ZA200203995B - Imidazole derivatives as phosphodiesterase VII inhibitors. - Google Patents

Imidazole derivatives as phosphodiesterase VII inhibitors. Download PDF

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ZA200203995B
ZA200203995B ZA200203995A ZA200203995A ZA200203995B ZA 200203995 B ZA200203995 B ZA 200203995B ZA 200203995 A ZA200203995 A ZA 200203995A ZA 200203995 A ZA200203995 A ZA 200203995A ZA 200203995 B ZA200203995 B ZA 200203995B
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ZA200203995A
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Hans Michael Eggenweiler
Michael Wolf
Oliver Poeschke
Rochus Jonas
Michael Gassen
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Merck Patent Gmbh
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Description

® WO 01/29049 - 1 - PCT/EP00/09926
Imidazole derivatives as phosphodiesterase VII inhibitors
The invention relates to compounds of the formula I
R! Re
AN
— § X 0] in which rR! Ls H, A, benzyl, indan-5-v1, 1,2,3,4- tetrahydronaphthalen-5-vy1, dibenzothiophen-2-y1, or phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, A-CO-NH, benzyloxy, alkoxy,
COOH or COOA,
Rr? is H or 2a,
X is O or §,
Hal is F, Cl, Br or I,
A is alkyl with 1 to 6 C atoms, and the physiologically acceptable salts and/or solvates thereof as phosphodiesterase VII inhibitors.
The invention further relates to the use of the compounds of the formula I for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
® a
Benzopyranoimidazoles are described, for example, by
M. Trkovnik et al. in Org. Prep. Proced. Int. (1987), 19(6), 450-5 or by V.L. Savel’ev et al. in Khim.-Farm.
Zh. (1983), 17(6), 697-700.
Benzothiopyranoimidazole derivatives are disclosed, for example, by V.L. Savel’ev et al. in Khim. Geterotsikl.
Soedin. (1980), (4), 479-83.
The invention was based on the object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
It has been found that the compounds of the formula I and their salts have very valuable rharmacclegical properties while being well tolerated.
In particular, they show a specific inhibition of the “rolipram-insensitive” cAMP phosphodiesterase (PDE VII).
The biological activity of the compounds of the formula
I can be determined methods like those described, for example, by M.A. Giembycz et al. in Br. J. Pharmacol. (1996), 118, 1945-1958.
The affinity of the compounds for cAMP phospho- diesterase (PDE VII) is determined by measuring their
ICs, values (concentration of the inhibitor required to achieve 50% inhibition of enzyme activity).
The determinations were carried out by using homogenized SK-N-SH neuroblastoma cells in place of T lymphocytes, and CI-930 was employed to inhibit
PDE ITI. The latter is a selective PDE III inhibitor (J.A. Bristol et al., J. Med. Chem. 1984, 27(9), 1099- 1101).
The compounds of the formula I can be emploved for treating asthmatic disorders.
The antiasthmatic effect can be determined, for example, in analogy to the method of T. Olson, Acta allergologica 26, 438-447 (1971).
° Ss
Since cAMP inhibits osteoclastic cells and stimulates osteoblastic cells (S. Kasugai et al., M 681 and
K. Miyamoto, M 682, in Abstracts of the American
Society for Bone and Mineral Research 18th Annual
Meeting, 1996), the compounds of the formula I can be employed for treating osteoporosis.
The compounds additionally show an antagonistic effect on the production of TNFa (tumour necrosis factor) and are therefore suitable for treating allergic and inflammatory disorders, autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis,
Crohn's disease, diabetes mellitus or ulcerative colitis, transplant rcjcction reactions, cachexia and sepsis.
The antiinflammatory effect of the substances of the formula I and their efficacy in the treatment of, for example, autoimmune diseases such as multiple sclerosis or rheumatoid arthritis can be determined in analogy to the methods of N. Sommer et al., Nature Medicine 1, 244-248 (1995) or L. Sekut et al., Clin. Exp. Immunol. 100, 126-132 (1895).
The compounds can be employed for treating cachexia.
The anticachectic effect can be tested in TNF-dependent models of cachexia (P. Costelli et al., J. Clin.
Invest. 95, 2367 ff (1995); J.M. Argiles et al., Med.
Res. Rev. 17, 477 ff (19%97)).
PDE VII inhibitors may also inhibit the growth of tumour cells and are therefore suitable for tumour therapy (for PDE IV inhibitors, cf. D. Marko et al.,
Cell Biochem. Biophys. 28, 75 ff (1998)).
They can additionally be employed for the therapy of sepsis and for the treatment of memory disturbances, atherosclerosis, atopic dermatitis and AIDS, as well as for the treatment of T-cell-dependent diseases (L. Li et al., Science, 1999, 283, 848-851).
® a
The invention further relates to the use of phosphodiesterase VII inhibitors for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
The compounds of the formula I can be employed as active pharmaceutical ingredients for PDE YIT inhibition in human and veterinary medicine.
A is alkyl with 1-6 C atoms and has 1, 2, 3, 4, 5 or 6
C atoms and is preferably methyl, ethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. A is also cycloalkyl such as, for example, cyclohexyl.
Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy.
Hal is preferably F or Cl.
A-CO-NH is preferably acetamido.
A base of the formula I can be converted with an acid into the relevant acid addition salt, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequently evaporating. Acids particularly suitable for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and organic acids,
J 5 in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds. of the formula I.
The invention further relates to pharmaceutical preparations comprising at least one phosphodiesterase
VII inhibitor of the formula I and/or one of its physiologically acceptable salts and/or solvates for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
This usually entails the substances being administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between about 0.02 and 10 mg/kg of body weight. The specific dose for each patient depends, however, on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the
® - 6 - rate of excretion, medicinal substance combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
The pharmaceutical preparations can be used as pharmaceuticals in human or veterinary medicine.
Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc. petrolatum. Used in particular for oral administration are tablets, pills, coated tablets, capsules, powders, granules, syrups, suspensions or drops, for rectal administration are suppositories, for parenteral administration are solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, and for topical administration are ointments, creams or dusting powders. The novel compounds can also be lyophilized and the resulting lyophilizates be used for example for producing products for injection. The indicated preparations can be sterilized and/or comprise excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colorants, flavourings and/or several other active ingredients, for example one or more vitamins.
The invention particularly relates to the compounds of the formula I listed in the following examples and their physiologically acceptable salts and/or solvates as PDE VII inhibitors, and to the use thereof for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as,
° Sg - for example rheumatoid arthritis, multiple sclerosis,
Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
Examples: 1-Phenyl-[l]benzopyrano(3,4-dlimidazol-4- (1H) -one, 1-Benzyl-[1l]benzopyrano[3,4-dlimidazol-~4- (1H) -one, 1-Cyclohexyl-[l]lbenzopyrano(3,4-dlimidazol-4- (1H) -one, 1-Cyclopentyl-[l]benzopyrano[3,4-d]limidazol-4- (1H) -one, 1-Butyl-[llbenzopyrano([3,4-d]limidazol-4- (1H) -one, 1 Isopropyl [(llbenzopyranc(3,4-dlimidazol-4-{1H)-one, 1-Propyl-[l]lbenzopyrano(3,4-d]imidazol-4- (1H) -one, 1-Ethyl-[l]lbenzopyrano([3,4-dlimidazol-4- (1H) -one, 1-Methyl-[l]benzopyrano([3,4-dlimidazol-4- (1H) -one, [l1]Benzopyrano{3,4-d]limidazol-4- (1H) -one, 2-Methyl-[l]lbenzopyrano([3,4-dlimidazol-4- (1H) -one, l-Phenyl-[l]lbenzothiopyrano([3,4-d]imidazol-4- (1H) -one, 1-Benzyl-[llbenzothiopyrano[3,4-dlimidazol-4- (1H) -one, 1-Cyclohexyl-[1l]lbenzothiopyrano([3,4-d]imidazol-4- (1H) -one, 1-Cyclopentyl-[l]benzothiopyrano[3,4-d]limidazol-4- (1H) -one, 1-Butyl-[l]lbenzothiopyrano([3,4-d]limidazol-4- (1H) -one, 1-Isopropyl-[llbenzothiopyrano[3,4-d]imidazol-4- (1H) -one, 1-Propyl-[llbenzothiopyrano(3,4-dlimidazol-4- (1H) -one, 1-Ethyl-[1l]benzothiopyrano[3,4-d]imidazol-4- (1H) -one, 1-Methyl-[1l]benzothiopyrano[3,4-dlimidazol-4- (1H) -one, [l]Benzothiopyrano([3,4-d]imidazol-4- (1H) -one, 2-Methyl-[l]benzothiopyrano[3,4-dlimidazol-4- (1H) -one, 1-(2-Chlorophenyl-[1]benzopyrano(3,4-dlimidazol-4- (1H) - one, 1-(4-Methyl-phenyl)-[1l]benzopyrano(3,4-d]limidazol-4- (1H) -one, 1-(4-Fluorophenyl)-[1l]benzopyrano(3,4-d]imidazol-4- (1H) -one, 1-(2,4-Dimethyl-phenyl) -[1l]benzopyrano[3,4-d]imidazol- 4- (1H) -one,
® - 8 - 1-(3-Chlorophenyl)~-[l]lbenzopyrano[3,4-dlimidazol-4- (1H) -one, 1-(2,4-Dichlorophenyl) -[1l]lbenzopyrano[3,4-dlimidazol-4- (1H) -one,
1-(2,5-Dichlorophenyl)-[1]benzopyrano[3,4-dlimidazol-4- (1H) -one, 1-(4-Acetamido-phenyl)-[1llbenzopyrano(3,4-dlimidazol-4- (1H) -one, 1-(2-Fluorophenyl)-{llbenzopyrano(3,4-d]imidazol-4-
(1H) -one, 1-(3-Fluorophenyl)-[llbenzopyrano[3,4-d]imidazol-4- (1H) -one, 1-(2-Benzyloxy-phenyl)-[1l]benzopyrano[3,4-dlimidazol-4- {1II) one,
1-(2,6-Dimethyl-phenyl)-[1l]benzopyrano(3,4-d]imidazol- 4- (1H) -one, 1-(Indan-5-yl)-[l]benzopyrano(3, 4-d]imidazol-4- (1H) - one,
1- (2-Methoxy-phenyl)-[1l]lbenzopyrano[3,4-d]imidazol-4-
(1H) -one, 1-(2,3-Dimethyl-phenyl)-[1]benzopyrano[3,4-d]imidazol- (1H) ~4-one, 1-(2,3-Dichlorophenyl)-[1l]benzopyrano[3,4-dlimidazol-4- (1H) -one,
1-(3-Chloro-4-methyl-phenyl)-[1]lbenzopyrano{3,4- d]imidazol-4- (1H) -one, 1-(2,5-Dimethyl-phenyl)-[1l]benzopyrano(3, 4-d]imidazol- 4- (1H) -one, 1-(4-Chlorophenyl)-[1l]lbenzopyrano([3,4-dlimidazol-4-
(lH) -one, 1-(1,2,3,4-Tetrahydronaphthalen-5-yl)-[1]benzopyrano- (3,4-d]imidazol-4- (1H) -one,
1- (Dibenzothiophen-2-yl)-[1]benzopyrano(3,4-d]imidazol- 4- (1H) -one,
1-(3-Methoxy-phenyl)-[1l]lbenzopyranol3,4-dlimidazol-4- (1H) -one, 1-(4-Carboxy-2-methyl-phenyl)-[1l]lbenzopyrano[3, 4- dlimidazol-4- (1H) -one,
® "2
The following examples relate to pharmaceutical preparations:
Example A: Vials
A solution of 100g of a phosphodiesterase VII inhibitor of the formula I and 5 g of disodium hydrogen phosphate in 3 1 of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterilized by filtration, dispensed into vials, lyophilized under sterile conditions and sealed sterile. Each vial contains 5 mg of active ingredient.
Example B: Suppositories
A mixture of 20 g of a phosphodiesterase VII inhibitor of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and left to cool. Each suppository contains 20 mg of active ingredient.
Example C: Solution
A solution is prepared from 1 g of a phosphodiesterase
VII inhibitor of the formula I, 9.38 g of NaH,;PQ4 - 2H;0, 28.48 g of Na;HPO4-12H,0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The pH is adjusted to 6.8, the volume is made up to 1 1, and the solution is radiation-sterilized. The solution can be used in the form of eyedrops.
Example D: Ointment 500 mg of a phosphodiesterase VII inhibitor of the formula I are mixed with 99.5 g of petrolatum under aseptic conditions.
Example E: Tablets
A mixture of 1 kg of phosphodiesterase VII inhibitor of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed to tablets in a conventional way so that each tablet contains 10 mg of active ingredient.
® - 10 -
Example F: Coated tablets
Tablets are compressed in analogy to Example E and are then coated in a conventional way with a coating consisting of sucrose, potato starch, talc, tragacanth and colorant.
Example G: Capsules 2 kg of phosphodiesterase VII inhibitor of the formula
I are packed in a conventional way into hard gelatin capsules so that each capsule contains 20 mg of the active ingredient.
Example H: Ampoules
A solution of 1 kg of phosphodiesterase VII inhibitor of the formula I in 60 1 of double-distilled water is sterilized by filtration, dispensed into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.
Example I: Inhalation spray 14 g of phosphodiesterase VII inhibitor of the formula
I are dissolved in 10 1 of isotonic NaCl solution, and the solution is dispensed into commercial spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray actuation (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (9)

PCT/EP00/09926 ¢ ~11- Patent Claims
1. Use of compounds of the formula I rR R2 Nord NT Z "Ng in which R' is H, A, benzyl, indan-5-y1, 1,2,3,4- tetrahydronaphthalen-5-vy1, dibenzothicphen-2-v1, or phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, Aa, A-CO-NH, Dbenzyloxy, alkoxy, COOH or CO0OO0A, R* is HE or A, oo X is 0 or Sg, Hal is F, Cl, Br or I,
i. A is alkyl with 1 to 6 C atoms, and the physiologically acceptable salts and/or solvates thereof for producing a pharmaceutical as phosphodiesterase VII inhibitor.
2. Use of compounds of the formula IT according to claim 1 according to claim 1 and/or their physiologically acceptable salts or solvates for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejeccicn reactions, ’ cachexia, tumour growth or tumour metastases, AMENDED SHEET
® -12- PCT/EP00/09926 sepsis, memory disturbances, atherosclerosis and AIDS.
3. Use of phosphodiesterase VII inhibitors for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
4. A substance or composition for use in a method of treatment for inhibiting phosphodiesterase VII, said substance or composition comprising compounds of the formula I R' Re — AN ZN in which rl is H, A, benzyl, indan-5-yl1, 1,2,3,4- tetrahydronaphthalen-5-yl, dibenzothiophen-2-yl, or phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or COOA, rR? is H or A, X is O or 8S, Hal is F, Cl, Br or I, A is alkyl with 1 to 6 C atoms, \ and/or their physiologically acceptable salts and/or solvates, and said method comprising administering said : substance or composition. AMENDED SHEET
. Vv -13- PCT/EP00/09926
5. A substance or composition for use in a method for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS, and said substance or composition comprising compounds of the formula I according to «claim 1 and/or their physiologically acceptable salts or solvates, and said method comprising administering said substance or composition.
6. A substance or composition for use in a method for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example rheumatoid arthritis, multiple sclerosis, Crohn’s disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS, and said substance or composition comprising phosphodiesterase VII inhibitors, and said method comprising administering said substance or composition.
7. Use according to c¢laim 1, or claim 2, or claim 3, substantially as herein described and illustrated.
8. A substance or composition for use in a method of treatment according to claim 4 or claim 5, or claim 6, substantially as herein described and illustrated. AMENDED SHEET
’ | . -14- PCT/EP00/09926
9. A new use of a compound as defined in claim 1 or of a physiologically acceptable salt and/or solvate thereof, a new use of phosphodiesterase VII inhibitors, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200203995A 1999-10-21 2002-05-20 Imidazole derivatives as phosphodiesterase VII inhibitors. ZA200203995B (en)

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DE19950647A DE19950647A1 (en) 1999-10-21 1999-10-21 Benzopyranoimidazolone and benzothiopyranoimidazolone derivatives as phosphodiesterase-VII inhibitors useful for treatment of e.g. asthma, psoriasis, osteoporosis, cachexia, sepsis, tumors and AIDS

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HU228316B1 (en) 2001-12-13 2013-03-28 Daiichi Sankyo Company Pyrazolopyrimidinone derivatives having pde7-inhibitory activity
DE10163991A1 (en) * 2001-12-24 2003-07-03 Merck Patent Gmbh Pyrrolo-pyrimidine
JP2006219373A (en) 2003-06-13 2006-08-24 Daiichi Asubio Pharma Co Ltd Pyridinylpyrazolopyrimidinone derivative having pde 7 inhibition
JP2006219374A (en) 2003-06-13 2006-08-24 Daiichi Asubio Pharma Co Ltd Imidazotriazinone derivative having pde 7 inhibition
EP1775298B1 (en) 2004-07-01 2013-03-20 Daiichi Sankyo Company, Limited Thienopyrazole derivative having pde7 inhibitory activity
US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
CN104758291B (en) 2007-03-27 2020-03-03 奥默罗斯公司 Use of PDE7 inhibitors for the treatment of movement disorders
US9220715B2 (en) 2010-11-08 2015-12-29 Omeros Corporation Treatment of addiction and impulse-control disorders using PDE7 inhibitors
US20120115849A1 (en) 2010-11-08 2012-05-10 Demopulos Gregory A Treatment of Addiction and Impulse-Control Disorders Using PDE7 Inhibitors
WO2024038089A1 (en) 2022-08-18 2024-02-22 Mitodicure Gmbh Use of a therapeutic agent with phosphodiesterase-7 inhibitory activity for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and/or exertional intolerance

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US4305954A (en) * 1981-02-11 1981-12-15 E. I. Du Pont De Nemours And Company Antiinflammatory 3,4-dihydro(or 1,4-dihydro)-2-[(substituted)thio]-[1]benzopyrano[3,4-d]imidazoles and their corresponding sulfoxides and sulfones
WO2000023091A2 (en) * 1998-10-15 2000-04-27 Bioimage A/S Specific therapeutic interventions obtained by interference with redistribution and/or targeting of cyclic nucleotide phosphodiesterases of i-kappa-b kinases
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