JP3468777B2 - Diphenylpyridylethane 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). ) 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 2503-2.
510] and eosinophils [G. Dent et al., (1991) Br. J. Pharmacol. 10
3 1339-1346], controlling cAMP degradation.
And it was demonstrated 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 under development as potential anti-inflammatory agents, especially for the prevention and treatment of asthma, due to their anti-inflammatory and bronchodilator effects.

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 6558-6571] was also shown to be encoded by a separate gene.

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 a functional recombinant enzyme by expressing the cDNA in a suitable host cell [Bolger et al., 1993 supra; Oberno.
lte et al., 1993, supra; M. Mclaughlin et al., (1993) J. Biol. Ch.
em.268 6470-6476] and rat PDE IV A, B and D full-length cDNAs [R. Davis et al., (1991) Proc. Natl. Acad. Sc.
i. USA 86 3604-3608; JVSwinnen et al., (1991) J. Bio.
Chem.266 18370-18377] has been reported. These cDNAs were isolated by conventional hybridization methods. However, using this method, human and rat PDE
Only a portion of the IVC cDNA is available [Bolger et al., Supra, 1
993 and Swinnen et al., Supra, 1989 and international patent application WO 91 /
16457].

Attempts to synthesize PDE IV inhibitors to treat 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 carrageenin, 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 ¹ is, (a) -CH = NOH, (b) -CH (OH) CH 3, (c) -CO-CH 3, (d) -CO-N [CH 2 CH 2] 2 _{N-CH 3, (e)} -CO-N [CH 2 CH 2 CH 2 CH 2], and is selected from (f)-5-tetrazolyl; R ² and R ³ are independently, (a) C _{1- 7} alkyl, (b) substituted C _1-7 alkyl (wherein the substituents are F, C
l, Br or I), (c) 2-phenethyl or 2-indanyl optionally mono- or di-substituted on the benzene ring, wherein the 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) -CO Selected from the group consisting of ₂ H); R ⁴ is (a) hydrogen, (b) C _1-6 alkyl, (c) phenyl, benzyl, optionally mono- or di-substituted on the benzene ring. Or 2-phenethyl (wherein the 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 , selected from the group consisting of (8) —CO ₂ H); R ⁵ and R ⁸ are each independently _{To, (a) -CF 3, (} b) C 1-6 alkyl, (c) optionally mono- or di-substituted phenyl on the benzene ring, benzyl or 2-phenethyl (wherein the 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) -CO} 2 is selected from to) selected from the group consisting of H; R ⁶ and R ⁷ are independently selected from (a) hydrogen, and (b) C _1-6 alkyl; Alternatively, R ⁶ and R ⁷ are taken together to form a saturated 5-, 6- or 7-membered heterocycle (wherein the heterocycle contains a heteroatom nitrogen and is an additional heteroatom or NR which is optionally an O or S atom). ^Four
And optionally a carbonyl group); HET is halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6
Alkylthio, benzyl, 2-phenethyl, NHCOR ⁵ , NR
⁶ R ⁷ , NHS (O) ₂ R ⁸ , OH, selected from pyridyl or imidazolyl and its N-oxides optionally mono- or di-substituted with a substituent selected from the group consisting of CF or CF ₃ ; X is , N, N → O or CH]] or a pharmaceutically acceptable salt thereof.

This embodiment, R ² is, F, Cl, optionally mono-substituted group selected from the group consisting of Br and I, a di- or tri-substituted cyclopentyl, compound species R ³ is methyl included.

In the above species, R ¹ is (a) -CH = NOH, (b) -CH (OH) CH ₃ , (c) -CO-CH ₃ , (d) -CO-N [CH ₂ CH ₂ ]. be R ³ is _{methyl; 2 N-CH 3, (} e) -CO-N [CH 2 CH 2 CH 2 CH 2], and (f) is selected from 5-tetrazolyl; R ² is cyclopentyl; R ⁵ and R ⁸ are each independently (a) —CF ₃ , (b) C _1-3 alkyl, (c) optionally mono- or di-substituted phenyl, benzyl or 2-phenethyl on the benzene ring (here And the substituents on the ring are independently (1) halo, (2) C _1-3 alkoxy, (3) C _1-3 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 and R ⁷ are independently (a) hydrogen, and (b) C Selected from _1-3 alkyl; or R ⁶ And R ⁷ are taken together to 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); HET is halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6
Alkylthio, benzyl, 2-phenethyl, NHCOR ⁵ , NR
⁶ R ⁷ , NHS (O) ₂ R ⁸ , OH, selected from pyridyl or imidazolyl and its N-oxides optionally mono- or di-substituted with a substituent selected from the group consisting of CF or CF ₃ ; X is , N, N → O or CH.

The above groups, R ¹ is, (a) -CH = NOH, (b) CH (OH) -CH 3, (c) -CO-CH 3, (d) -CO-N [CH 2 CH 2] be R ³ is _{methyl; 2 N-CH 3, (} e) -CO-N [CH 2 CH 2 CH 2 CH 2], and (f) is selected from 5-tetrazolyl; R ² is cyclopentyl; R ⁵ and R ⁸ are each independently selected from (a) —CF ₃ , (b) C _1-3 alkyl; R ⁶ and R ⁷ are independently (a) hydrogen, and (b) C _{1 -3} alkyl, or R ⁶ and R ^{7 taken} together are a saturated 5-, 6- or 7-membered heterocycle, wherein the heterocycle contains a heteroatom nitrogen and optionally at an O or S atom. Some additional heteroatoms or NR ⁴
And optionally a carbonyl group); HET is halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6
Alkylthio, benzyl, 2-phenethyl, NHCOR ⁵ , NR
⁶ R ⁷ , NHS (O) ₂ R ⁸ , OH, CN or CF ₃ selected from pyridyl or imidazolyl and its N-oxide optionally mono- or di-substituted with a substituent selected from the group consisting of; Included are subclasses of compounds selected from 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) (R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4- (4-methylpiperazinocarbonyl) phenyl ] Ethyl} pyridine, (b) (R) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyrrolidinocarbonylphenyl) ethyl] pyridine, (c) (R)- 4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzaldehyde oxime, (d) (R) -4- {2- (3-cyclopentyloxy-4-methoxy) Phenyl) -2- [4- (tetrazol-5-yl) phenyl] ethyl} pyridine, (e) (R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) ) -2- [4- (1-Hydroxyethyl) phenyl] ethyl} pyridine, and (f) (R) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-acetyl). Phenyl) ethyl] pyridine.

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 medical 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 0.01 per kg body weight per day.
~ About 140 mg, or about 0.5 per patient per day
Dosage levels of mg to about 7 g are useful. For example, inflammation
It may be effectively treated by administering about 0.01 to 50 mg of compound per kg of body weight per day, or about 0.5 mg to about 3.5 g of compound per patient per day.

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. The appropriate bromoaryl-1,3-dioxolane derived Grignard reagent was added diastereoselectively to the acylsultam Michael receptor II to give the triarylpropanoylsultam intermediate. The chiral complement is then removed in a one-pot process by subsequent treatment with a suitable lithium thiolate, saponification with aqueous hydroxide, followed by aqueous acidic treatment, followed by decarboxylation and aldehyde removal. Deprotected. Thus, the arene carboxaldehyde intermediate 1
Got The intermediate was oxidized with sodium chlorite to obtain an arenecarboxylic acid intermediate 2. Acid 2 was treated with an amine in the presence of diethyl cyanophosphonate and triethylamine to prepare the carboxamide.

Scheme 2 Hydroxylamine hydrochloride is reacted with arene carboxaldehyde intermediate 1 to give an oxime derivative (Scheme 2)
Got Dehydration of the oxime with trichloromethyl chloroformate (or other suitable dehydrating agent such as acetic anhydride, ethyl orthoformate / H ⁺ , CCl ₃ COCl / Et ₃ N) gives the corresponding arene nitrile, which is 5 by reacting with the appropriate azide
-Converted into a tetrazolyl derivative.

Scheme 3 Addition of methylmagnesium bromide to arene carboxaldehyde intermediate 1 to give the corresponding secondary alcohol,
This was oxidized with pyridinium chlorochromate to obtain an acetyl derivative.

Representative compounds Table 1 shows compounds of the invention: 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: 10% inactivated fetal bovine serum (FBS); 1% (v / v) penicillin / streptomycin; 25 mM Hepes, pH 7.4; and 500 mg / ml at a density of 5 × 10 ⁶ cells / 175 cm ^2. 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 mg / ml.
DNA, and 9 mg / ml lipofectamine reagent in Opti-MEM were incubated for 7 hours at 37 ° C., 5% CO ₂ .
Incubate the solution with Opti-MEM containing 20% FBS.
1: 2 dilution and incubated overnight. After overnight incubation, the medium was replaced with complete medium containing 500 mg / 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 mg / 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. Centrifuge the cell suspension at 150 g for 10 minutes to
The MP content was measured. The cells were then resuspended in Hank's buffered saline at a density of 0.2 × 10 ⁶ cells / ml. The cells were preincubated for 15 minutes at room temperature and then further incubated with 10 mM prostaglandin I ₂ (PGI ₂ ) and indicator compound.
Incubated for 10 minutes. Basal cAMP levels were quantified by incubating cells in 0.1% DMSO. Incubation was stopped by adding HCl (final concentration 0.1N) and cells were measured for cAMP as described below.

Rabbit anti-succinyl cAMP serum (100 ml) reconstituted in ScintiStrip ^™ wells (final volume 300 ml) for 18 hours at room temperature.
, Whole cell reactant or known cAMP standard solution (100 ml) and ¹²⁵
Total cell cAMP content was quantified by incubation with I-cAMP TME (30 pmol). cAMP standard solution in the absence of sample
The cpm (B _O ) was quantified. 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 _O = [(standard or sample opm-non-specific cpm)
/ (B _o cpm-nonspecific cpm)] × 100. Scint
In iStrip ^™ wells, ¹²⁵ I-cAMP TME alone was incubated with assay buffer (50 nM acetate; pH 5.8) to quantify non-specific cpm. 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 mM b-mercaptoethanol (Braunsonic
Model 2000) sonicated for 10 seconds with CHO power settings
-K1 was dissolved. Sonicate strips at 4 ° C for 90 minutes 10
Centrifugation at 0,000 xg gave a soluble granular fraction of cells. 50 mM Tris, pH 7.5 in the presence of varying concentrations of inhibitor;
10 mM MgCl ₂ ; 1 mM EDTA; and 100 nM (or specified) ³ H-c
PDE activity was measured in a solution containing AMP (final volume 100 ml). The reaction mixture containing the enzyme was added to 96-well View Plates.
(Packard) incubated at 30 ° C for 10 minutes, 18 mM Z
Phosphodiesterase Scintillation Proxim with nSO ₄
Incubation was stopped by adding 50 ml of City Assay (SPA) Beads (Amersham). Wallac 1450 mBeta LSC
Plates were counted in a counter to quantify the amount of 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.
Concentrations of 1 nM to 1 mM induced a concentration-dependent increase in cAMP in neutrophils and / or eosinophils.

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 at concentrations of 0.1 nM to 1 mM caused 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 mM.

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 a concentration of 1 nM to 100 mM reversed the contraction induced by both histamine and carbachol in a concentration-dependent manner. The compound is generally
It is more potent in histamine-induced tone than 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 mM, 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 , 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)] reduced the deposition of eosinophils and other inflammatory leukocytes. It also reduced inflammatory damage to the lungs of animals treated with the compounds of the Examples.

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 in the dose response curve to histamine and a very significant increase in the maximum increase in lung resistance. Intraperitoneal or oral administration of ozone (0.00
1 to 10 mg / kg) 1 hour prior to administration,
A dose-dependent inhibition of ozone-induced hyperreactivity was produced.

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.

SPA-based PDE activity assay protocol AM of cAMP by type IV cAMP-specific phosphodiesterase
Compounds that inhibit hydrolysis to P were screened in a 96 well plate format as follows: 96 well plates 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 zero point titrations by non-linear regression fit of standard 4-parameter / multiple binding site equations.

Purified GS of human recombinant phosphodiesterase IVa (met-248) produced from baculovirus / Sf-9 expression system
The IC ₅₀ values shown in Table 2 were quantified for 100 nM cAMP using the T fusion protein.

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.

The invention is illustrated by the following non-limiting examples. In the examples, unless otherwise stated: (i) All operations are at room or ambient temperature, ie 18-
It was carried out at temperatures in the range of 25 ° C; evaporation of the solvent was carried out under reduced pressure (60
0 to 4000 Pascal: 4.5 to 30 mmHg) using a rotary evaporator under a bath temperature of 60 ° C. or lower; the reaction progress was followed by thin layer chromatography (TLC),
Reaction times are shown for illustration only; melting points are uncalibrated, "d" indicates decomposition; melting points shown are those obtained for materials prepared as described. The polymorph may be due to the isolation of substances with different melting points in several preparations; the structure and purity of all final products are
Confirmed using one or more of TLC, 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
acid DBU = 1,8-diazabicyclo [5.4.0] undec-7
-En 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 OXONE = 2KHSO_Five・ KHSO_Four・ K₂SO_Four PCC = pyridinium chlorochromate PDC = pyridinium dichromate PDE = phosphodiesterase Ph = phenyl Phe = benzenediyl Pye = pyridinediyl r.t. = room temperature rac. = racemic compound SAM = aminosulfonyl or sulfonamide or SO
₂NH₂ SPA = Scintillation proximity assay TBAF = tetra-n-butylammonium fluoride Th = 2- or 3-thienyl TFAA = trifluoroacetic anhydride THF = tetrahydrofuran Thi = thiophenediyl TLC = thin layer chromatography TMS-CN = trimethylsilyl cyanide Tz = 1H (or 2H) -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 (R) -4- {2- (3-cyclopentyloxy-4-)
Methoxyphenyl) -2- [4- (4-methylpiperazinocarbonyl) phenyl] ethyl} pyridine Carboxylic acid 2 (100 mg, 0.24 mmol) in DMF (2 ml), 1
A solution of -methylpiperazine (0.03 ml, 0.26 mmol), diethyl cyanophosphonate (0.05 ml, 0.31 mmol) and triethylamine (0.05 ml, 0.34 mmol) was stirred at room temperature for 16 hours before adding EtOAc. The organic phase washed with water and brine, dried (MgSO _4), and evaporated. Flash chromatography of the residue (silica gel, CH ₂ Cl ₂ / MeOH 90: 1
0) to give the title compound as a white solid (60 mg,
50%). ¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (m, 2H), 1.75 (m, 6
H), 2.30 (s, 3H), 2.30 (m, 2H), 2.45 (m, 2H), 3.30
(D, 2H), 3.40 (m, 2H), 3.75 (m, 2H), 3.80 (s, 3H), 4.
15 (t, 1H), 4.60 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H),
6.75 (d, 1H), 6.90 (d, 2H), 7.20 (d, 2H), 7.30 (d, 2
H), 8.40 (d, 2H).

Example 2 (R) -4- [2- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-pyrrolidinocarbonylphenyl) phenyl] ethyl} pyridine Follow the procedure described in Example 1 except that 1-methylpiperazine is replaced by pyrrolidine to give the title product as an off-white solid. It was ¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (m, 2H), 1.80 (m, 8
H), 1.95 (m, 2H), 3.30 (d, 2H), 3.40 (t, 2H), 3.60
(T, 2H), 3.80 (s, 3H), 4.15 (t, 1H), 4.60 (m, 1H), 6.
60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.90 (d, 2H),
7.20 (d, 2H), 7.45 (d, 2H), 8.40 (d, 2H).

Example 3 (R) -4- [1- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-pyridyl) ethyl] benzaldehyde oxime Aldehyde 1 in pyridine (4 ml) (406 mg, 1.0 mmol)
Hydroxylamine hydrochloride (100mg, 1.4mmol)
Was added and the reaction mixture was stirred at room temperature for 18 hours. Then
The volatiles were evaporated and EtOAc was added to the residue. The organic phase was washed with 5% aqueous NaHCO ₃ , dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography (silica gel, CH ₂ Cl ₂ / MeOH 95: 5) to give the title compound (306 mg, 89%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (m, 2H), 1.80 (m, 6
H), 3.30 (d, 2H), 3.80 (s, 3H), 4.15 (t, 1H), 4.65
(M, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.75 (d, 1H), 6.
90 (d, 2H), 7.20 (d, 2H), 7.45 (d, 2H), 7.60 (s, 1H),
8.10 (s, 1H), 8.40 (d, 2H).

Example 4 (R) -4- {2- (3-cyclopentyloxy-4-)
Methoxyphenyl) -2- [4- (tetrazol-5-yl) phenyl] ethyl} pyridine Step 1: (R) -4- [1- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-pyridyl) ethyl] benzenenitrile The product of Example 3 (R) in acetonitrile (4 ml).
To a 0 ° C. solution of 4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzaldehyde oxime (425 mg, 1.0 mmol) was added trichloromethyl chloroformate (0.18 ml, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then water was added. The mixture was then extracted with EtOAc. 5% organic phase
Wash with aqueous NaHCO ₃ , water and brine and dry (MgS
O ₄ ), evaporated to give the title compound (350 mg, 86%) as an off-white solid.

Step 2: (R) -4- {2- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- [4- (tetrazol-5-yl) phenyl] ethyl} pyridine The product of Step 1 (R) -4- [1- (3-cyclopentyl) in 1,2-dichlorobenzene (4 ml) Oxy-4
-Methoxyphenyl) -2- (4-pyridyl) ethyl]
A solution of benzene-nitrile (350 mg, 0.88 mmol) and tributyltin azide (1.17 g, 3.5 mmol) was stirred at 150 ° C for 2 hours. The reaction mixture was then cooled to room temperature and acetic acid (0.
5 ml) was added. After 15 minutes, aqueous 1N NaOH was added and the aqueous phase was washed 3 times with ether. The aqueous phase is then 25% aqueous
After adjusting the pH to 7 by treatment with NH ₄ OAc and 6N HCl, CH ₂
Extracted twice with Cl ₂ . Then, the organic phase dried (MgSO _4),
Evaporate to give the title compound as a yellow solid (341mg, 88%).
Got ¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (m, 2H), 1.80 (m, 6
H), 3.30 (m, 1H), 3.45 (m, 1H), 3.80 (s, 3H), 4.20
(M, 1H), 4.70 (m, 1H), 6.70 (s, 1H), 6.80 (m, 2H), 7.
00 (d, 2H), 7.20 (d, 2H), 7.90 (d, 2H), 8.40 (d, 2
H).

Example 5 (R) -4- {2- (3-cyclopentyloxy-4-)
Methoxyphenyl) -2- [4- (1-hydroxyethyl) phenyl] ethyl} pyridine Aldehyde 1 (509 mg, 1.3 mmol) -7 in THF (4 ml).
Methylmagnesium bromide (in toluene-THF) at 8 ° C solution
1.4M solution; 1.1 ml, 1.5 mmol) was added dropwise and the mixture was warmed to room temperature. After 6 hours, 5% aqueous NaHCO ₃ was added and the mixture was EtOA.
Extracted twice with c. The organic layer is washed with brine and dried (MgS
O ₄ ) and evaporated. The residue was purified by flash chromatography (silica gel, hexane / EtOAc 25:75) to give the title compound as a colorless gum (275mg, 52
%) Was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ1.45 (d, 3H), 1.55 (m, 2
H), 1.75 (m, 6H), 2.40 (s, 1H), 3.30 (m, 2H), 3.80
(S, 3H), 4.15 (t, 1H), 4.65 (m, 1H), 4.85 (m, 1H), 6.
60 (s, 1H), 6.65 (d, 1H), 6.70 (d, 1H), 6.90 (d, 2H),
7.15 (d, 2H), 7.25 (d, 2H), 8.30 (d, 2H).

Example 6 (R) -4- [2- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-acetylphenyl) ethyl] pyridine CH ₂ Cl ₂ (3 ml) pyridinium chlorochromate (272
mg, 1.3 mmol) and a suspension of molecular sieves, CH ₂ C
The product of Example 5 (R) -4- {2- in ₁₂ (4 ml).
(3-Cyclopentyloxy-4-methoxyphenyl)
A solution of 2- [4- (1-hydroxyethyl) phenyl] ethyl} pyridine (205mg, 0.49mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then the volatiles were evaporated. The residue was then triturated with EtOAc and filtered through Celite. The filtrate was evaporated to give a residue which was purified by flash chromatography (silica gel, hexane / EtOAc 25:75) to give the title compound as a white foam (39mg, 19%). ¹ H NMR (400 MHz, CDCl ₃ ): δ1.55 (m, 2H), 1.75 (m, 6
H), 2.55 (s, 3H), 3.30 (d, 2H), 3.80 (s, 3H), 4.20
(T, 1H), 4.65 (m, 1H), 6.60 (s, 1H), 6.65 (d, 1H), 6.
75 (d, 1H), 6.90 (d, 2H), 7.25 (d, 2H), 7.85 (d, 2H),
8.40 (d, 2H).

Preparation of Intermediate Intermediate 1 (R) -4- [1- (3-cyclopentyloxy-4-
Methoxyphenyl) -2- (4-pyridyl) ethyl] benzaldehyde 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 simultaneously acquiring water with Dean-Stark. The organic phase was then washed successively with 5% aqueous NaHCO ₃ , water and brine, dried (MgSO ₄ ) and evaporated. Distill the residue under reduced pressure (bp: 112 ℃ / 0.4mmHg),
The title compound (79.8 g, 97%) was obtained 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 stirring the mixture at room temperature for 2 hours, the solution was made into an acyl sultam II (Celltech, WO95 / 1 in THF (700 ml).
No. 7386, June 29, 1995) (43.2 g, 80.5 mmol) was added dropwise to a 0 ° C solution. After stirring the reaction mixture at room temperature for 16 hours,
10% aqueous NH ₄ Cl was added. The mixture was extracted with EtOAc, the organic phase is 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,
The reaction mixture was stirred at room temperature for 3 days. The volatiles were then evaporated and the resulting residue was combined with EtOH (80 ml) and water (40
ml). Sodium hydroxide (4.5 g, 113 mmol) was added and 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, then
The mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and 1N
Of 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).

Intermediate 2: (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 aldehyde 1 (508 mg, 1.27 mmol) and 2-methyl-2 in t-BuOH (6 ml).
-Butene (0.94 ml, 8.9 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 19 hours and then 25% aqueous NH 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).

Continuation of front page (51) Int.Cl. ⁷ identification code FI C07D 401/10 C07D 401/10 // A61P 11/06 A61P 11/06 37/08 37/08 43/00 111 43/00 111 (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 (56) References Table 7-504442 (JP, A) Table 10-503173 (JP, A) Table 9 -510691 (JP, A) Special Table 8-505158 (JP, A) (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 213/00-213/53 C07D 401/00-401/10 A61K 31/00-31/496 CA (STN) REGISTRY (STN)

Claims (12)

(57) [Claims] 1. Formula I: Wherein, R ¹ is, (a) -CH = NOH, (b) -CO-N [CH 2 CH 2] 2 N-CH 3, (c) -CO-N [CH 2 CH 2 CH 2 CH ₂ ] and (d) -5-tetrazolyl; R ² and R ³ are independently (a) C _1-7 alkyl, (b) substituted C _1-7 alkyl (wherein the substituent is F , Cl, Br
Or I), (c) 2-, optionally mono- or di-substituted on the benzene ring.
Phenethyl or 2-indanyl (wherein the 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 , selected from the group consisting of (8) -CO ₂ H)); HET is halo, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 alkylthio, benzyl, 2-phenethyl, NHCOR ⁵ , NR ⁶ R
⁷ , selected from pyridyl or imidazolyl and its N-oxide optionally mono- or di-substituted with a substituent selected from the group consisting of NHS (O) ₂ R ⁸ , OH, CN or CF ₃ ; x is N , N → O or CH; R ⁵ and R ⁸ are each independently (a) —CF ₃ , (b) C _1-6 alkyl, (c) optionally mono- or di-substituted on the benzene ring. Phenyl, benzyl or 2-phenethyl (wherein the 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 , selected from the group consisting of (8) -CO ₂ H)); R ⁶ and R ⁷ are independently , (a) hydrogen, and (b) C _1-6 selected from alkyl; or R ⁶ and R ⁷ are saturated 5 together, 6- or 7-membered heterocyclic ring (complex- Includes a heteroatom nitrogen, optionally,
Additional heteroatoms that are O or S atoms or NR ⁴ and optionally carbonyl groups) can be formed; wherein R ⁴ is (a) hydrogen, (b) C _1-6 alkyl. (C) phenyl, benzyl or 2-phenethyl optionally mono- or di-substituted on the benzene ring (wherein the 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 , and (8) -CO ₂ H. ) Is selected from. ] The compound which has these, or its pharmaceutically acceptable salt. 2. R ² is cyclopentyl optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of F, Cl, Br and I and R ³ is methyl. The compound of claim 1, wherein Wherein R ¹ is, (a) -CH = NOH, (b) -CO-N [CH 2 CH 2] 2 N-CH 3, (c) -CO-N [CH 2 CH 2 CH 2 CH ₂ ], and (d) -5-tetrazolyl; R ² is cyclopentyl; R ³ is methyl; HET is halo, C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio, benzyl, 2-phenethyl, NHCOR ⁵ , NR ⁶ R
⁷ , selected from pyridyl or imidazolyl and its N-oxide optionally mono- or di-substituted with a substituent selected from the group consisting of NHS (O) ₂ R ⁸ , OH, CN or CF ₃ ; X is N , N → O or CH; R ⁵ and R ⁸ are each independently (a) -CF ₃ , (b) C _1-3 alkyl, (c) optionally mono- or di-substituted on the benzene ring. Phenyl, benzyl or 2-phenethyl (wherein the substituents on the ring are independently (1) halo, (2) C _1-3 alkoxy, (3) C _1-3 alkylthio, (4) CN , (5) CF ₃ , (6) C _1-3 alkyl, (7) N ₃ , selected from the group consisting of (8) -CO ₂ H); R ⁶ and R ⁷ are independently (a) hydrogen, and (b) C _1-3 selected from alkyl; or R ⁶ and R ⁷ are saturated 5 together, 6- or 7-membered heterocyclic ring (the Ring includes a hetero atom of nitrogen, optionally,
Compounds according to claim 1, characterized in that they contain additional heteroatoms which are O or S atoms or NR ⁴ and optionally carbonyl groups). Wherein R ¹ is, (a) -CH = NOH, (b) -CO-N [CH 2 CH 2] 2 N-CH 3, (c) -CO-N [CH 2 CH 2 CH 2 CH ₂ ], and (d) -5-tetrazolyl; R ² is cyclopentyl; R ³ is methyl; HET is halo, C _1-6 alkyl, C _1-6 alkoxy, C _{1- 6} alkylthio, benzyl, 2-phenethyl, NHCOR ⁵ , NR ⁶ R
⁷ , NHS (O) ₂ R ⁸ , OH, selected from pyridyl and its N-oxide optionally mono- or di-substituted with a substituent selected from the group consisting of CN or CF ₃ ; X is CH; R ⁵ and R ⁸ are each independently selected from (a) -CF ₃ , (b) C _1-3 alkyl; R ⁶ and R ⁷ are independently (a) hydrogen, and (b) C Selected from _1-3 alkyl; or R ⁶ and R ^{7 taken} together are a saturated 5-, 6- or 7-membered heterocycle (wherein the heterocycle contains a heteroatom nitrogen, optionally
Compounds according to claim 3, characterized in that they contain additional heteroatoms which are O or S atoms or NR ⁴ and optionally carbonyl groups). 5. (a) (R) -4- {2- (3-cyclopentyloxy-4-methoxyphenyl) -2- [4-
(4-Methylpiperazinocarbonyl) phenyl] ethyl} pyridine, (b) (R) -4- [2- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyrrolidinocarbonylphenyl) ethyl ] Pyridine, (c) (R) -4- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (4-pyridyl) ethyl] benzaldehyde oxime, (d) (R) -4- {2 -(3-Cyclopentyloxy-4-methoxyphenyl) -2- [4- (tetrazol-5-yl) phenyl] ethyl} pyridine, The compound according to claim 1, or a pharmaceutical thereof. Acceptable salt. 6. A non-toxic and therapeutically effective amount of claim 1, 2,
A pharmaceutical composition for treating asthma, comprising the 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 claim 1, 2, 3, 4 or 5 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.