J, 2H), 7.16 (d, 2H), 7.25
(D, 1H), 7.33 (d, 1H), 7.40 (s, 1H), 7.55−7.65 (m, 4
H), 8.36 (d, 2H).

Step 6: 4- {2- (3,4-difluoromethoxy) phenyl-2- [4- (1,1,1,3,3,3-hexafluoro-2
-Hydroxypropan-2-yl) phenyl] ethyl}
Pyridine The product of Step 5 above was used as the starting material and the SEM protecting group removal procedure described in Step 5 of Example 7 was used. The title compound was purified by chromatography eluting with a 3: 2 mixture of ethyl acetate and hexanes to give the product as a thick colorless syrup in 82% yield. Titration with ether and hexane gave the title compound as a white solid (mp = 138-140 ° C). ¹ H NMR (400 MHz, acetone-d ₆ ) δ3.50 (d, 2H), 4.61
(T, 1H), 6.92 (t, large J, 2H), 7.18 (d, 2H), 7.24
(D, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 7.51 (s, 1H, O
H), 7.55 (d, 2H), 7.70 (d, 2H), 8.35 (d, 2H).

Example 10 4- {2- (3,4-difluoromethoxy) phenyl-2
-[4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) phenyl] ethyl} pyridine-N-oxide 4- {2- (in dichloromethane (15 ml). 3,4-Difluoromethoxy) phenyl-2- [4- (1,1,1,3,3,3
-Hexafluoro-2-hydroxypropan-2-yl) phenyl] ethyl} pyridine (132 mg),
80-85% (65 mg) of m-chloroperoxybenzoic acid was added and the mixture was stirred at room temperature. After 2 hours, 40 mg of oxidant was added. After 1 hour, calcium hydroxide (1 g) was added and the mixture was stirred for 5 minutes then filtered through a Celite bed. The filtrate was evaporated and the residue was chromatographed on silica gel eluting with a 1: 9 mixture of methanol and dichloromethane to give the title compound (83mg) as a white solid foam. ¹ H NMR (400 MHz, acetone-d ₆ ) δ3.45-3.57 (m, 2
H), 4.59 (t, 1H), 6.91 (t, large J, 1H), 6.94 (t, large J, 1H), 7.18 (d, 2H), 7.30 (d, 1H), 7.33 (d, 1H) , 7.
40 (s, 1H), 7.55 (d, 2H), 7.57 (s, 1H, OH), 7.71 (d, 2
H), 7.92 (d, 1H).

Example 11 3,5-Dichloro-4- {2- (3,4-difluoromethoxy) phenyl-2- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane- 2-yl) phenyl]
Ethyl} pyridine Step 1: 3,5-dichloro-4- {2- [3,4-bis (difluoromethoxy) -2- [4- (2- (2-trimethylsilyl) ethoxymethoxy) -1,1,1 , 3,3,3-Hexafluoropropan-2-ylphenyl] ethyl} pyridine To freshly prepared lithium diisopropylamide (0.3M; 5ml, 1.5mmol) in THF at -78 ° C, THF (5ml). A solution of 3,5-dichloro-4-picoline (295 mg, 1.82 mmol) in was added. The dark yellow solution was stirred at −78 ° C. for 30 minutes and then via cannula, Example A in THF (10 ml).
Chloride (760 mg, 1.21 mmol) from Step 3 of Step (-78
C) solution. The resulting mixture was warmed to room temperature and stirred for 2 days. After quenching by adding saturated aqueous ammonium chloride, the mixture was partitioned between ethyl acetate and water. The organic residue was chromatographed on silica gel eluting with a 1: 5 mixture of ethyl acetate and hexane to give the desired product (32 mg) as a colorless syrup. ¹ H NMR (400 MHz, acetone-d ₆ ) δ0.05 (s, 9H), 0.98
(T, 2H), 3.73 (m, 2H), 3.85 (t, 2H), 4.62 (t, 1H), 4.
90 (s, 2H), 6.93 (t, large J, 1H), 6.95 (t, large J, 1
H), 7.24-7.30 (m, 2H), 7.36 (s, 1H), 7.51 (d, 2H),
7.61 (d, 2H), 8.43 (s, 2H).

  60% of the starting chloride was also recovered.

Step 2: 3,5-dichloro-4- {2- (3,4-difluoromethoxy) phenyl-2- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane- 2-yl) phenyl] ethyl} pyridine Product of step 1 (32 mg, 0.054 mm) in THF (0.8 ml).
ol) was added 1M tetrabutylammonium fluoride in THF (0.27 ml) and the mixture was refluxed for 2 hours. After cooling, the mixture was quenched by addition of saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The crude organic product was chromatographed on silica gel eluting with a 1: 3 mixture of ethyl acetate and hexanes to give the title compound (11 mg) as a thick colorless syrup. ¹ H NMR (400 MHz, acetone-d ₆ ) δ3.68-3.85 (m, 2
H), 4.63 (t, 1H), 6.93 (t, large J, 1H), 6.96 (t, large J, 1H), 7.28 (s, 2H), 7.33 (s, 1H), 7.43 (s, 1H, O
H), 7.51 (d, 2H), 7.72 (d, 2H), 8.43 (s, 2H).

Follow the procedure described in Example 1 except that the carboxylic acid intermediate 1 is replaced with o-toluic acid and the methanesulfonamide is the product of Step 6 4- [1- (3-cyclopentyloxy-4-methoxyphenyl). ) -2- (4-Pyridyl) ethyl] benzenesulfonamide to give the title compound (63%) as a white solid. ¹ H NMR (400 MHz, acetone-d ₆ ) δ1.5-1.6 (m, 2H),
1.65-1.85 (m, 6H), 2.23 (s, 3H), 3.40 (m, 2H), 3.70
(S, 3H), 4.45 (t, 1H), 4.75 (m, 1H), 6.81 (s, 2H), 6.
90 (s, 1H), 7.10-7.20 (m, 4H), 7.30 (t, 1H), 7.50
(M, 3H), 7.95 (d, 2H), 8.30 (d, 2H).

Preparation of Intermediate Intermediate 1: (R) -4- [1- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-pyridyl) ethyl] benzoic acid Step 1: 2- (4-Bromophenyl) -1,3-dioxolane 4-Bromobenzaldehyde (66.5 g, 359 mmol) in benzene (400 ml), ethylene glycol (22 ml, 395 mmo)
A solution of l) and p-toluenesulfonic acid monohydrate (120 mg) was refluxed for 3 hours while capturing water with Dean-Stark. The organic phase was then washed successively with 5% aqueous NaHCO ₃ , water and brine, dried (MgSO ₄ ) and evaporated. The residue was distilled under reduced pressure (bp: 112 ° C / 0.4mmHg) to give the title compound (79.8g, 97%) as a colorless liquid.

Step 2: (1R, 5S) -N-{(3R) -3- (3-cyclopentyloxy-4-methoxyphenyl) -3- [4
-(1,3-Dioxolan-2-yl) phenyl] -2-
(4-Pyridyl) propanoyl} -10,10-dimethyl-
3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane-
THF (40 m) was added to magnesium shavings (6.16 g, 254 mmol) in THF (140 ml) containing 3,3-dioxide 1,2-dibromoethane (0.1 ml).
a solution of the product of step 1 2- (4-bromophenyl) -1,3-dioxolane (55.3 g, 241 mmol) in
Add at a rate sufficient to maintain a gentle reflux. After the mixture was stirred at room temperature for 2 hours, the solution was added with THF (700 ml).
Acyl sultam II (Celltech, WO95
/ 17386, June 29, 1995) (43.2g, 80.5mmol) at 0 ℃
Dropped into the solution. The reaction mixture was stirred at room temperature for 16 hours and then 10% aqueous NH ₄ Cl was added. The mixture was extracted with EtOAc,
The organic phase washed with water and brine, dried (MgSO _4), and evaporated. The residue was recrystallized twice in EtOH to give the title compound (25.6g, 46%) as an off-white solid.

Step 3: (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl)
Ethyl] benzaldehyde Propanethiol (4.6ml, 51mmol) in THF (150ml)
N-Butyllithium (2.4 M solution in hexane; 10.6 ml, 25 mmol) was added dropwise to the 0 ° C. solution of. After 15 minutes, the product of Step 2 (1R, 5S) -N-{(3R) -3- (3-cyclopentyloxy-4-methoxyphenyl) -3- [4-1,
3-Dioxolan-2-yl) phenyl] -2- (4-
Pyridyl) propanoyl} 10,10-dimethyl-3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane-3,3-dioxide (9.7 g, 14.1 mmol) was added as a solid and the reaction mixture was stirred at room temperature for 3 times. It was stirred for a day. The volatiles were then evaporated and the resulting residue was dissolved in EtOH (80ml) and water (40ml). Sodium hydroxide (4.5 g, 113 mmol) was added,
The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, treated with 6N HCl to pH 4.5 and then heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and 1N NaOH
To pH 14 and then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO _4), and evaporated. The residue was purified by flash chromatography (silica gel, ether) to give the title compound as a white foam (2.3g, 41%). ¹ H NMR (400 MHz, CDCl ₃ ) δ1.55 (m, 2H), 1.75 (m, 6
H), 3.30 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60
(M, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.
90 (d, 2H), 7.35 (d, 2H), 7.75 (d, 2H), 8.40 (d, 2H),
9.95 (s, 1H).

Step 4: (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl)
Ethyl] benzoic acid NaClO ₂ (149 mg, 1.64 mmol) and NaH ₂ PO _{4 in} water (1 ml)
A solution of H ₂ O (227 mg, 1.64 mmol) was added to the aldehyde of step 3 (508 mg, 1.27 mmol) and 2- in t-BuOH (6 ml).
Methyl-2-butene (0.94 ml, 8.9 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 19 hours, then 25% aq.
₄ OAc was added. The mixture was then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgSO _4), and evaporated to give the title compound as a white solid (540 mg). ¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (m, 2H), 1.75 (m, 6
H), 3.35 (m, 2H), 3.80 (s, 3H), 4.20 (t, 1H), 4.60
(M, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 7.
00 (d, 2H), 7.25 (d, 2H), 8.00 (d, 2H), 8.45 (d, 2
H).

Intermediate 2: (R) -4- [1- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetic acid Step 1: 4-Bromophenylacetaldehyde 4-bromostyrene (50.0 g, 0.2 in CH ₂ Cl ₂ (550 ml).
74mol) solution was added dropwise to a solution of lead tetraacetate (127g, 0.273mol) in trifluoroacetic acid (275ml) at 10 ° C (1 hour).
did. After the addition was complete, the reaction mixture was left at room temperature for 30 minutes,
Poured slowly into water (2 L). The resulting mixture was stirred for 15 minutes and filtered through Celite. The aqueous layer was extracted twice with CHCl ₃ and the combined organic extracts were washed successively with water (3 times) and saturated aqueous NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated.
The crude yellow liquid was purified by column chromatography on silica (EtOAc / hexane 1: 9) to give the title compound (44.8g, 82%) as a pale yellow liquid.

Step 2: 2-[(4-bromophenyl) methyl] -1,3
-Dioxolane A solution of 4-bromophenylacetaldehyde from step 1 (44.5 g, 224 mmol), ethylene glycol (13.7 ml, 246 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in toluene (300 ml) was added. The mixture was refluxed for 3 hours while capturing water with Dean-Stark. Then the reaction mixture, 5% aqueous NaHCO ₃ (2 times), washed successively with water and brine, dried (MgSO _4), and concentrated. The residue was distilled under reduced pressure (bp 110 to 115 ° C / 0.5 mmHg) to obtain the title compound (30.0 g, 55%) as a colorless liquid.

Step 3: (1R, 5S) -N-{(3R) -3- (3-cyclopentyloxy-4-methoxyphenyl) -3- [4
-(1,3-Dioxolan-2-ylmethyl) phenyl]
2- (4-Pyridyl) propanoyl} -10,10-dimethyl-3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane-3,3-dioxide The product of step 2 in THF (20 ml). 2-[(4-bromophenyl) methyl] -1,3-dioxolane (27.2 g, 1
Solution (12 mmol) in magnesium shavings (2.8 ml) in THF (70 ml) at a rate sufficient to maintain a gentle reflux (several iodine crystals and heat were required to initiate the reaction).
5 g, 117 mmol). After stirring the mixture at room temperature for 2 hours, the acylsultam II (20.0 g, 37.3 mm) in THF (350 ml) was added.
ol) was added dropwise at 0 ° C. The reaction mixture was stirred for 16 hours at room temperature and quenched by addition of saturated aqueous NH ₄ Cl. The organic layer was concentrated, diluted with EtOAc and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were, 25% aqueous NH ₄ OAc buffer, water and successively washed with brine, dried (MgSO _4), and evaporated. The residue was recrystallized in EtOH (minimum amount of CHCl ₃ required to ensure dissolution) to give the title compound (12.2 g, 46%) as a white solid.

Step 4: (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl)
Ethyl] phenylacetaldehyde diethyl acetal n-butyllithium (2.4M solution in hexane; 13.2 ml, 3
1.3 mmol) was added dropwise at 0 ° C. to a solution of 1-propanethiol (3.47 ml, 38.3 mmol) in THF (160 ml). After 30 minutes, the product of Step 3 (1R, 5S) -N-{(3R) -3
-(3-Cyclopentyloxy-4-methoxyphenyl) -3- [4- (1,3-dioxolan-2-ylmethyl) phenyl] -2- (4-pyridyl) propanoyl}
-10,10-Dimethyl-3-thia-4-azatricyclo [5.2.1.0 ^1,5 ] decane-3,3-dioxide (12.2 g, 17.4 m
mol) was added as a solid and the reaction mixture was stirred at room temperature for 2.5 hours. The volatiles were then evaporated and the resulting residue was dissolved in EtOH (100ml) and water (50ml). Sodium hydroxide (5.57 g, 139 mmol) was added and the mixture was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and 6N HCl
To pH 4.5 and then heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and treated with 1N NaOH to pH.
To 14 and then extracted 3 times with EtOAc. The combined organic extracts were, 25% aqueous NH ₄ OAc buffer, water and successively washed with brine, dried (MgSO _4), and concentrated. Column chromatography of the residue on silica (acetone / ether
1: 9 → 1: 4 → 1: 3) to give the title compound (1.17 g, 14%) as an off-white gum.

Step 5: (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl)
Ethyl] phenylacetaldehyde A product of step 4 (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl in acetone (30 ml) and water (1.3 ml). ] -Phenylacetaldehyde diethyl ether (1.
A solution of 14 g, 2.33 mmol) and pyridinium p-toluenesulfonate (0.761 g, 3.03 mmol) was heated under reflux for 20 hours.
The reaction mixture was then cooled to room temperature and diluted with EtOAc, 5
Wash successively with% aqueous NaHCO ₃ (twice) and brine, dry (MgSO ₄ ) and concentrate. Column chromatography of the residue on silica (EtOAc / hexane 3: 2 → 7: 3 → 4: 1 → 1:
0) to give the title compound as a white foam (0.3
81g, 39%) was obtained.

Step 6: (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl)
Ethyl] phenylacetic acid Sodium chlorite (80%; 131mg, 1.ml) in water (1.1ml).
16 mmol) and sodium phosphate monobasic acid monohydrate (160 m
g, 1.16 mmol) was added to the product of step 5 (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) in t-BuOH (8 ml).
Ethyl] phenylacetaldehyde (371mg, 0.893mmo
l) and 2-methyl-2-butene (665 μl, 6.25 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, then 25% aqueous NH ₄ OAc buffer was added (a few drops of acetic acid were needed to bring the pH to 7). Then the mixture is extracted with EtOAc.
Extracted twice with and the combined organic extracts were extracted with 25% aqueous NH ₄ OAc.
Washed successively with buffer, water and brine, dehydrated (MgS
O ₄ ), concentrated. The residue was purified by column chromatography on silica (0.5% AcOH in EtOAc).
Residual AcOH was co-evaporated twice with toluene to give the title compound (319 mg, 83%) as a white foam. ¹ H NMR (400 MHz, acetone-d ₆ ) δ1.50-1.61 (m, 2
H), 1.63-1.88 (m, 6H), 3.40 (d, 2H), 3.54 (s, 2H),
3.70 (s, 3H), 4.34 (t, J = 8Hz, 1H), 4.75 (m, 1H), 6.78
(M, 2H), 6.90 (s, 1H), 7.15 (d, J = 6Hz, 2H), 7.20 (d,
J = 8Hz, 2H), 7.30 (d, J = 8Hz, 2H), 8.33 (d, J = 5Hz, 2
H).

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI C07D 213/52 C07D 213/52 213/61 213/61 213/89 213/89 // C07D 213/30 213/30 (72) Inventor Girard, Eve Canada, Kebetsk Ashiyu 9, Ashiyu 3, L. 1, Kirkland, Trans Canada Highway 16711 (72) Inventor Deyusyalum, Eve Canada, Kebetsk Ashiyu 9, Ashiyu 3-El-1, Kirkland, Trans-Canada Highway 16711 (72) Inventor Buruan, Marc Canada, Kebetsk-Ashiyu-9-Ashiyu-3el-1, Kirkland, Trans- Canada Highway 16711 (72) Inventor Amel, Pierre Kebetsk Ashiyu 9 Ashi, Canada・ 3 ・ L ・ 1, Kirkland, Trans-Canada Highway ・ 16711 (72) Inventor Girard, Mario Canada, Kebetsk Ashiyu ・ 9 ・ Ashiyu ・ 3 ・ El ・ 1, Kirkland, Trans-Canada Highway 16711 (56) References Tokuhyo 7-504442 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 213/00-213/89 CA (STN) REGISTRY (STN )

Claims (12)

(57) [Claims] 1. Formula I: wherein R is Selected from (a) hydrogen, (b) C _1-6 alkyl, (c) halo, and (d) CF ₃ ; R ¹ is — (CH ₂ ) _m —CO—N (R ⁴ ) —S ( _O) 2 -R ⁵ (wherein, m is 0, 1 or _{2), - (CH 2)} m -CO-N (R 4) -S (O) 2 -NR 6 R 7, - (CH _{2) m -S (O) 2} -N (R 4) -CO-R 4, - (CH 2) is selected from _{m -S (O) 2 -N (} R 4) -CO-NR 6 R 7; R ² and R ³ are independently (a) C _1-7 alkyl, (b) substituted C _1-7 alkyl (wherein the substituents are F, Cl,
Br or I), (c) optionally mono- or di-substituted 2-phenethyl or 2-indanyl (wherein the substituents on the benzene ring are independently (1) halo, (2) C _{1- 6} alkoxy, (3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _1-6 alkyl, (7) N ₃ , (8) -CO ₂ H R ⁴ is (a) hydrogen, (b) C _1-6 alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl (wherein on the benzene ring). The substituents are independently (1) halo, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _1-6 alkyl, _{(7) N 3, (8} ) -CO 2 is selected from the group consisting of H) is selected from; R ^5, R ⁸ and R ¹¹ are each _{independently, (a) -CF 3, (} b) C 1 _-6 Alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl (wherein the substituents on the benzene ring is independently (1) halo, (2) C _1-6 alkoxy, ( 3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _1-6 alkyl, (7) N ₃ , (8) -CO ₂ H)) each R ^6, R ^7, R ⁹ and R ¹⁰ are independently, (a) is selected from hydrogen and (b) C _1-6 alkyl; selected or R ⁶ and R ⁷ together, saturated 5-membered, 6-membered or 7-membered heterocycle (wherein the heterocycle contains a heteroatom nitrogen, optionally
Additional heteroatoms that are O or S atoms or NR ⁴ and optionally carbonyl groups may be formed; HET may be optionally mono- or di-substituted pyridyl and imidazolyl, where the substituents are Independently, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁸ , NR ⁹ R ¹⁰ , NHS (O)
₂ R ¹¹ , OH, CN or CF ₃ ) and its N-oxide; X is selected from N, N → O or CH] or a pharmaceutically acceptable compound thereof. Possible salt. 2. A compound according to claim 1, characterized in that R ² is cyclopentyl and R ³ is methyl. 3. R is selected from (a) hydrogen, (b) C _1-4 alkyl, (c) halo, and (d) CF ₃ ; R ¹ is — (CH ₂ ) _m —CO— _{^{N (R 4) -S (O}} ) 2 -R 5 ( wherein, m is 0, 1 or _{2), - (CH 2)} m -CO-N (R 4) -S (O) 2 - ^{NR 6 R 7, - (CH} 2) m -S (O) 2 -N (R 4) -CO-R 4, - (CH 2) m -S (O) 2 -N (R 4) -CO- Selected from NR ⁶ R ⁷ ; R ² is cyclopentyl; R ³ is methyl; R ⁴ is (a) hydrogen, (b) C _1-6 alkyl, (c) optionally mono- or di-substituted Phenyl, benzyl or 2-phenethyl (wherein the substituents on the benzene ring are independently (1) halo, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN, (5) CF ₃ , (6) C _1-6 alkyl, (7) N ₃ , (8) -CO ₂ H Is selected from that selected from the group); the R ^5, R ⁸ and R ¹¹ are each _{independently, (a) -CF 3, (} b) C 1-6 alkyl, mono- or di-substituted optionally (c) Phenyl, benzyl or 2-phenethyl (wherein the substituents on the benzene ring are independently (1) halo, (2) C _1-6 alkoxy, (3) C _1-6 alkylthio, (4) CN , (5) CF ₃ , (6) C _1-6 alkyl, (7) N ₃ , selected from the group consisting of (8) -CO ₂ H); R ⁶ , R ⁷ , R ⁹ and R ¹⁰ is independently selected from (a) hydrogen and (b) C _1-6 alkyl; or R ⁶ and R ^{7 taken} together represent a saturated 5-membered, 6-membered or 7-membered heterocycle The heterocycle contains a heteroatom nitrogen, optionally
Additional heteroatoms which are O or S atoms or NR ⁴ and optionally carbonyl groups may be formed; HET may be optionally mono- or di-substituted pyridyl and imidazolyl, wherein the substituents are Independently, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁸ , NR ⁹ R ¹⁰ , NHS (O)
₂ R ¹¹ , OH, CN or CF ₃ ) and its N-oxides; X is selected from N, N → O or CH. The described compound. Wherein R is, (a) hydrogen, (b) C _1-3 alkyl, is selected from (c) halo, and (d) CF _3; is in the ortho position with respect to and R ^1; R ¹ _{but, - (CH 2) m -CO} -N (R 4) -S (O) 2 -R 5 ( wherein, m is 0, 1 or _{2), - (CH 2)} m -CO-N _{^{(R 4) -S (O)}} 2 -NR 6 R 7, - (CH 2) m -S (O) 2 -N (R 4) -CO-R 4, - (CH 2) m -S (O ) _2- N (R ⁴ ) -CO-NR ⁶ R ⁷ ; R ² is cyclopentyl; R ³ is methyl; R ⁴ is (a) hydrogen, (b) C _1-6 alkyl is selected from; to R ^5, R ⁸ and R ¹¹ are each independently, is (a) -CF _3, selected from, (b) C _1-6 ^{alkyl, R 6, R 7, R} 9 and R ¹⁰ Each independently, selected from (a) hydrogen and (b) C _1-6 alkyl; or R ⁶ and R ^{7 taken} together are A 5-membered, 6-membered or 7-membered heterocycle (wherein the heterocycle contains a heteroatom nitrogen, optionally
Additional heteroatoms, which are O or S atoms, or NR ⁴ , and optionally a carbonyl group) can be formed; HET is optionally mono- or di-substituted pyridyl, wherein the substituents are independently From halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁸ , NR ⁹ R ¹⁰ , NHS (O) ₂ R ¹¹ , OH, CN or CF _3. Selected from the group consisting of) and its N-oxides; X is CH. 5. (a) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2-
(4-pyridyl) ethyl] benzoyl} methanesulfonamide, (b) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl } Benzenesulfonamide, (c) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} trifluoromethanesulfonamide, (d) ) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzoyl} o-toluenesulfonamide, (e) N-{(R ) -4- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetyl} benzenesulfonamide, f) N-{(R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] phenylacetyl} trifluoromethanesulfonamide, and (g) N- ( o-toluoyl) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4
-Pyridyl) ethyl] benzenesulfonamide, characterized in that it is selected from the group consisting of:
The compound according to. 6. A non-toxic and therapeutically effective amount of claim 1, 2,
A pharmaceutical composition for treating asthma, comprising a compound according to 3, 4, or 5 and a pharmaceutically acceptable carrier. 7. A pharmaceutical composition for treating a disease by increasing the intracellular level of cAMP, which is a non-toxic and therapeutically effective amount according to claim 1, 2, 3, 4 or 5. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier. 8. An acceptable amount of a formula of claim 1, 2, 3, 4 or 5 which inhibits phosphodiesterase IV and increases cyclic adenosine-3 ', 5'-monophosphate. A phosphodiesterase IV inhibitory pharmaceutical composition comprising a compound of I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 9. A method according to claim 1, for use in the treatment of asthma.
A compound of formula (I) according to 2, 3, 4 or 5 or a pharmaceutically acceptable salt thereof. 10. A formula according to claim 1, 2, 3, 4 or 5 for use in treating a disease by increasing intracellular levels of cyclic adenosine-3 ', 5'-monophosphate. A compound of (I) or a pharmaceutically acceptable salt thereof. 11. Formula (I) according to claim 1, 2, 3, 4 or 5 in the manufacture of a medicament for treating asthma.
Use of the compound of 1 or a pharmaceutically acceptable salt thereof. 12. A method according to claims 1 and 2 in the manufacture of a medicament for increasing cyclic adenosine-3 ', 5'-monophosphate levels by inhibiting phosphodiesterase.
Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to 3, 4 or 5.