CA2166721C - Bicyclic tetrahydro pyrazolopyridines - Google Patents
Bicyclic tetrahydro pyrazolopyridinesInfo
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- CA2166721C CA2166721C CA002166721A CA2166721A CA2166721C CA 2166721 C CA2166721 C CA 2166721C CA 002166721 A CA002166721 A CA 002166721A CA 2166721 A CA2166721 A CA 2166721A CA 2166721 C CA2166721 C CA 2166721C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Compounds of formula (I) wherein R1, R2, R3 and X
are as defined. The compounds of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
are as defined. The compounds of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
Description
2~66~21 '~O 95I01980 PCT/IB94/00156 -1_ BICYCLIC TETRAHYDRO PYRAZOLOPYRIDINES
Background of the Invention This invention relates to a series of bicyclic tetrahydro pyrazolopyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (hereinafter TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases; and AIDS, septic shock and other diseases involving the production of TNF.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans and to pharmaceutical compositions useful therefor.
Since the recognition that cyclic AMP is an intracellular second messenger (E.W. Sutherland, and T. W. Rall, Pharmacol. Rev., 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE
have been recognized (J.A. Beavo and D. H. Reifsnyder, TIPS, 1990, 11, 150), and their selective inhibition has led to improved drug therapy (C.D. Nicholson, R. A.
Challiss and M. Shahid, TIPS, 1991, 12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M.W.
Verghese et al., J. Mol. Cell Cardiol., 1989) 12 (Suppl. II), S 61 ) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Druas, eds S. R.
O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE
type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers) FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E.
Spooner et al., Clinical Immunology and Immunopatholo4y, 1992, 62, S11 ).
Summary of the Invention The present invention relates to compounds of the formula:
I
and the pharmaceutically acceptable salts thereof;
wherein R1 is hydrogen, (C1-C~)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or methylene (C3-C5)cycloalkyl (i.e., (C3-C5)cycloalkyl-methyl), wherein each alkyl or alkenyl group may be optionally substituted with up to two (C1-C2)alkyl or trifluoromethyl groups or up to three halogens;
X is oxygen or two hydrogen atoms;
R2 and R3 are each independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C3-C~)cycloalkyl, cyclopropylmethyl, (C1-C14)alkoxy, (C2-C~)alkenyl, 2-indanyl, (C4-C~)heterocyclic group containing oxygen, sulphur, S02 or NR5 wherein R5 is hydrogen or (C1-C4)alkyl, or a group of the formula:
(R4)a II
(wherein a is an integer from 1 to 5; b and c are 0 or 1; R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, ,y~~
Background of the Invention This invention relates to a series of bicyclic tetrahydro pyrazolopyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (hereinafter TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases; and AIDS, septic shock and other diseases involving the production of TNF.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans and to pharmaceutical compositions useful therefor.
Since the recognition that cyclic AMP is an intracellular second messenger (E.W. Sutherland, and T. W. Rall, Pharmacol. Rev., 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE
have been recognized (J.A. Beavo and D. H. Reifsnyder, TIPS, 1990, 11, 150), and their selective inhibition has led to improved drug therapy (C.D. Nicholson, R. A.
Challiss and M. Shahid, TIPS, 1991, 12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M.W.
Verghese et al., J. Mol. Cell Cardiol., 1989) 12 (Suppl. II), S 61 ) and airway smooth muscle relaxation (T. J. Torphy in Directions for New Anti-Asthma Druas, eds S. R.
O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE
type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers) FEBS Letters, 1991, 285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E.
Spooner et al., Clinical Immunology and Immunopatholo4y, 1992, 62, S11 ).
Summary of the Invention The present invention relates to compounds of the formula:
I
and the pharmaceutically acceptable salts thereof;
wherein R1 is hydrogen, (C1-C~)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or methylene (C3-C5)cycloalkyl (i.e., (C3-C5)cycloalkyl-methyl), wherein each alkyl or alkenyl group may be optionally substituted with up to two (C1-C2)alkyl or trifluoromethyl groups or up to three halogens;
X is oxygen or two hydrogen atoms;
R2 and R3 are each independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C3-C~)cycloalkyl, cyclopropylmethyl, (C1-C14)alkoxy, (C2-C~)alkenyl, 2-indanyl, (C4-C~)heterocyclic group containing oxygen, sulphur, S02 or NR5 wherein R5 is hydrogen or (C1-C4)alkyl, or a group of the formula:
(R4)a II
(wherein a is an integer from 1 to 5; b and c are 0 or 1; R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, ,y~~
C02R6, CONR6R~, NR6R~, N02 or S02NR6R~ wherein R6 and R~ are each independently hydrogen or (C1-C4)alkyl; wherein Z is oxygen, sulphur, S02 or NR8 wherein R8 is hydrogen or (C1-C4)alkyl; and Y is (C1-C5)alkylene or (C2-C6)alkenylene each optionally substituted with up to two (C1-C~)alkyl or (C3-C~)cycloalkyl groups; or a group of the formula:
W
wherein p is an integer from 1 to 3, W is oxo or hydroxyl, R9 is (C1-C3)alkyl; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxy or heterocyclic group may be optionally substituted with one to fourteen, preferably one to five, substituents selected from the group consisting of (C1-C2)alkyl, trifluoromethyl and halogen, with the proviso that:
(1) when R1 is ethyl and R2 is 4-methylphenyl, then R3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl, (2) when R2 is 4-methylphenyl and R3 is 4-fluorophenyl, then R1 cannot be phenyl, methyl or n-propyl, (3) when R1 is ethyl and R2 is phenyl, then R3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, (4) when Rl is ethyl and R2 is 4-methoxyphenyl, then R3 cannot be 4-fluorophenyl, and (5) one of R2 or R3 must be other than hydrogen, (C1-C14)alkyl, (C2-C~)alkenyl, (C3-C~)cycloalkyl, cyclopropylmethyl, pyridyl, (C1-C2)alkylpyridyl or a group of the formula:
~4)a II
wherein b is one and c is zero or b and c are each zero, a is zero or one and R4 is (C1-C5)alkyl, (C1-C5)alkoxy, halo, trifluoromethyl, or di(C1-C4)alkylamino.
In one embodiment, the invention relates to a compound of formula I wherein R1 is (C1-C3)alkyl and R2 and R3 are each independently selected from the group consisting of (C3-C~)cycloalkyl, (C4-C~)heterocyclic group containing S02 or a group of the formula:
~4)a ITI
wherein a is an integer from 1 to 5 and R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy or halogen. An example of the (C4-C~)heterocyclic group containing S02 is 3-sulfolanyl.
In another embodiment, the invention relates to a compound of formula I wherein R1 is ethyl or isopropyl; R2 is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl and R3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, - 4a - 21 6 6 7 2 1 4-fluorophenyl or 3,4-dichlorophenyl.
The present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
The present invention further relates to a use of a compound according to formula I and the pharmaceutically acceptable salts thereof for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF).
The present invention further relates to a use of a compound of the formula I and the pharmaceutically acceptable salts thereof for treating an inflammatory condition in mammals.
The present invention further relates to a pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflaa~atory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier.
This invention further relates to a use of a compound according to formula I and the pharmaceutically - 4b -acceptable salts thereof for treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflaaanatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
Specific preferred compounds disclosed in this specification include both within and outside the scope claimed in this application, as follows:
3-ethyl-1-(4-methoxyphenyl)-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(4-fluorophenyl)-6-(2-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(3-methylphenyl)-7-oxo 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
''O 95I01980 ~ ~ ~ PCT/1B94/00156 3-isopropyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfolanyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(3-sulfolanyl)-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine.
Detailed Description of the Invention The term "halogen", as used herein, unless otherwise indicated, includes chloro, fluoro and bromo.
Unless indicated otherwise, the alkyl, alkoxy and alkenyl groups referred to herein may be straight chained or if comprising three or more carbons may be straight chained, branched, cyclic or a combination of cyclic and branched or straight chained moieties.
The "inflammatory diseases" which can be treated according to this invention include, but are not limited to asthma, chronic obstructive pulmonary disease, bronchitis and arthritis.
R' , R2 and R3, as used herein, unless otherwise indicated, are as defined above with reference to formula I.
The following reaction schemes illustrate, but are not limiting to the preparation of the compounds of the present invention.
21b6721 SCHEnE i NH ly ~NRZ 2 I R 1 R2~N OH
Iv v 0 VI
wRi R~~N OCH3 VII
SCHEnE 2 Ri i ~R
~ N I 0 R 5 ~.. N I N.~J
R R~
VIII IX
i Ri ~N~N.N
R
X
2 i 66l'2 - 'NO 95l01980 PCT/IB94/00156 _7_ In Reaction 1 of Scheme 1, the 2-pyrrolidinone compound of formula IV is converted to the corresponding N-(aryl)-2-pyrrolidone compound V wherein "aryl" is a group of the formula II by reacting IV with an aryl halide neat in the presence of copper power and potassium carbonate. Suitable aryl halides include 1-iodo- or 1-bromo- 4-methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4-methylbenzene) 2-methylbenzene, 3-trifluoromethylbenzene) 2-trifluoromethylbenzene) 3,4-dimethoxybenzene or 3-cyclopentoxy-4-methoxybenzene. The reaction temperature will generally be in the range of about 110 ~ C to about 170 ~ C, preferably about 150 ~ C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions.
In Reaction 2 of Scheme 1, R' halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed and thereafter cooled to atemperature between about -15~C
to about 15 ~ C, preferably about 0 ~ C. The N-(aryl)-2-pyrrolidone compound of formula V is then added and the reaction mixture is warmed to room temperature while being stirred for a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours. Suitable alkyl halides include bromomethane, bromoethane or bromopropane. The preferred anhydrous aprotic solvent is anhydrous ether. Upon completion of the reaction, the desired intermediate may be isolated in a conventional manner, e.g., by first washing the combined organics with water and brine, then drying over sodium sulfate, filtering and concentrating under reduced pressure to afford a readily-recoverable precipitate in the form of a white solid.
The above precipitate is converted to the corresponding 1 (2,5,6-tetrahydropyridine compound of formula VI by dispersing the precipitate in a mixture of a non-polar aprotic solvent and base. Upon vigorous stirring, ethyl oxalyl chloride is added and the reaction mixture is heated to reflux for a time period between about 1.5 hours to about 4.5 hours, preferably about 3.0 hours. The preferred non-polar aprotic solvent is benzene and the preferred base is sodium hydroxide. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in ethanol. After heating at reflux for a time period between about 1 hour and about 3 hours, preferably about 1.5 hours, the mixture is concentrated under reduced pressure and acidified to pH=3 with hydrochloric acid.
_g_ In Reaction 3 of Scheme 1, the compound of formula VI is converted to the corresponding 3-methoxy-1,2,5,6-tetrahydropyridine compound VII by heating to reflux a reaction mixture of VI and 3-methyl-1-p-tolyltriazene in an aprotic solvent.
The preferred aprotic solvent is 1,2-dichloroethane. The time period for the reaction is between about 30 minutes to about 120 minutes, preferably about 45 minutes.
In Reaction 1 of Scheme 2, the 1,2,5,6-tetrahydropyridine compound of formula VIII, wherein R5 is hydrogen or methyl, is converted to the corresponding 4,5,6,7-tetrahydro-7-oxo-1 H-pyrazolo[3,4-c]pyridine compound IX by reacting VIII with a hydrazine of the formula R3HNNHz. Both derivatives of the compound of formula VIII, 3-hydroxy and 3-methoxy, may be used as starting materials under one of three different sets of reaction conditions.
Under one set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX by reacting VIII with a hydrazine hydrochloride and sodium alkoxide in an anhydrous polar erotic solvent. The preferred sodium alkoxide is sodium methoxide and the preferred anhydrous polar erotic solvent is anhydrous ethanol. The reaction mixture is heated to reflux for a time period between about 9 hours to about 15 hours, preferably about 12 hours.
Under a second set of reaction conditions, the 1,2,5,6-tetrahydro-pyridine compound VIII is converted to the corresponding compound of formula IX by reacting VIII with hydrazinobenzoic acid in an anhydrous polar erotic solvent, preferably ethanol.
The reaction mixture is heated to reflux for a time period between about 16 hours to about 24 hours, preferably about 20 hours. The compound IX so formed may be further reacted to give the corresponding 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo(3,4-c]pyridine compound by reacting IX with sodium methoxide in a polar erotic solvent, preferably methanol, for a time period between about 15 minutes to about 45 minutes, preferably 30 minutes. The polar erotic solvent is removed under reduced pressure, the solid residue is suspended in a non-polar aprotic solvent, perferably benzene, and thereafter) the non-polar solvent is removed under reduced pressure. The resulting dry solid is suspended in cold ether and treated with oxalyl chloride and N,N-dimethylformamide and allowed to stir for a time period between about 30 minutes .to about 90 minutes, preferably 60 minutes. The solvent is then removed and the crude residue is dissolved in dry tetrahydrofuran. The resulting -g_ solution is added dropwise to stirred ammonium hydroxide at a temperature between about -10~C to about 10~C, preferably 0~C.
Under a third set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX
by reacting VIII with a hydrazine hydrochloride in a polar erotic solvent, preferably methanol. The reaction mixture is heated to a temperature between about 70~C
to about 110 ~ C, preferably about 90 ~ C, under a gentle stream of nitrogen until all of the solvent is removed. The neat mixture is then heated to a temperature between about 120 ~ C to about 180 ~ C, preferably about 150 ~ C, for a time period between about 30 minutes to about 90 minutes, preferably 60 minutes.
The compounds so formed of formula IX may be converted to the corresponding 6-Rz-4,5,6,7-tetrahydro-7-oxo-1 H-pyrazolo [3,4-c]pyridine compound, wherein R2 is other than the group of formula II, by reacting a solution of IX
in a polar aprotic solvent, preferably acetonitrile, with a solution of ammonium cerium (IV) nitrate in water at a temperature between about -15~C to about 15~C, preferably about 0~C, for a time period between about 20 minutes to about 50 minutes, preferably about 35 minutes. Upon completion of the reaction, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are then washed with saturated sodium bicarbonate followed by sodium sulfite. The compound so formed in a polar aprotic solvent, preferably tetrahydrofuran, is treated with sodium hydride, heated to reflux and stirred for a time period between about 30 minutes to about 60 minutes, preferably 45 minutes. The reaction mixture is cooled to a temperature between about 20 ~ C to about 30 ~ C, preferably about 25 ~ C, and an alkyl halide of formula RZ halide, wherein R~ is as defined with reference to formula I other than a group of formula II, is added. The reaction mixture is stirred and heated to reflux for a time period between about 12 hours to about 20 hours, preferably 16 hours.
In Reaction 2 of Scheme 2, the 2-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine compound IX is converted to the corresponding compound of formula X
by reacting IX with a reducing agent, preferably lithium aluminum hydride, in a non-polar aprotic solvent, preferably ether. The reaction is stirred for a time period between about 12 hours to about 20 hours, preferably 16 hours. Water and base) preferably sodium hydroxide, is then added and the reaction mixture is stirred for a time period between WO 95/01980 ~ PCT/IB94/00156 about 1.5 hours to about 2.5 hours, preferably 2 hours, and filtered. The filtrate is concentrated to a white solid.
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit phosphodiesterase IV (PDEQ) and, consequently, demonstrate their effectiveness for treating inflammatory diseases is shown by the following in vitro assay.
BIOLOGICAL ASSAY
(Human lung PDE,~) Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using a Tekmar Tissumizer~ (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000 x g for 70 minutes at 4~C. The supernatant is filtered twice through a 0.22,um filter and applied to a Mono-D
FPLC column (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1 ml/minute is used to apply the sample to the column, followed by a 2 ml/minute flow rate for subsequent washing and elution. Sample is eluted using an increasing, step-wise NaCI
gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are collected.
Fractions are assayed for specific PDE,~ activity, determined by [3H]CAMP hydrolysis and the ability of a known PDE,~ inhibitor (e.g. rolipram) to inhibit that hydrolysis.
Appropriate fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at -20~C until use.
Compounds are dissolved in DMSO at a concentration of 10 mM and diluted 1:25 in water (400 ,uM compound, 4% DMSO). Further serial dilutions are made in 4~~
DMSO to achieve desired concentrations. Final DMSO concentration in assay tube is 1 %. In duplicate the following are added, in order, to a 12 x 75 mm glass tube (all concentrations are given as final concentrations in assay tube).
i) 25 ,ul compound or DMSO (1 %, for control and blank) ii) 25 NI pH 7.5 Tris buffer iii) [3H]cAMP (1 ,uM) iv) 25 NI PDE", enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (37~C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water WO 95I01980 ~ b ~ PCTIIB94/00156 bath for 4 minutes. Washing buffer (0.5 ml, 0.1 M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1 M NaCI, pH 8.5) is added to each tube on an ice bath.
The contents of each tube are applied to an Affi-Gel 601 column (Biorad Laboratories, P.O. Box 1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinity gel, 1 ml bed volume) previously equilibrated with washing buffer. [3H)cAMP is washed with 2 x 6 ml washing buffer, and [3H]5'AMP is then eluted with 4 ml of 0.25M
acetic acid.
After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, vortexed and counted for [3H].
inhibition = 1 - avera a cpm test compound) - average cpm Lblank) average cpm (control) - average cpm (blank) ICSO is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [3H]CAMP to [3H]5'AMP.
(TNF) The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:
Peripheral blood (100 mls) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by Ficoll/Hypaque and washed three times in incomplete HESS. Cells are resuspended in a final concentration of 1 x 1 O6 cells per ml in pre-warmed RPMI
(containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 106 cells in 1.0 ml in 24-well plates. The cells are incubated at 37~C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10N1) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10N1) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37~C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). ICSo determinations are made for each compound based on linear regression analysis.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with HCI, HBr, HN03, HZS04, H3P04, CH3S03H, p-CH3C6HQS03H, CH3COZH, gluconic acid, tartaric acid, malefic acid and succinic acid. Pharmaceutically-acceptable cationic salts of the compounds of this WO 95/01980 2 ~ ~; 6 7 21 PCT/IB94/00156 invention of formula I wherein R4 is COZRs and R6 is hydrogen include, but are not limited to, those of sodium, potassium, calcium, magnesium) ammonium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine and diethanolamine.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of the compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter also referred to as the active compounds of the present invention) are generally in the range of from 0.1-100 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.1 to 50 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required.
For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1 ~~
(w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For administration to humans for the inhibition of TNF, a variety of conventional routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration 25 will, in any event, determine the appropriate dose for the individual subject.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovales either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously.
~VO 95/01980 ~ ~ ~ PCT/IB94/00156 For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic.
Thus in a further aspect the invention provides pharmaceutical compositions comprising a compound of the formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.
Example 1 3-Ethyl-1-~4-methoxyehenyl)-6-phenyl-7-oxo-4,5,6,7-tetrah~dro-1 H-pyrazolof3,4-c ridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydro-pyridine (1.0 g, 4.1 mmole), 4-methoxyphenylhydrazine hydrochloride (0.8 g, 4.6 mmole) and sodium methoxide (0.11 grams, 2 mmole) in 35 ml anhydrous ethanol (distilled from Mg) was heated at reflux. After 12 hours, the solvent was removed by rotory evaporation under reduced pressure, and the crude residue was chromatographed on a 4x20 cm silica column using 1:1 ether/hexane as eluent to give 345 mg of the title compound as a red oil that crystallized upon standing at room temperature. The desired 1-(4-methoxyphenyl) regioisomer is less polar than the 2-(4-methoxyphenyl) byproduct.
M.P. 43-45~C, IR (chloroform) lactam C=O, 1665 cm-'; 'H NMR (300 MHz, CDC13) d 1.32(t,J=7.6Hz,3H),2.74(q,J=7.6Hz,2H),2.96(t,J=6.6Hz,2H),3.79(s,3H), 4.10 (t,J = 6.6 Hz, 2H), 6.89 (d,J = 9.0 Hz, 2H), 7.22-7.39 (m, 5H), 7.45 (d,J
= 9.0 Hz, 2H); Anal. calcd. for C2, Hz, N302: C, 72.60; H, 6.09; N, 12.09. Found; C, 72.48; H, 6.08; N, 11.66; MS m/z (M+) 347.
Examples 2-15 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 1, affords the following compounds.
Ex.#R' Rz R3 M.p.C Mass Spectra Mass Spectra or or Analysis (ealcd.)Analysis (found) %C, %H, %N %C, %H) %N
2 ethyl phenyl methyl 80-83 70.56, 6.71, 70.61, 6.77, 16.46 15.51 3 ethyl phenyl ten-butyl120-121?2.70, 7.79, 72.50, 7.96, 14.13 14.16 4 ethyl 4-methoxy4-methoxy42-45 70.01, 6.14, 70.05, 6.07, 11.13 11.00 phenyl phenyl ethyl 4-fluorotert-butyl92-94 (M') 315.1747HRMS (M') phenyl 315.1741 6 ethyl phenyl 3,4- (oil) [M' ] 386.26 MS m/z [M+]
dichloro-phenyl 7 ethyl 4-fluoro4-methoxy129-130'69.03, 5.52, 68.75, 5.37, 11.50 11.43 phenyl phenyl 5 8 methylphenyl 4-fluoro139-140[M'] 321.3 MS m/z [M') phenyl 9 ethyl phenyl cyclopent73-75 (M+) 309.1841HRMS (M+) yl 309.1823 methylphenyl 4-methoxy167-168(M+) 333.1477HRMS (M+) phenyl 333.1477 11 ethyl phenyl 5-phenyl(oil) (M+) 388.2389HRMS (M+) pentyl 388.239S
12 methyl4-methoxy4-fluoro140-14268.36, 5.16, 67.92, 5.03, 11.96 11.72 phenyl phenyl 10 13 methyl4-methoxy3-fluoro133-13868.36, 5.16, 68.04, S.04, 11.96 11.7S
phenyl phenyl 14 ethyl 4-methoxy3,4- 50-60 60.59, 4.60, 60.34, 4.56, 10.09 9.86 phenyl dichloro-phenyl ethyl 3-methoxymethyl (oil) [M' ] 285.3S MS m/z [M' ] 286 phenyl Recrystallizing solvents: aisopropyl ether. b5% Ethyl acetate in petroleum ether.
15 Example 16 3-Ethyl-1-(4-phenylcarboxylic acid)-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo f3,4-clp~rridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydro-pyridine (1.0 grams, 4.08 mmole), 4-hydrazinobenzoic acid (0.68 grams, 4.49 mmole) and 30 ml of anhydrous ethanol was heated at reflux. After 20 hours, the mixture was concentrated by rotory evaporation under reduced pressure, and the solid residue was suspended in a mixture of ethyl acetate (500 ml) and pH 4 buffer (200 ml). The organic layer was separated (leaving behind most of the 2-(4-phenylcarboxylic acid) byproduct), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
Recrystallization from methanol gives 0.64 grams of the title compound as an orange solid. M.P. 261-263~C, 'H NMR (300 MHz, DMSO-d6j, d 1.23 (t,J = 7.6 Hz, 3H), 2.68 (q,J - 7.6 Hz, 2H), 2.94 (t,J = 6.5 Hz, 2H), 4.05 (t,J = 6.5 Hz, 2H), 7.20-7.41 (m) 5H), 7.65 (d,J = 8.6 Hz) 2H), 7.96 (d,J = 8.6 Hz) 2H)) 13.05 (s) 1 H); MS m/z (M+) 362.
Example 17 1-(4-Benzamide)-3-ethyl-6-(4-methoxyphenyll-7-oxo-4.5.6,7-tetrahydro-1 H-prrazolof3,4-clpyridine To a stirred solution of sodium methoxide in methanol (prepared from 6.6 mg Na) is added 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-cjpyridine (96 mg, 0.25 mmole). After 30 minutes, methanol was removed under reduced pressure, the solid residue was suspended in benzene, and the benzene was removed under reduced pressure. The resulting dry solid was suspended in cold ether (ice-bath) and treated with oxalyl chloride (31 NI, 0.35 mmole) and anhydrous N,N-dimethylformamide (1 drop). After stirring for 1 hour the valatiles are removed under reduced pressure, and the crude residue was dissolved in dry tetrahydrofuran. The resulting solution was added dropwise to briskly stirred ammonium hydroxide at 0 ~ C. After warming to ambient temperature over 2 hours the reaction mixture was concentrated under reduced pressure until a yellow solid begins to precipitate. At this time the mixture was diluted with water to approximately 100 ml and filtered, and the precipitate was washed with water to give 81 mg of the title compound. Decomposition point 243-245 ~ C; ' H NMR (DMSO-ds) 1.24 (t,J = 7.6 Hz, 3H), 2.68 (q,J = 7.6 Hz, 2H), 2.93 (t,J = 6.5 Hz, 2H), 3.75 (s, 3H), 3.99 (t,J
= 6.5 Hz, 2H), 6.94 (d,J = 9.1 Hz, 2H), 7.27 (d,J = 9.0 Hz, 2H), 7.43 (s, 1 H), 7.59 (d,J = 8.5 Hz, 2H), 7.90 (d,J = 8.6 Hz, 2H), 8.04 (s, 1 H); Anal. calcd. for CZZHZZN403: C, 67.68; H, 5.68; N, 14.35. Found: C, 67.19; H) 5.31; N, 13.55. HRMS calcd. for CZZHzzNa03 [M+]
391.1770. Found 391.1781.
The starting 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-cj pyridine was prepared using the appropriate reagents according to the procedure of example 16.
WO 95/01980 2 ~ 6 6 7 21 PCT/IB94/00156 Example 18 1-(3 4-dichloropheny~-3-ethy~3-methoxyphenyl)-7-oxo-4.5.6,7-tetrahydro-1 H-pyrazolo f 3,4-cl pyridine A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydro-pyridine (0.49 grams,1.7 mmole), 3,4-dichlorophenylhydrazine hydrochloride (0.40 grams, 1.87 mmole) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave 0.46 grams of white needles. M.P. 97-99~C,'H NMR (250 MHz, CDCI3) 1.31 (t,J = 7.5 Hz, 3H), 2.73 (q,J = 7.6 Hz. 2H), 2.96 (t,J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.09 (t,J
= 6.6 Hz, 2H), 6.78-6.91 (m, 3H), 7.29-7.49 (m, 3H), 7.73 (d,J = 1.8 Hz, 1 H); MS m/z [M+] 416.
Examples 19-42 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 18, affords the following compounds.
Ex.#R' RZ R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.}Analysis (found) , %C, %H, %N %C, %H, %N
19 methyl4-methoxy3-4- 143-144'59.71, 4.26, 56.13, 4.02, 10.45 9.65 phenyl dichloro-phenyl 20 ethyl 3-methoxycyclo- 64-65 [M' ] 340.2025HRMS [M+]
phenyl pentyl 340.2046 21 ethyl 4-methoxycyclo- 96-98 70.77, 7.42, 70.44, 7.68, 12.38 11.69 phenyl pentyl 22 methyl4-methoxycyclo- 121-12270.13, 7.12, 69.48, 7.10, 12.91 12.70 phenyl pentyl 23 iso- phenyl 3,4- oil [M'] 400.0983HRMS [M']
propyl dichloro 400.0966 phenyl 24 ethyl 3,4-dimeth-cyclo- 107-108[M'] 369.46 MS m/z [M']
oxyphenylpentyl 25 ethyl 3,4-dimeth-3,4- 190-19159.20, 4.74, 59.41, 4.46, 9.41 9.71 oxyphenyldichloro-phenyl vo 95/01980 216 6 7 21 Ex.# R' R2 R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
26 iso- 4-methoxy3,4- 145-147'61.40, 4.92, 61.29, 4.81, 9.76 9.53 propylphenyl dichloro phenyl 27 propyl4-methoxycyclo- 102-103'71.36, 7.70, 70.98, 7.66, 11.89 11.73 phenyl pentyl 28 iso- 3-methoxy3,4- 126-12T61.40, 4.92, 61.55, 5.10, 9.76 9.97 propylphenyl dichloro-phenyl 29 ethyl 4-methoxy-3,4- 54-56 62.40, 5.44, 62.15, 5.S0, 8.40 7.97 3-cyclo-dichloro-pentoxy-phenyl phenyl 30 ethyl 4-methoxy-cyclo- 88-89 [M' ] 423.S5 MS m/z [M' ) 423 3-cyclo-pentyl pentoxy-phenyl 31 ethyl 3-methoxy4-fluoro-139-140'69.03, 5.79, 69.05, 5.42, 11.50 11.57 phenyl phenyl 32 ethyl 2-methoxycyclo- 119-12070.77, 7.42, 70.63, 7.16, 12.38 12.01 phenyl pentyl 33 ethyl 2-methoxy4-fluoro-103-104'[M' ] 365.41 MS m/z [M' ) 366 phenyl phenyl 34 ethyl 3-methylcyclo- oil 74.27, 7.79, 74.54, 7.89, 12.99 12.63 phenyl pentyl 35 ethyl 3-methyl4-fluoro-oil 72.19,5.77, 72.06, 5.55, 12.02 11.52 phenyl phenyl 36 ethyl 3-trifluoro-cyclo- oil 63.65, 5.87, 63.9S, 5.73, 11.13 10.97 methyl- pentyl phenyl 37 ethyl 3-trifluoro-4-fluoro-139-140'62.53) 4.25, 62.60, 4.08, 10.42 10.41 methyl- phenyl phenyl 38 ethyl 4-methyl-cyclo- 93-94 74.27, 7.79, 74.10, 7.52, 12.99 12.59 phenyl pentyl 39 ethyl 2-methyl-4-fluoro-141-142b72.19, S.77, 72.36) 5.52) 12.03 12.09 phenyl phenyl 40 ethyl 2-methyl-cyclo- 130-131MW 323.44 MS m/z 323 phenyl pentyl 21 ~6~2~
Ex.# R' Rz R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
41 ethyl 2-trifluoro-4-fluoro-48-50 MW 403.38 MS m/z 404 methyl- phenyl phenyl 42 ethyl 3-methyl-3-sulfo-oil MW 373.47 MS m/z 374 phenyl lanyl Recrystallizing solvents: B 5% Ethyl acetate/petroleum ether. b Isopropyl ether.
' Ethyl acetate/hexane. dEthyl ether. e5% Ethyl acetate/pentane. 'Pentane.
Example 43 1-Cvclohexvl-3-ethyl-6-(3-methoxvphenvl)-7-oxo-4.5.6.7-tetrahvdro-1 H-pyrazolo(3,4-clpyridine A solution of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-pyridine (0.80 grams, 2.8 mmole) and cyclohexylhydrazine hydrochloride (0.54 grams, 3.6 mmole) in methanol (15 ml) was warmed to 90~C under a gentle stream of nitrogen until all of the solvent was removed. The neat mixture was then heated to approximately 150~C under nitrogen for 1 hour. After cooling to room temperature, the mixture was dissolved in ether and washed with 1 N hydrochloric acid followed by brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
Chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent gives 0.47 grams of the title compound as a yellow oil. ' H NMR (250 MHz, CDCI3) 1.20-1.52 (m, 6H, including t at 1.23, J = 7.6 Hz, 3H), 1.64-1.74 (m, 1 H), 1.80-2.06 (m, 6H), 2.67 (q,J
= 7.6 Hz, 2H), 2.87 (t,J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.97 (t,J = 6.7 Hz, 2H), 5.13 (tt, J
= 4.3 and 11.3 Hz, 1 H), 6.79-6.93 (m, 3H), 7.31 (t,J = 8.1 Hz) 1 H); HRMS
calculated for C2,H2,N30z[M+]: 353.2103. Found: 353.2094.
Examples 44-57 Reaction of the appropriate hydrazine hydrochloride with the requisite 4 alkanoyl-3-methoxy-2-oxo-1,2,5.6-tetrahydropyridine, analogous to the procedure of Example 43, affords the following compounds.
Ex.# R' Rz R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
44 iso- 4-methoxycyclo- 102-103'[M'] 354 MS [M'] 354 propylphenyl pentyl p VO 95/01980 ~ PCT/IB94100156 Ex.# R' R2 R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
45 iso- 3-methoxycyclo- 99-10071.36, 7.70, 71.10, 7.56, 11.89 11.73 propylphenyl pentyl 46 ethyl 3-methoxycyclobutyl73-74b70.13, 7.12, 70.10, 7.22, 12.91 12.93 phenyl 47 ethyl phenyl methylene60-62'73.19, 7.17, 73.34, 7.08, 14.23 13.95 cyclo-propyl 48 ethyl 3-methoxymethyleneoil [M' ] 326 MS [M' ] 326 phenyl cyclo-propyl 49 ethyl 4-methoxy-phenyl 156-157b72.60, 6.09, 72.35, 5.91, 12.10 12.02 phenyl 50 ethyl 3-methoxy-3-sulfo-oil 58.59, 5.95, 58.46, 6.03, 10.79 9.82 phenyl lanyl 51 ethyl 3-methoxy-4-trifluoro-124-12563.61, 4.85, 63.40, 4.51, 10.12 10.09 phenyl methyl-phenyl 52 ethyl 3-methyl-cyclobutyloil 73.75, 7.49, 73.22, 7.56, 13.S8 13.03 phenyl 53 ethyl 3-trifluoro-3-sulfo-oil MW 427.44 MS m/z 428 methyl- lanyl phenyl 54 ethyl 3-trifluoro-cyclobutyloil 62.80, 5.55, 63.01, 5.54, i 1.56 i 1.19 methyl-phenyl 55 ethyl phenyl 2-indanyl155-156'77.28, 6.49, 77.35, 6.48, 11.76 11.08 56 ethyl 2-methyl-cyclobutyl100-102MW 309.41 MS m/z 310 phenyl 57 ethyl 3-methoxy-2-indanyl60-62'MW 387.48 MS m/z 388, 389, phenyl 390 Recrystallization solvents: ~Ethyl acetate/pentane. bEthyl ether/pentane.
'Isopropyl ether/pentane. dEthyl/acetate/petroleum ether. ~Ethyl acetate.
'Ethyl acetate/hexane.
WO 95/01980 ~ ~ ~ PCT/IB94/00156 Example 58 3-Ethyl-6-(4-fluorophenyl -~1-(4-methoxVphenyl)-4,5.6,7-tetrahydro-1 H-p~rrazolo(3,4-clp riy dine To a stirred solution of 3-Ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (0.3 grams, 0.82 mmole) in 50 ml ether was added lithium aluminum hydride (33 mg, 0.86 mmole). After stirring for 16 hours water (0.5 ml) was added followed by 3N sodium hydroxide (1 ml). After stirring for 2 hours the white precipitate was filtered through celite and the filtrate is concentrated under reduced pressure. Chromatography on a silica gel column using 1:3 ethyl acetate/hexane as eluent gives 0.12 grams of the title compound as a pale yellow paste. ' H NMR (250 MHz, CDCI3) 1.28 (t,J = 7.6 Hz, 3H), 2.66 (q,J = 7.6 Hz, 2H), 2.71 (t,J = 5.7 Hz, 2H), 3.49 (t,J = 5.7 Hz, 2H), 3.84 (s, 3H), 4.23 (s, 2H), 6.84-6.99 (m, 6H), 7.36 (d,J = 9.0 Hz, 2H); MS m/z [M+] 352.
Examples 59-63 Reaction of the appropriate 7-oxo-2,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine with lithium aluminum hydride, analogous to the procedure of Example 58, affords the following compounds.
Ex.#R' Rz R3 M.p.C Mol. WeightMass Spectra (M'] (found) 59 ethyl 4-methoxy-3-cyclopentyloil 409.57 409 cyclopentoxy phenyl 60 ethyl phenyl 3,4-dichloro-oil 372.30 371.373 phenyl 61 ethyl phenyl cyclopentyloil 295.43 296 62 ethyl 3-methoxy cyclobutyloil 311.43 312 phenyl 63 ethyl 3-methoxy cyclohexyloil 339.48 340 phenyl .
Example 64 1-cyclopentyl-3-ethyl-7-oxo-4,5,6.7-tetrahydro-1 H-pyrazolo(3,4-cl~rridine A stirred solution of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo(3,4-c]pyridine (2.58 grams, 7.60 mmoles) in acetonitrile (90 ml) at 0~C is treated with a solution of ceric ammonium nitrate (12.5 grams, 22.8 mmoles) ~''VO 95I01980 216 6 7 21 PCT/IB94/00156 in water (110 ml). After stirring for 35 minutes the mixture is diluted with water (550 ml) and extracted with ethyl acetate (100 ml x 4). The combined organics are washed with 50~~ saturated sodium bicarbonate (250 ml) followed by 10% sodium sulfite until the aqueous wash becomes pale yellow. The organic layer is then washed further with saturated bicarbonate and brine, and treated with decolorizing charcoal. After stirring for 30 minutes the mixture is dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The brown residue is recrystallized from ether to give .814 grams of a tan solid. M. P. 143-145 ~ C; MS (M/Z) 234; ' H NMR
(250 MHz, CDCl3) 1.21 (t, J = 7.6 Hz, 3H), 1.62-2.13 (m, 8H), 2.62 (q, J = 7.6 Hz, 2H)) 2.73 (t, J
= 6.8 Hz, 2H), 3.51 (dt, J = 2.7 and 6.8 Hz, 2H), 5.47 (s, 1 H), 5.61 (pentet, J = 7.7 Hz, 1 H).
Example 65 1-c5rclopentyl-3-ethyl-6-cycloprop I~yl-7-oxo-4.5.6,7-tetrahydro-1 H-pyrazolo(3,4-clpyridine A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (0.21 grams, 0.92 mmoies) in THF (5 ml) is treated with 60% sodium hydride in mineral oil (40 mg, 1.01 mmoles). After stirring at reflux over 45 minutes the reaction mixture is cooled to 25 ~ C and (bromomethyl) cyclopropane (0.31 grams, 2.29 mmoles) is added. The mixture is stirred at reflux for 16 hours and then cooled to 25~C before concentrating under reduced pressure. Chromatography on silica gel eluting with 1:1 ethyl acetate/hexane gives 0.19 grams of the title compound as a colorless oil. MS m/z [M+] 288; ' H NMR (300 MHz, CDC13) 0.26-0.31 (m, 2H), 0.50-0.56 (m, 2H), 0.85-1.06 (m, 1 H), 1.20 (t, J = 7.6 Hz, 3H), 1.62-2.08 (m, 8H), 2.61 (q, J = 7.6 Hz, 2H), 2.74 (t, J=6.8Hz,2H),3.39(d,J=6.9Hz,2H),3.63(t,J=6.8Hz,2H),5.67(pentet,J=
7.8 Hz, 1 H).
Preparation 1 4-isobutyryl-3-methoxy-1-phenyl-2-oxo-1,2.5,6-tetrahydropyridine A stirred solution of freshly distilled diisopropylamine (0.16 ml, 2.21 mmole) in anhydrous tetrahydrofuran (4 ml) was cooled to 0 ~ C and treated with 2.5 M n-butyl lithium (0.85 ml, 2.11 mmole). After 15 minutes the mixture was cooled to -78~C and a pre-cooled solution of 4-propionyl-3-methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine (0.52 grams, 2.0 mmole) in tetrahydrofuran (4 ml) was added dropwise via cannula. After approximately 20 minutes methyl iodide (0.20 ml, 3.0 mmole) was added to the bright orange-red solution and the mixture was allowed to come to room temperature over 2.5 hours. The reaction mixture is poured into saturated aqueous ammonium chloride and the organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
Chromatography on a silica gel column using 1:4 ethyl acetate/hexane as eluent gives 0.12 grams of the title compound as a yellow oil and 0.1 grams of recovered starting material. ' H NMR (250 MHz, CDCI3) 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (heptet, 1 H), 3.82 (t, 2H), 3.97 (s, 3H), 7.21-7.45 (m, 5H); MS m/z [M+] 274.
Preparations 2-3 Reaction of the appropriate 3-methoxy-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine with lithium diisopropylamine and methyl iodide, analogous to the procedure of preparation 1, affords the following compounds of formula VII.
Prep# Rz m.p. C M.W. Mass Spectra [M+]
2 4-methoxyphenyloil 303.36 304 3 3-methoxyphenyloil 303.36 304 Preparation 4 3-Methoxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine A solution of 3-hydroxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine (5.9 grams, 23 mmole) and 3-methyl-1-p-tolyltriazine (5.1 grams, 34 mmole) in 1,2-dichloroethane was heated to reflux for 45 minutes. The mixture was allowed to cool to room temperature and was poured into water and acidified with 6N
hydrochloric acid. The aqueous layer was extracted 3 times with methylene chloride, and the combined organics are washed with 1 N hydrochloric acid followed by water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting quantitative brown oil was clean by thin layer chromatography and ' H NMR and was used without purification. ' H NMR (300 MHz, CDCI3) 1.12 (t,J =
7.2 Hz, 3H), 2.34 (s, 3H), 2.71 (t,J = 6.7 Hz, 2H), 2.93 (q,J = 7.2 Hz, 2H), 3.77 (t,J =
6.8 Hz, 2H), 3.94 (s, 3H), 7.20 (s, 4H); MS [M+] 273.
Preparations 5-14 WO 95/01980 2 ~ b 6 7 21 PCT/IB94/00156 Reaction of the appropriate 3-hydroxy-1-aryl-2-oxo-4-alkanoyl-1,2,5,6-tetrahydropyridine with 3-methyl-1-p-tolyltriazine, analogous to the procedure of Preparation 4, affords the following compounds of formula VI.
Prep# R' Rz m.p. M.W. Mass C Spectra IM+l 5 ethyl phenyl oil 259.31 260 6 methyl 4-methoxyphenyl oil 275.30 275 7 ethyl 4-methoxyphenyl 81-82 289.33 289 8 n-propyl 4-methoxyphenyl oil 303.36 303 9 ethyl 3-methoxyphenyl 59-60 289.33 289, 10 ethyl 2-methoxyphenyl oil 289.33 289 11 ethyl 3,4-dimethoxyphenyloil 319.26 319 12 ethyl 3-cyclopentoxy-4-oil 373.45 373 methoxyphenyl 13 ethyl 3-methylphenyl oil 273.33 273 14 ethyl 3-trifluoromethylphenyloil 327.30 327 Preparation 15 -3-Hvdroxv-1-(3-methvlphenvl)-2-oxo-4-propionvl-1.2.5.6-tetrahvdropvridine To a stirred suspension of magnesium turnings (1.9 grams, 79 mmole) in 30 ml of anhydrous ether was added dropwise bromoethane (5.9 ml, 79 mmole). A mild reflux was initiated after approximately 1 ml was added. After all of the magnesium was consumed, the reaction mixture was cooled to 0~C and N-(3-methylphenyl)-2-pyrrolidone (8.7 grams, 50 mmole) was added at once. After warming to room temperature and stirring for 2 hours the reaction mixture was poured over ice and extracted with ethyl acetate. The combined organics are washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8.8 grams of a white solid.
The above solid is dispersed in a mixture of 40 ml benzene and 86 ml 1 N
sodium hydroxide, and with vigorous mechanical stirring ethyl oxalyl chloride (7.2 ml, 64 mmole) was added. After stirring at reflux over 1.5 hours the layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organics are washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber oil. GCMS [M+] 305.
The above intermediate was dissolved in 20 ml anhydrous ethanol and treated with a solution of sodium methoxide in methanol (prepared from the careful addition of sodium (1.0 grams) to 10 ml anhydrous methanol). After being stirred at reflux over 1.5 hours, the mixture was concentrated under reduced pressure and 100 ml of water was added. The mixture was acidified to pH 3 with 6N hydrochloric acid and the dull yellow precipitate was filtered and washed with water. Recrystallization from 75 ml isopropyl ether affords 6.8 grams of pale yellow crystals. M.P. 115-116~; 'H NMR (300 MHz, CDC13) 1.16 (t,J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.74-2.82 (m, 4H), 3.85 (t,J =
6.8 Hz, 2H), 7.08-7.14 (m) 3H), 7.30 (t,J = 7.7 Hz, 1 H); MS m/z (M+] 259.
Preparations 16-29 Reaction of the appropriate 2-pyrrolidinone with the requisite alkylmagnesium bromide, followed by treatment with ethyl oxalyl chloride and base, analogous to that reported in Preparation 15, affords the following compounds of formula VI.
Prep# R' RZ m.p. M.W. Mass C Spectra (M+]
16 methyl phenyl oil 231.25 231 17 ethyl phenyl 140-142 245.28 245 18 ethyl 4-fluorophenyl 133-135 263.27 263 19 methyl 4-methoxyphenyl oil 261.28 262 20 ethyl 4-methoxyphenyl 121-122 275.30 276 21 n-propyl 4-methoxyphenyl 125-126 289.33 289 22 ethyl 3-methoxyphenyl 129-130 275.30 275 23 ethyl 2-methoxyphenyl 119-120 275.30 275 24 ethyl 4-methylphenyl 110-112 259.30 260 25 ethyl 2-methylphenyl oil 259.30 259 26 ethyl 3-trifluoromethylphenyl117-118 313.28 313 27 ethyl 2-trifluoromethylphenyloil 313.28 313 28 ethyl 3,4-dimethoxyphenyl179-180 305.33 306 ''VO 95I01980 ~ b ~ ~ PCT/IB94/00156 Prep#R' Rz m.p. M.W. Mass C
Spectra [M+]
29 ethyl 3-cyclopentoxy-4-133-134 359.42 360 methoxyphenyl Preparation 30 N-(2-MethoxVphenyl?-2-pVrrolidone A mixture of 2-pyrrolidone (15.0 grams, 176 mmole), 2-iodoanisole (7.6 ml, 59 mmole), copper powder (7.5 grams, 117 mmole) and potassium carbonate (8.1 grams, 59 mmole) are stirred under nitrogen at 150~C. After 18 hours, the reaction mixture was filtered through a 6x15 cm pad of silica gel eluting with 1:1 ethyl acetate/hexane to give a pale yellow oil. The unreacted reagents are removed by vacuum distillation (0.6 mm, 80-100~C) Veaving 9.2 grams of the title compound as a honey-like oil. 'H
NMR (300 MHz, CDCI3) 2.20 (pentet, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (s, 3H), 6.93-7.02 (m, 2H), 7.25-7.30 (m, 2H); MS m/z [M+] 191.
Preparations 31-39 Reactions of the appropriate iodo- or bromobenzene with 2-pyrrolidinone, analogous to that reported in Preparation 30, affords the following compounds of formula V.
Prep# R M.W. Mass Spectra [M+]
31 4-methoxyphenyl 191.22 191 32 3-methoxyphenyl 191.22 191 33 3-methylphenyl 175.23 175 34 4-methylphenyl 175.23 175 35 2-methylphenyl 175.23 175 36 3-trifluoromethylphenyl229.20 229 37 2-trifluoromethylphenyl229.20 229 38 3,4-dimethoxyphenyl221.26 221 39 3-cyclopentoxy-4-275.35 275 methoxyphenyl
W
wherein p is an integer from 1 to 3, W is oxo or hydroxyl, R9 is (C1-C3)alkyl; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxy or heterocyclic group may be optionally substituted with one to fourteen, preferably one to five, substituents selected from the group consisting of (C1-C2)alkyl, trifluoromethyl and halogen, with the proviso that:
(1) when R1 is ethyl and R2 is 4-methylphenyl, then R3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl, (2) when R2 is 4-methylphenyl and R3 is 4-fluorophenyl, then R1 cannot be phenyl, methyl or n-propyl, (3) when R1 is ethyl and R2 is phenyl, then R3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, (4) when Rl is ethyl and R2 is 4-methoxyphenyl, then R3 cannot be 4-fluorophenyl, and (5) one of R2 or R3 must be other than hydrogen, (C1-C14)alkyl, (C2-C~)alkenyl, (C3-C~)cycloalkyl, cyclopropylmethyl, pyridyl, (C1-C2)alkylpyridyl or a group of the formula:
~4)a II
wherein b is one and c is zero or b and c are each zero, a is zero or one and R4 is (C1-C5)alkyl, (C1-C5)alkoxy, halo, trifluoromethyl, or di(C1-C4)alkylamino.
In one embodiment, the invention relates to a compound of formula I wherein R1 is (C1-C3)alkyl and R2 and R3 are each independently selected from the group consisting of (C3-C~)cycloalkyl, (C4-C~)heterocyclic group containing S02 or a group of the formula:
~4)a ITI
wherein a is an integer from 1 to 5 and R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy or halogen. An example of the (C4-C~)heterocyclic group containing S02 is 3-sulfolanyl.
In another embodiment, the invention relates to a compound of formula I wherein R1 is ethyl or isopropyl; R2 is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl and R3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, - 4a - 21 6 6 7 2 1 4-fluorophenyl or 3,4-dichlorophenyl.
The present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
The present invention further relates to a use of a compound according to formula I and the pharmaceutically acceptable salts thereof for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF).
The present invention further relates to a use of a compound of the formula I and the pharmaceutically acceptable salts thereof for treating an inflammatory condition in mammals.
The present invention further relates to a pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflaa~atory diseases, AIDS, septic shock and other diseases involving the production of TNF comprising a pharmaceutically effective amount of a compound according to formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier.
This invention further relates to a use of a compound according to formula I and the pharmaceutically - 4b -acceptable salts thereof for treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflaaanatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
Specific preferred compounds disclosed in this specification include both within and outside the scope claimed in this application, as follows:
3-ethyl-1-(4-methoxyphenyl)-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(4-fluorophenyl)-6-(2-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(3-methylphenyl)-7-oxo 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;
''O 95I01980 ~ ~ ~ PCT/1B94/00156 3-isopropyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclopentyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfolanyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-(3-sulfolanyl)-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine;
3-ethyl-1-cyclobutyl-6-(2-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine.
Detailed Description of the Invention The term "halogen", as used herein, unless otherwise indicated, includes chloro, fluoro and bromo.
Unless indicated otherwise, the alkyl, alkoxy and alkenyl groups referred to herein may be straight chained or if comprising three or more carbons may be straight chained, branched, cyclic or a combination of cyclic and branched or straight chained moieties.
The "inflammatory diseases" which can be treated according to this invention include, but are not limited to asthma, chronic obstructive pulmonary disease, bronchitis and arthritis.
R' , R2 and R3, as used herein, unless otherwise indicated, are as defined above with reference to formula I.
The following reaction schemes illustrate, but are not limiting to the preparation of the compounds of the present invention.
21b6721 SCHEnE i NH ly ~NRZ 2 I R 1 R2~N OH
Iv v 0 VI
wRi R~~N OCH3 VII
SCHEnE 2 Ri i ~R
~ N I 0 R 5 ~.. N I N.~J
R R~
VIII IX
i Ri ~N~N.N
R
X
2 i 66l'2 - 'NO 95l01980 PCT/IB94/00156 _7_ In Reaction 1 of Scheme 1, the 2-pyrrolidinone compound of formula IV is converted to the corresponding N-(aryl)-2-pyrrolidone compound V wherein "aryl" is a group of the formula II by reacting IV with an aryl halide neat in the presence of copper power and potassium carbonate. Suitable aryl halides include 1-iodo- or 1-bromo- 4-methoxybenzene, 3-methoxybenzene, 2-methoxybenzene, 3-methylbenzene, 4-methylbenzene) 2-methylbenzene, 3-trifluoromethylbenzene) 2-trifluoromethylbenzene) 3,4-dimethoxybenzene or 3-cyclopentoxy-4-methoxybenzene. The reaction temperature will generally be in the range of about 110 ~ C to about 170 ~ C, preferably about 150 ~ C, for a time period of about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions.
In Reaction 2 of Scheme 1, R' halide is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed and thereafter cooled to atemperature between about -15~C
to about 15 ~ C, preferably about 0 ~ C. The N-(aryl)-2-pyrrolidone compound of formula V is then added and the reaction mixture is warmed to room temperature while being stirred for a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours. Suitable alkyl halides include bromomethane, bromoethane or bromopropane. The preferred anhydrous aprotic solvent is anhydrous ether. Upon completion of the reaction, the desired intermediate may be isolated in a conventional manner, e.g., by first washing the combined organics with water and brine, then drying over sodium sulfate, filtering and concentrating under reduced pressure to afford a readily-recoverable precipitate in the form of a white solid.
The above precipitate is converted to the corresponding 1 (2,5,6-tetrahydropyridine compound of formula VI by dispersing the precipitate in a mixture of a non-polar aprotic solvent and base. Upon vigorous stirring, ethyl oxalyl chloride is added and the reaction mixture is heated to reflux for a time period between about 1.5 hours to about 4.5 hours, preferably about 3.0 hours. The preferred non-polar aprotic solvent is benzene and the preferred base is sodium hydroxide. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in ethanol. After heating at reflux for a time period between about 1 hour and about 3 hours, preferably about 1.5 hours, the mixture is concentrated under reduced pressure and acidified to pH=3 with hydrochloric acid.
_g_ In Reaction 3 of Scheme 1, the compound of formula VI is converted to the corresponding 3-methoxy-1,2,5,6-tetrahydropyridine compound VII by heating to reflux a reaction mixture of VI and 3-methyl-1-p-tolyltriazene in an aprotic solvent.
The preferred aprotic solvent is 1,2-dichloroethane. The time period for the reaction is between about 30 minutes to about 120 minutes, preferably about 45 minutes.
In Reaction 1 of Scheme 2, the 1,2,5,6-tetrahydropyridine compound of formula VIII, wherein R5 is hydrogen or methyl, is converted to the corresponding 4,5,6,7-tetrahydro-7-oxo-1 H-pyrazolo[3,4-c]pyridine compound IX by reacting VIII with a hydrazine of the formula R3HNNHz. Both derivatives of the compound of formula VIII, 3-hydroxy and 3-methoxy, may be used as starting materials under one of three different sets of reaction conditions.
Under one set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX by reacting VIII with a hydrazine hydrochloride and sodium alkoxide in an anhydrous polar erotic solvent. The preferred sodium alkoxide is sodium methoxide and the preferred anhydrous polar erotic solvent is anhydrous ethanol. The reaction mixture is heated to reflux for a time period between about 9 hours to about 15 hours, preferably about 12 hours.
Under a second set of reaction conditions, the 1,2,5,6-tetrahydro-pyridine compound VIII is converted to the corresponding compound of formula IX by reacting VIII with hydrazinobenzoic acid in an anhydrous polar erotic solvent, preferably ethanol.
The reaction mixture is heated to reflux for a time period between about 16 hours to about 24 hours, preferably about 20 hours. The compound IX so formed may be further reacted to give the corresponding 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo(3,4-c]pyridine compound by reacting IX with sodium methoxide in a polar erotic solvent, preferably methanol, for a time period between about 15 minutes to about 45 minutes, preferably 30 minutes. The polar erotic solvent is removed under reduced pressure, the solid residue is suspended in a non-polar aprotic solvent, perferably benzene, and thereafter) the non-polar solvent is removed under reduced pressure. The resulting dry solid is suspended in cold ether and treated with oxalyl chloride and N,N-dimethylformamide and allowed to stir for a time period between about 30 minutes .to about 90 minutes, preferably 60 minutes. The solvent is then removed and the crude residue is dissolved in dry tetrahydrofuran. The resulting -g_ solution is added dropwise to stirred ammonium hydroxide at a temperature between about -10~C to about 10~C, preferably 0~C.
Under a third set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VIII is converted to the corresponding compound of formula IX
by reacting VIII with a hydrazine hydrochloride in a polar erotic solvent, preferably methanol. The reaction mixture is heated to a temperature between about 70~C
to about 110 ~ C, preferably about 90 ~ C, under a gentle stream of nitrogen until all of the solvent is removed. The neat mixture is then heated to a temperature between about 120 ~ C to about 180 ~ C, preferably about 150 ~ C, for a time period between about 30 minutes to about 90 minutes, preferably 60 minutes.
The compounds so formed of formula IX may be converted to the corresponding 6-Rz-4,5,6,7-tetrahydro-7-oxo-1 H-pyrazolo [3,4-c]pyridine compound, wherein R2 is other than the group of formula II, by reacting a solution of IX
in a polar aprotic solvent, preferably acetonitrile, with a solution of ammonium cerium (IV) nitrate in water at a temperature between about -15~C to about 15~C, preferably about 0~C, for a time period between about 20 minutes to about 50 minutes, preferably about 35 minutes. Upon completion of the reaction, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are then washed with saturated sodium bicarbonate followed by sodium sulfite. The compound so formed in a polar aprotic solvent, preferably tetrahydrofuran, is treated with sodium hydride, heated to reflux and stirred for a time period between about 30 minutes to about 60 minutes, preferably 45 minutes. The reaction mixture is cooled to a temperature between about 20 ~ C to about 30 ~ C, preferably about 25 ~ C, and an alkyl halide of formula RZ halide, wherein R~ is as defined with reference to formula I other than a group of formula II, is added. The reaction mixture is stirred and heated to reflux for a time period between about 12 hours to about 20 hours, preferably 16 hours.
In Reaction 2 of Scheme 2, the 2-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine compound IX is converted to the corresponding compound of formula X
by reacting IX with a reducing agent, preferably lithium aluminum hydride, in a non-polar aprotic solvent, preferably ether. The reaction is stirred for a time period between about 12 hours to about 20 hours, preferably 16 hours. Water and base) preferably sodium hydroxide, is then added and the reaction mixture is stirred for a time period between WO 95/01980 ~ PCT/IB94/00156 about 1.5 hours to about 2.5 hours, preferably 2 hours, and filtered. The filtrate is concentrated to a white solid.
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit phosphodiesterase IV (PDEQ) and, consequently, demonstrate their effectiveness for treating inflammatory diseases is shown by the following in vitro assay.
BIOLOGICAL ASSAY
(Human lung PDE,~) Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4 Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenized using a Tekmar Tissumizer~ (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at full speed for 30 seconds. The homogenate is centrifuged at 48,000 x g for 70 minutes at 4~C. The supernatant is filtered twice through a 0.22,um filter and applied to a Mono-D
FPLC column (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1 ml/minute is used to apply the sample to the column, followed by a 2 ml/minute flow rate for subsequent washing and elution. Sample is eluted using an increasing, step-wise NaCI
gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are collected.
Fractions are assayed for specific PDE,~ activity, determined by [3H]CAMP hydrolysis and the ability of a known PDE,~ inhibitor (e.g. rolipram) to inhibit that hydrolysis.
Appropriate fractions are pooled, diluted with ethylene glycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at -20~C until use.
Compounds are dissolved in DMSO at a concentration of 10 mM and diluted 1:25 in water (400 ,uM compound, 4% DMSO). Further serial dilutions are made in 4~~
DMSO to achieve desired concentrations. Final DMSO concentration in assay tube is 1 %. In duplicate the following are added, in order, to a 12 x 75 mm glass tube (all concentrations are given as final concentrations in assay tube).
i) 25 ,ul compound or DMSO (1 %, for control and blank) ii) 25 NI pH 7.5 Tris buffer iii) [3H]cAMP (1 ,uM) iv) 25 NI PDE", enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes) The reaction tubes are shaken and placed in a water bath (37~C) for 20 minutes, at which time the reaction is stopped by placing the tubes in a boiling water WO 95I01980 ~ b ~ PCTIIB94/00156 bath for 4 minutes. Washing buffer (0.5 ml, 0.1 M 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1 M NaCI, pH 8.5) is added to each tube on an ice bath.
The contents of each tube are applied to an Affi-Gel 601 column (Biorad Laboratories, P.O. Box 1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinity gel, 1 ml bed volume) previously equilibrated with washing buffer. [3H)cAMP is washed with 2 x 6 ml washing buffer, and [3H]5'AMP is then eluted with 4 ml of 0.25M
acetic acid.
After vortexing, 1 ml of the elution is added to 3 ml scintillation fluid in a suitable vial, vortexed and counted for [3H].
inhibition = 1 - avera a cpm test compound) - average cpm Lblank) average cpm (control) - average cpm (blank) ICSO is defined as that concentration of compound which inhibits 50% of specific hydrolysis of [3H]CAMP to [3H]5'AMP.
(TNF) The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:
Peripheral blood (100 mls) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by Ficoll/Hypaque and washed three times in incomplete HESS. Cells are resuspended in a final concentration of 1 x 1 O6 cells per ml in pre-warmed RPMI
(containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 106 cells in 1.0 ml in 24-well plates. The cells are incubated at 37~C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10N1) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10N1) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37~C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). ICSo determinations are made for each compound based on linear regression analysis.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with HCI, HBr, HN03, HZS04, H3P04, CH3S03H, p-CH3C6HQS03H, CH3COZH, gluconic acid, tartaric acid, malefic acid and succinic acid. Pharmaceutically-acceptable cationic salts of the compounds of this WO 95/01980 2 ~ ~; 6 7 21 PCT/IB94/00156 invention of formula I wherein R4 is COZRs and R6 is hydrogen include, but are not limited to, those of sodium, potassium, calcium, magnesium) ammonium, N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine and diethanolamine.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of the compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter also referred to as the active compounds of the present invention) are generally in the range of from 0.1-100 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.1 to 50 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required.
For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1 ~~
(w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For administration to humans for the inhibition of TNF, a variety of conventional routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration 25 will, in any event, determine the appropriate dose for the individual subject.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovales either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously.
~VO 95/01980 ~ ~ ~ PCT/IB94/00156 For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic.
Thus in a further aspect the invention provides pharmaceutical compositions comprising a compound of the formula I and the pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.
Example 1 3-Ethyl-1-~4-methoxyehenyl)-6-phenyl-7-oxo-4,5,6,7-tetrah~dro-1 H-pyrazolof3,4-c ridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydro-pyridine (1.0 g, 4.1 mmole), 4-methoxyphenylhydrazine hydrochloride (0.8 g, 4.6 mmole) and sodium methoxide (0.11 grams, 2 mmole) in 35 ml anhydrous ethanol (distilled from Mg) was heated at reflux. After 12 hours, the solvent was removed by rotory evaporation under reduced pressure, and the crude residue was chromatographed on a 4x20 cm silica column using 1:1 ether/hexane as eluent to give 345 mg of the title compound as a red oil that crystallized upon standing at room temperature. The desired 1-(4-methoxyphenyl) regioisomer is less polar than the 2-(4-methoxyphenyl) byproduct.
M.P. 43-45~C, IR (chloroform) lactam C=O, 1665 cm-'; 'H NMR (300 MHz, CDC13) d 1.32(t,J=7.6Hz,3H),2.74(q,J=7.6Hz,2H),2.96(t,J=6.6Hz,2H),3.79(s,3H), 4.10 (t,J = 6.6 Hz, 2H), 6.89 (d,J = 9.0 Hz, 2H), 7.22-7.39 (m, 5H), 7.45 (d,J
= 9.0 Hz, 2H); Anal. calcd. for C2, Hz, N302: C, 72.60; H, 6.09; N, 12.09. Found; C, 72.48; H, 6.08; N, 11.66; MS m/z (M+) 347.
Examples 2-15 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 1, affords the following compounds.
Ex.#R' Rz R3 M.p.C Mass Spectra Mass Spectra or or Analysis (ealcd.)Analysis (found) %C, %H, %N %C, %H) %N
2 ethyl phenyl methyl 80-83 70.56, 6.71, 70.61, 6.77, 16.46 15.51 3 ethyl phenyl ten-butyl120-121?2.70, 7.79, 72.50, 7.96, 14.13 14.16 4 ethyl 4-methoxy4-methoxy42-45 70.01, 6.14, 70.05, 6.07, 11.13 11.00 phenyl phenyl ethyl 4-fluorotert-butyl92-94 (M') 315.1747HRMS (M') phenyl 315.1741 6 ethyl phenyl 3,4- (oil) [M' ] 386.26 MS m/z [M+]
dichloro-phenyl 7 ethyl 4-fluoro4-methoxy129-130'69.03, 5.52, 68.75, 5.37, 11.50 11.43 phenyl phenyl 5 8 methylphenyl 4-fluoro139-140[M'] 321.3 MS m/z [M') phenyl 9 ethyl phenyl cyclopent73-75 (M+) 309.1841HRMS (M+) yl 309.1823 methylphenyl 4-methoxy167-168(M+) 333.1477HRMS (M+) phenyl 333.1477 11 ethyl phenyl 5-phenyl(oil) (M+) 388.2389HRMS (M+) pentyl 388.239S
12 methyl4-methoxy4-fluoro140-14268.36, 5.16, 67.92, 5.03, 11.96 11.72 phenyl phenyl 10 13 methyl4-methoxy3-fluoro133-13868.36, 5.16, 68.04, S.04, 11.96 11.7S
phenyl phenyl 14 ethyl 4-methoxy3,4- 50-60 60.59, 4.60, 60.34, 4.56, 10.09 9.86 phenyl dichloro-phenyl ethyl 3-methoxymethyl (oil) [M' ] 285.3S MS m/z [M' ] 286 phenyl Recrystallizing solvents: aisopropyl ether. b5% Ethyl acetate in petroleum ether.
15 Example 16 3-Ethyl-1-(4-phenylcarboxylic acid)-6-phenyl-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo f3,4-clp~rridine A mixture of 3-hydroxy-2-oxo-1-phenyl-4-propionyl-1,2,5,6-tetrahydro-pyridine (1.0 grams, 4.08 mmole), 4-hydrazinobenzoic acid (0.68 grams, 4.49 mmole) and 30 ml of anhydrous ethanol was heated at reflux. After 20 hours, the mixture was concentrated by rotory evaporation under reduced pressure, and the solid residue was suspended in a mixture of ethyl acetate (500 ml) and pH 4 buffer (200 ml). The organic layer was separated (leaving behind most of the 2-(4-phenylcarboxylic acid) byproduct), washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
Recrystallization from methanol gives 0.64 grams of the title compound as an orange solid. M.P. 261-263~C, 'H NMR (300 MHz, DMSO-d6j, d 1.23 (t,J = 7.6 Hz, 3H), 2.68 (q,J - 7.6 Hz, 2H), 2.94 (t,J = 6.5 Hz, 2H), 4.05 (t,J = 6.5 Hz, 2H), 7.20-7.41 (m) 5H), 7.65 (d,J = 8.6 Hz) 2H), 7.96 (d,J = 8.6 Hz) 2H)) 13.05 (s) 1 H); MS m/z (M+) 362.
Example 17 1-(4-Benzamide)-3-ethyl-6-(4-methoxyphenyll-7-oxo-4.5.6,7-tetrahydro-1 H-prrazolof3,4-clpyridine To a stirred solution of sodium methoxide in methanol (prepared from 6.6 mg Na) is added 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-cjpyridine (96 mg, 0.25 mmole). After 30 minutes, methanol was removed under reduced pressure, the solid residue was suspended in benzene, and the benzene was removed under reduced pressure. The resulting dry solid was suspended in cold ether (ice-bath) and treated with oxalyl chloride (31 NI, 0.35 mmole) and anhydrous N,N-dimethylformamide (1 drop). After stirring for 1 hour the valatiles are removed under reduced pressure, and the crude residue was dissolved in dry tetrahydrofuran. The resulting solution was added dropwise to briskly stirred ammonium hydroxide at 0 ~ C. After warming to ambient temperature over 2 hours the reaction mixture was concentrated under reduced pressure until a yellow solid begins to precipitate. At this time the mixture was diluted with water to approximately 100 ml and filtered, and the precipitate was washed with water to give 81 mg of the title compound. Decomposition point 243-245 ~ C; ' H NMR (DMSO-ds) 1.24 (t,J = 7.6 Hz, 3H), 2.68 (q,J = 7.6 Hz, 2H), 2.93 (t,J = 6.5 Hz, 2H), 3.75 (s, 3H), 3.99 (t,J
= 6.5 Hz, 2H), 6.94 (d,J = 9.1 Hz, 2H), 7.27 (d,J = 9.0 Hz, 2H), 7.43 (s, 1 H), 7.59 (d,J = 8.5 Hz, 2H), 7.90 (d,J = 8.6 Hz, 2H), 8.04 (s, 1 H); Anal. calcd. for CZZHZZN403: C, 67.68; H, 5.68; N, 14.35. Found: C, 67.19; H) 5.31; N, 13.55. HRMS calcd. for CZZHzzNa03 [M+]
391.1770. Found 391.1781.
The starting 3-ethyl-6-(4-methoxyphenyl)-1-(4-phenylcarboxylic acid)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo [3,4-cj pyridine was prepared using the appropriate reagents according to the procedure of example 16.
WO 95/01980 2 ~ 6 6 7 21 PCT/IB94/00156 Example 18 1-(3 4-dichloropheny~-3-ethy~3-methoxyphenyl)-7-oxo-4.5.6,7-tetrahydro-1 H-pyrazolo f 3,4-cl pyridine A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydro-pyridine (0.49 grams,1.7 mmole), 3,4-dichlorophenylhydrazine hydrochloride (0.40 grams, 1.87 mmole) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave 0.46 grams of white needles. M.P. 97-99~C,'H NMR (250 MHz, CDCI3) 1.31 (t,J = 7.5 Hz, 3H), 2.73 (q,J = 7.6 Hz. 2H), 2.96 (t,J = 6.6 Hz, 2H), 3.79 (s, 3H), 4.09 (t,J
= 6.6 Hz, 2H), 6.78-6.91 (m, 3H), 7.29-7.49 (m, 3H), 7.73 (d,J = 1.8 Hz, 1 H); MS m/z [M+] 416.
Examples 19-42 Reaction of the appropriate hydrazine hydrochloride with the requisite 4-alkanoyl-3-methoxy-2-oxo-1,2,5,6-tetrahydropyridine, analogous to the procedure of Example 18, affords the following compounds.
Ex.#R' RZ R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.}Analysis (found) , %C, %H, %N %C, %H, %N
19 methyl4-methoxy3-4- 143-144'59.71, 4.26, 56.13, 4.02, 10.45 9.65 phenyl dichloro-phenyl 20 ethyl 3-methoxycyclo- 64-65 [M' ] 340.2025HRMS [M+]
phenyl pentyl 340.2046 21 ethyl 4-methoxycyclo- 96-98 70.77, 7.42, 70.44, 7.68, 12.38 11.69 phenyl pentyl 22 methyl4-methoxycyclo- 121-12270.13, 7.12, 69.48, 7.10, 12.91 12.70 phenyl pentyl 23 iso- phenyl 3,4- oil [M'] 400.0983HRMS [M']
propyl dichloro 400.0966 phenyl 24 ethyl 3,4-dimeth-cyclo- 107-108[M'] 369.46 MS m/z [M']
oxyphenylpentyl 25 ethyl 3,4-dimeth-3,4- 190-19159.20, 4.74, 59.41, 4.46, 9.41 9.71 oxyphenyldichloro-phenyl vo 95/01980 216 6 7 21 Ex.# R' R2 R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
26 iso- 4-methoxy3,4- 145-147'61.40, 4.92, 61.29, 4.81, 9.76 9.53 propylphenyl dichloro phenyl 27 propyl4-methoxycyclo- 102-103'71.36, 7.70, 70.98, 7.66, 11.89 11.73 phenyl pentyl 28 iso- 3-methoxy3,4- 126-12T61.40, 4.92, 61.55, 5.10, 9.76 9.97 propylphenyl dichloro-phenyl 29 ethyl 4-methoxy-3,4- 54-56 62.40, 5.44, 62.15, 5.S0, 8.40 7.97 3-cyclo-dichloro-pentoxy-phenyl phenyl 30 ethyl 4-methoxy-cyclo- 88-89 [M' ] 423.S5 MS m/z [M' ) 423 3-cyclo-pentyl pentoxy-phenyl 31 ethyl 3-methoxy4-fluoro-139-140'69.03, 5.79, 69.05, 5.42, 11.50 11.57 phenyl phenyl 32 ethyl 2-methoxycyclo- 119-12070.77, 7.42, 70.63, 7.16, 12.38 12.01 phenyl pentyl 33 ethyl 2-methoxy4-fluoro-103-104'[M' ] 365.41 MS m/z [M' ) 366 phenyl phenyl 34 ethyl 3-methylcyclo- oil 74.27, 7.79, 74.54, 7.89, 12.99 12.63 phenyl pentyl 35 ethyl 3-methyl4-fluoro-oil 72.19,5.77, 72.06, 5.55, 12.02 11.52 phenyl phenyl 36 ethyl 3-trifluoro-cyclo- oil 63.65, 5.87, 63.9S, 5.73, 11.13 10.97 methyl- pentyl phenyl 37 ethyl 3-trifluoro-4-fluoro-139-140'62.53) 4.25, 62.60, 4.08, 10.42 10.41 methyl- phenyl phenyl 38 ethyl 4-methyl-cyclo- 93-94 74.27, 7.79, 74.10, 7.52, 12.99 12.59 phenyl pentyl 39 ethyl 2-methyl-4-fluoro-141-142b72.19, S.77, 72.36) 5.52) 12.03 12.09 phenyl phenyl 40 ethyl 2-methyl-cyclo- 130-131MW 323.44 MS m/z 323 phenyl pentyl 21 ~6~2~
Ex.# R' Rz R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
41 ethyl 2-trifluoro-4-fluoro-48-50 MW 403.38 MS m/z 404 methyl- phenyl phenyl 42 ethyl 3-methyl-3-sulfo-oil MW 373.47 MS m/z 374 phenyl lanyl Recrystallizing solvents: B 5% Ethyl acetate/petroleum ether. b Isopropyl ether.
' Ethyl acetate/hexane. dEthyl ether. e5% Ethyl acetate/pentane. 'Pentane.
Example 43 1-Cvclohexvl-3-ethyl-6-(3-methoxvphenvl)-7-oxo-4.5.6.7-tetrahvdro-1 H-pyrazolo(3,4-clpyridine A solution of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-pyridine (0.80 grams, 2.8 mmole) and cyclohexylhydrazine hydrochloride (0.54 grams, 3.6 mmole) in methanol (15 ml) was warmed to 90~C under a gentle stream of nitrogen until all of the solvent was removed. The neat mixture was then heated to approximately 150~C under nitrogen for 1 hour. After cooling to room temperature, the mixture was dissolved in ether and washed with 1 N hydrochloric acid followed by brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
Chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent gives 0.47 grams of the title compound as a yellow oil. ' H NMR (250 MHz, CDCI3) 1.20-1.52 (m, 6H, including t at 1.23, J = 7.6 Hz, 3H), 1.64-1.74 (m, 1 H), 1.80-2.06 (m, 6H), 2.67 (q,J
= 7.6 Hz, 2H), 2.87 (t,J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.97 (t,J = 6.7 Hz, 2H), 5.13 (tt, J
= 4.3 and 11.3 Hz, 1 H), 6.79-6.93 (m, 3H), 7.31 (t,J = 8.1 Hz) 1 H); HRMS
calculated for C2,H2,N30z[M+]: 353.2103. Found: 353.2094.
Examples 44-57 Reaction of the appropriate hydrazine hydrochloride with the requisite 4 alkanoyl-3-methoxy-2-oxo-1,2,5.6-tetrahydropyridine, analogous to the procedure of Example 43, affords the following compounds.
Ex.# R' Rz R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
44 iso- 4-methoxycyclo- 102-103'[M'] 354 MS [M'] 354 propylphenyl pentyl p VO 95/01980 ~ PCT/IB94100156 Ex.# R' R2 R3 M.p.C Mass Spectra Mass Spectra or or Analysis (calcd.)Analysis (found) %C, %H, %N %C, %H, %N
45 iso- 3-methoxycyclo- 99-10071.36, 7.70, 71.10, 7.56, 11.89 11.73 propylphenyl pentyl 46 ethyl 3-methoxycyclobutyl73-74b70.13, 7.12, 70.10, 7.22, 12.91 12.93 phenyl 47 ethyl phenyl methylene60-62'73.19, 7.17, 73.34, 7.08, 14.23 13.95 cyclo-propyl 48 ethyl 3-methoxymethyleneoil [M' ] 326 MS [M' ] 326 phenyl cyclo-propyl 49 ethyl 4-methoxy-phenyl 156-157b72.60, 6.09, 72.35, 5.91, 12.10 12.02 phenyl 50 ethyl 3-methoxy-3-sulfo-oil 58.59, 5.95, 58.46, 6.03, 10.79 9.82 phenyl lanyl 51 ethyl 3-methoxy-4-trifluoro-124-12563.61, 4.85, 63.40, 4.51, 10.12 10.09 phenyl methyl-phenyl 52 ethyl 3-methyl-cyclobutyloil 73.75, 7.49, 73.22, 7.56, 13.S8 13.03 phenyl 53 ethyl 3-trifluoro-3-sulfo-oil MW 427.44 MS m/z 428 methyl- lanyl phenyl 54 ethyl 3-trifluoro-cyclobutyloil 62.80, 5.55, 63.01, 5.54, i 1.56 i 1.19 methyl-phenyl 55 ethyl phenyl 2-indanyl155-156'77.28, 6.49, 77.35, 6.48, 11.76 11.08 56 ethyl 2-methyl-cyclobutyl100-102MW 309.41 MS m/z 310 phenyl 57 ethyl 3-methoxy-2-indanyl60-62'MW 387.48 MS m/z 388, 389, phenyl 390 Recrystallization solvents: ~Ethyl acetate/pentane. bEthyl ether/pentane.
'Isopropyl ether/pentane. dEthyl/acetate/petroleum ether. ~Ethyl acetate.
'Ethyl acetate/hexane.
WO 95/01980 ~ ~ ~ PCT/IB94/00156 Example 58 3-Ethyl-6-(4-fluorophenyl -~1-(4-methoxVphenyl)-4,5.6,7-tetrahydro-1 H-p~rrazolo(3,4-clp riy dine To a stirred solution of 3-Ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (0.3 grams, 0.82 mmole) in 50 ml ether was added lithium aluminum hydride (33 mg, 0.86 mmole). After stirring for 16 hours water (0.5 ml) was added followed by 3N sodium hydroxide (1 ml). After stirring for 2 hours the white precipitate was filtered through celite and the filtrate is concentrated under reduced pressure. Chromatography on a silica gel column using 1:3 ethyl acetate/hexane as eluent gives 0.12 grams of the title compound as a pale yellow paste. ' H NMR (250 MHz, CDCI3) 1.28 (t,J = 7.6 Hz, 3H), 2.66 (q,J = 7.6 Hz, 2H), 2.71 (t,J = 5.7 Hz, 2H), 3.49 (t,J = 5.7 Hz, 2H), 3.84 (s, 3H), 4.23 (s, 2H), 6.84-6.99 (m, 6H), 7.36 (d,J = 9.0 Hz, 2H); MS m/z [M+] 352.
Examples 59-63 Reaction of the appropriate 7-oxo-2,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine with lithium aluminum hydride, analogous to the procedure of Example 58, affords the following compounds.
Ex.#R' Rz R3 M.p.C Mol. WeightMass Spectra (M'] (found) 59 ethyl 4-methoxy-3-cyclopentyloil 409.57 409 cyclopentoxy phenyl 60 ethyl phenyl 3,4-dichloro-oil 372.30 371.373 phenyl 61 ethyl phenyl cyclopentyloil 295.43 296 62 ethyl 3-methoxy cyclobutyloil 311.43 312 phenyl 63 ethyl 3-methoxy cyclohexyloil 339.48 340 phenyl .
Example 64 1-cyclopentyl-3-ethyl-7-oxo-4,5,6.7-tetrahydro-1 H-pyrazolo(3,4-cl~rridine A stirred solution of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo(3,4-c]pyridine (2.58 grams, 7.60 mmoles) in acetonitrile (90 ml) at 0~C is treated with a solution of ceric ammonium nitrate (12.5 grams, 22.8 mmoles) ~''VO 95I01980 216 6 7 21 PCT/IB94/00156 in water (110 ml). After stirring for 35 minutes the mixture is diluted with water (550 ml) and extracted with ethyl acetate (100 ml x 4). The combined organics are washed with 50~~ saturated sodium bicarbonate (250 ml) followed by 10% sodium sulfite until the aqueous wash becomes pale yellow. The organic layer is then washed further with saturated bicarbonate and brine, and treated with decolorizing charcoal. After stirring for 30 minutes the mixture is dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The brown residue is recrystallized from ether to give .814 grams of a tan solid. M. P. 143-145 ~ C; MS (M/Z) 234; ' H NMR
(250 MHz, CDCl3) 1.21 (t, J = 7.6 Hz, 3H), 1.62-2.13 (m, 8H), 2.62 (q, J = 7.6 Hz, 2H)) 2.73 (t, J
= 6.8 Hz, 2H), 3.51 (dt, J = 2.7 and 6.8 Hz, 2H), 5.47 (s, 1 H), 5.61 (pentet, J = 7.7 Hz, 1 H).
Example 65 1-c5rclopentyl-3-ethyl-6-cycloprop I~yl-7-oxo-4.5.6,7-tetrahydro-1 H-pyrazolo(3,4-clpyridine A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (0.21 grams, 0.92 mmoies) in THF (5 ml) is treated with 60% sodium hydride in mineral oil (40 mg, 1.01 mmoles). After stirring at reflux over 45 minutes the reaction mixture is cooled to 25 ~ C and (bromomethyl) cyclopropane (0.31 grams, 2.29 mmoles) is added. The mixture is stirred at reflux for 16 hours and then cooled to 25~C before concentrating under reduced pressure. Chromatography on silica gel eluting with 1:1 ethyl acetate/hexane gives 0.19 grams of the title compound as a colorless oil. MS m/z [M+] 288; ' H NMR (300 MHz, CDC13) 0.26-0.31 (m, 2H), 0.50-0.56 (m, 2H), 0.85-1.06 (m, 1 H), 1.20 (t, J = 7.6 Hz, 3H), 1.62-2.08 (m, 8H), 2.61 (q, J = 7.6 Hz, 2H), 2.74 (t, J=6.8Hz,2H),3.39(d,J=6.9Hz,2H),3.63(t,J=6.8Hz,2H),5.67(pentet,J=
7.8 Hz, 1 H).
Preparation 1 4-isobutyryl-3-methoxy-1-phenyl-2-oxo-1,2.5,6-tetrahydropyridine A stirred solution of freshly distilled diisopropylamine (0.16 ml, 2.21 mmole) in anhydrous tetrahydrofuran (4 ml) was cooled to 0 ~ C and treated with 2.5 M n-butyl lithium (0.85 ml, 2.11 mmole). After 15 minutes the mixture was cooled to -78~C and a pre-cooled solution of 4-propionyl-3-methoxy-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine (0.52 grams, 2.0 mmole) in tetrahydrofuran (4 ml) was added dropwise via cannula. After approximately 20 minutes methyl iodide (0.20 ml, 3.0 mmole) was added to the bright orange-red solution and the mixture was allowed to come to room temperature over 2.5 hours. The reaction mixture is poured into saturated aqueous ammonium chloride and the organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
Chromatography on a silica gel column using 1:4 ethyl acetate/hexane as eluent gives 0.12 grams of the title compound as a yellow oil and 0.1 grams of recovered starting material. ' H NMR (250 MHz, CDCI3) 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (heptet, 1 H), 3.82 (t, 2H), 3.97 (s, 3H), 7.21-7.45 (m, 5H); MS m/z [M+] 274.
Preparations 2-3 Reaction of the appropriate 3-methoxy-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine with lithium diisopropylamine and methyl iodide, analogous to the procedure of preparation 1, affords the following compounds of formula VII.
Prep# Rz m.p. C M.W. Mass Spectra [M+]
2 4-methoxyphenyloil 303.36 304 3 3-methoxyphenyloil 303.36 304 Preparation 4 3-Methoxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine A solution of 3-hydroxy-1-(4-methylphenyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine (5.9 grams, 23 mmole) and 3-methyl-1-p-tolyltriazine (5.1 grams, 34 mmole) in 1,2-dichloroethane was heated to reflux for 45 minutes. The mixture was allowed to cool to room temperature and was poured into water and acidified with 6N
hydrochloric acid. The aqueous layer was extracted 3 times with methylene chloride, and the combined organics are washed with 1 N hydrochloric acid followed by water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting quantitative brown oil was clean by thin layer chromatography and ' H NMR and was used without purification. ' H NMR (300 MHz, CDCI3) 1.12 (t,J =
7.2 Hz, 3H), 2.34 (s, 3H), 2.71 (t,J = 6.7 Hz, 2H), 2.93 (q,J = 7.2 Hz, 2H), 3.77 (t,J =
6.8 Hz, 2H), 3.94 (s, 3H), 7.20 (s, 4H); MS [M+] 273.
Preparations 5-14 WO 95/01980 2 ~ b 6 7 21 PCT/IB94/00156 Reaction of the appropriate 3-hydroxy-1-aryl-2-oxo-4-alkanoyl-1,2,5,6-tetrahydropyridine with 3-methyl-1-p-tolyltriazine, analogous to the procedure of Preparation 4, affords the following compounds of formula VI.
Prep# R' Rz m.p. M.W. Mass C Spectra IM+l 5 ethyl phenyl oil 259.31 260 6 methyl 4-methoxyphenyl oil 275.30 275 7 ethyl 4-methoxyphenyl 81-82 289.33 289 8 n-propyl 4-methoxyphenyl oil 303.36 303 9 ethyl 3-methoxyphenyl 59-60 289.33 289, 10 ethyl 2-methoxyphenyl oil 289.33 289 11 ethyl 3,4-dimethoxyphenyloil 319.26 319 12 ethyl 3-cyclopentoxy-4-oil 373.45 373 methoxyphenyl 13 ethyl 3-methylphenyl oil 273.33 273 14 ethyl 3-trifluoromethylphenyloil 327.30 327 Preparation 15 -3-Hvdroxv-1-(3-methvlphenvl)-2-oxo-4-propionvl-1.2.5.6-tetrahvdropvridine To a stirred suspension of magnesium turnings (1.9 grams, 79 mmole) in 30 ml of anhydrous ether was added dropwise bromoethane (5.9 ml, 79 mmole). A mild reflux was initiated after approximately 1 ml was added. After all of the magnesium was consumed, the reaction mixture was cooled to 0~C and N-(3-methylphenyl)-2-pyrrolidone (8.7 grams, 50 mmole) was added at once. After warming to room temperature and stirring for 2 hours the reaction mixture was poured over ice and extracted with ethyl acetate. The combined organics are washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8.8 grams of a white solid.
The above solid is dispersed in a mixture of 40 ml benzene and 86 ml 1 N
sodium hydroxide, and with vigorous mechanical stirring ethyl oxalyl chloride (7.2 ml, 64 mmole) was added. After stirring at reflux over 1.5 hours the layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organics are washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an amber oil. GCMS [M+] 305.
The above intermediate was dissolved in 20 ml anhydrous ethanol and treated with a solution of sodium methoxide in methanol (prepared from the careful addition of sodium (1.0 grams) to 10 ml anhydrous methanol). After being stirred at reflux over 1.5 hours, the mixture was concentrated under reduced pressure and 100 ml of water was added. The mixture was acidified to pH 3 with 6N hydrochloric acid and the dull yellow precipitate was filtered and washed with water. Recrystallization from 75 ml isopropyl ether affords 6.8 grams of pale yellow crystals. M.P. 115-116~; 'H NMR (300 MHz, CDC13) 1.16 (t,J = 7.2 Hz, 3H), 2.37 (s, 3H), 2.74-2.82 (m, 4H), 3.85 (t,J =
6.8 Hz, 2H), 7.08-7.14 (m) 3H), 7.30 (t,J = 7.7 Hz, 1 H); MS m/z (M+] 259.
Preparations 16-29 Reaction of the appropriate 2-pyrrolidinone with the requisite alkylmagnesium bromide, followed by treatment with ethyl oxalyl chloride and base, analogous to that reported in Preparation 15, affords the following compounds of formula VI.
Prep# R' RZ m.p. M.W. Mass C Spectra (M+]
16 methyl phenyl oil 231.25 231 17 ethyl phenyl 140-142 245.28 245 18 ethyl 4-fluorophenyl 133-135 263.27 263 19 methyl 4-methoxyphenyl oil 261.28 262 20 ethyl 4-methoxyphenyl 121-122 275.30 276 21 n-propyl 4-methoxyphenyl 125-126 289.33 289 22 ethyl 3-methoxyphenyl 129-130 275.30 275 23 ethyl 2-methoxyphenyl 119-120 275.30 275 24 ethyl 4-methylphenyl 110-112 259.30 260 25 ethyl 2-methylphenyl oil 259.30 259 26 ethyl 3-trifluoromethylphenyl117-118 313.28 313 27 ethyl 2-trifluoromethylphenyloil 313.28 313 28 ethyl 3,4-dimethoxyphenyl179-180 305.33 306 ''VO 95I01980 ~ b ~ ~ PCT/IB94/00156 Prep#R' Rz m.p. M.W. Mass C
Spectra [M+]
29 ethyl 3-cyclopentoxy-4-133-134 359.42 360 methoxyphenyl Preparation 30 N-(2-MethoxVphenyl?-2-pVrrolidone A mixture of 2-pyrrolidone (15.0 grams, 176 mmole), 2-iodoanisole (7.6 ml, 59 mmole), copper powder (7.5 grams, 117 mmole) and potassium carbonate (8.1 grams, 59 mmole) are stirred under nitrogen at 150~C. After 18 hours, the reaction mixture was filtered through a 6x15 cm pad of silica gel eluting with 1:1 ethyl acetate/hexane to give a pale yellow oil. The unreacted reagents are removed by vacuum distillation (0.6 mm, 80-100~C) Veaving 9.2 grams of the title compound as a honey-like oil. 'H
NMR (300 MHz, CDCI3) 2.20 (pentet, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (s, 3H), 6.93-7.02 (m, 2H), 7.25-7.30 (m, 2H); MS m/z [M+] 191.
Preparations 31-39 Reactions of the appropriate iodo- or bromobenzene with 2-pyrrolidinone, analogous to that reported in Preparation 30, affords the following compounds of formula V.
Prep# R M.W. Mass Spectra [M+]
31 4-methoxyphenyl 191.22 191 32 3-methoxyphenyl 191.22 191 33 3-methylphenyl 175.23 175 34 4-methylphenyl 175.23 175 35 2-methylphenyl 175.23 175 36 3-trifluoromethylphenyl229.20 229 37 2-trifluoromethylphenyl229.20 229 38 3,4-dimethoxyphenyl221.26 221 39 3-cyclopentoxy-4-275.35 275 methoxyphenyl
Claims (16)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or (C3-C5)cycloalkyl-methyl, wherein each alkyl or alkenyl group may be optionally substituted with up to two (C1-C2)alkyl or trifluoromethyl groups or up to three halogens;
X is oxygen or two hydrogen atoms;
R2 and R3 are each independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C2-C7)cycloalkyl, cyclopropylmethyl, (C1-C14)alkoxy, (C2-C7)alkenyl, 2-indanyl, (C4-C7)heterocyclic group containing oxygen, sulphur, SO2 or NR5 (wherein R5 is hydrogen or (C1-C4)alkyl), or a group of the formula:
(wherein a is an integer from 1 to 5; b and c are each zero or one; R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, NO2 or SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (C1-C4)alkyl; wherein Z is oxygen, sulphur, SO2 or NR8 wherein R8 is hydrogen or (C1-C4)alkyl; and Y is (C1-C5)alkylene or (C2-C6)alkenylene each optionally substituted with up to two (C1-C7)alkyl or (C3-C7)cycloalkyl groups; or a group of the formula:
wherein p is an integer from 1 to 3, W is oxo or hydroxyl, R9 is (C1-C3)alkyl; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxy and heterocyclic groups may be optionally substituted with one to fourteen substituents selected from the group consisting of (C1-C2)alkyl, trifluoromethyl and halogen) with the proviso that:
(1) when R1 is ethyl and R2 is 4-methylphenyl, then R3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl, (2) when R2 is 4-methylphenyl and R3 is 4-fluorophenyl, then R1 cannot be phenyl, methyl or n-propyl, (3) when R1 is ethyl and R2 is phenyl, then R3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, (4) when R1 is ethyl and R2 is 4-methoxyphenyl, then R3 cannot be 4-fluorophenyl, and (5) one of R2 or R3 must be other than hydrogen, (C1-C14)alkyl, (C2-C7)alkenyl, (C3-C7)cycloalkyl, cyclopropylmethyl, pyridyl, (C1-C2)alkylpyridyl or a group of the formula:
wherein b is one and c is zero or b and c are each zero, a is zero or one and R4 is (C1-C5)alkyl, (C1-C5)alkoxy, halo, trifluoromethyl, or di(C1-C4)alkylamino.
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, (C1-C3)alkyl, (C2-C3)alkenyl, (C3-C5)cycloalkyl or (C3-C5)cycloalkyl-methyl, wherein each alkyl or alkenyl group may be optionally substituted with up to two (C1-C2)alkyl or trifluoromethyl groups or up to three halogens;
X is oxygen or two hydrogen atoms;
R2 and R3 are each independently selected from the group consisting of hydrogen, (C1-C14)alkyl, (C2-C7)cycloalkyl, cyclopropylmethyl, (C1-C14)alkoxy, (C2-C7)alkenyl, 2-indanyl, (C4-C7)heterocyclic group containing oxygen, sulphur, SO2 or NR5 (wherein R5 is hydrogen or (C1-C4)alkyl), or a group of the formula:
(wherein a is an integer from 1 to 5; b and c are each zero or one; R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C2-C5)alkenyl, (C1-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, NO2 or SO2NR6R7 wherein R6 and R7 are each independently hydrogen or (C1-C4)alkyl; wherein Z is oxygen, sulphur, SO2 or NR8 wherein R8 is hydrogen or (C1-C4)alkyl; and Y is (C1-C5)alkylene or (C2-C6)alkenylene each optionally substituted with up to two (C1-C7)alkyl or (C3-C7)cycloalkyl groups; or a group of the formula:
wherein p is an integer from 1 to 3, W is oxo or hydroxyl, R9 is (C1-C3)alkyl; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxy and heterocyclic groups may be optionally substituted with one to fourteen substituents selected from the group consisting of (C1-C2)alkyl, trifluoromethyl and halogen) with the proviso that:
(1) when R1 is ethyl and R2 is 4-methylphenyl, then R3 cannot be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl, (2) when R2 is 4-methylphenyl and R3 is 4-fluorophenyl, then R1 cannot be phenyl, methyl or n-propyl, (3) when R1 is ethyl and R2 is phenyl, then R3 cannot be 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, (4) when R1 is ethyl and R2 is 4-methoxyphenyl, then R3 cannot be 4-fluorophenyl, and (5) one of R2 or R3 must be other than hydrogen, (C1-C14)alkyl, (C2-C7)alkenyl, (C3-C7)cycloalkyl, cyclopropylmethyl, pyridyl, (C1-C2)alkylpyridyl or a group of the formula:
wherein b is one and c is zero or b and c are each zero, a is zero or one and R4 is (C1-C5)alkyl, (C1-C5)alkoxy, halo, trifluoromethyl, or di(C1-C4)alkylamino.
2. The compound or salt according to claim 1, wherein R1 is (C1-C3)alkyl and R2 and R3 are each independently selected from the group consisting of (C3-C7)cycloalkyl, (C4-C7)heterocyclic group containing SO2 or a group of the formula:
wherein a is an integer from 1 to 5 and R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy or halogen.
wherein a is an integer from 1 to 5 and R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy or halogen.
3. The compound or salt according to claim 1, wherein R1 is ethyl or isopropyl; R2 is phenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-trifluoromethylphenyl and R3 is cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfolanyl, 4-fluorophenyl or 3,4-dichlorophenyl.
4. The compound or salt according to claim 1 or 2, wherein R2 or R3 is (C4-C7)heterocyclic group containing SO2.
5. The compound or salt according to claim 4, wherein X
is oxygen, R3 is heterocyclic group containing SO2 and R2 is as defined in claim 1 or 2 other than heterocyclic group containing SO2.
is oxygen, R3 is heterocyclic group containing SO2 and R2 is as defined in claim 1 or 2 other than heterocyclic group containing SO2.
6. The compound or salt according to claim 1, 4 or 5, wherein R3 is 3-sulfolanyl.
7. The compound or salt according to claim 1, wherein R2 or R3 is 2-indanyl.
8. The compound or salt according to claim 7, wherein R3 is 2-indanyl, R1 is (C1-C3)alkyl and R2 is (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C14)alkoxy or a group of the formula:
wherein a is an integer of from 1 to 5 and R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy or halogen.
wherein a is an integer of from 1 to 5 and R4 is hydrogen, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy or halogen.
9. The compound 3-ethyl-1-(3,4-dichlorophenyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine or a pharmaceutically acceptable salt thereof.
10. The compound 3-ethyl-1-(3-sulfolanyl)-6-(3-methylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine or a pharmaceutically acceptable salt thereof.
11. The compound 3-ethyl-1-(3-sulfolanyl)-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo-[3,4-c]pyridine or a pharmaceutically acceptable salt thereof.
12. The compound 3-ethyl-1-(3-sulfolanyl)-6-(3-trifluoromethylphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), comprising a pharmaceutically effective amount of the compound or salt according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.
14. A use of the compound or salt according to any one of claims 1 to 12 for the production of a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF).
15. A pharmaceutical composition for the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF, comprising a pharmaceutical effective amount of the compound or salt according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier.
16. A use of the compound or salt according to any one of claims 1 to 12 for the production of a pharmaceutical composition for treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8829293A | 1993-07-06 | 1993-07-06 | |
US08/088,292 | 1993-07-06 | ||
PCT/IB1994/000156 WO1995001980A1 (en) | 1993-07-06 | 1994-06-16 | Bicyclic tetrahydro pyrazolopyridines |
Publications (2)
Publication Number | Publication Date |
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CA2166721A1 CA2166721A1 (en) | 1995-01-19 |
CA2166721C true CA2166721C (en) | 1999-07-27 |
Family
ID=22210524
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA002166721A Expired - Fee Related CA2166721C (en) | 1993-07-06 | 1994-06-16 | Bicyclic tetrahydro pyrazolopyridines |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP0707585A1 (en) |
JP (1) | JP2944048B2 (en) |
KR (1) | KR100228949B1 (en) |
CN (1) | CN1048015C (en) |
AU (1) | AU695301B2 (en) |
BR (1) | BR9406946A (en) |
CA (1) | CA2166721C (en) |
CZ (1) | CZ3696A3 (en) |
EG (1) | EG20513A (en) |
FI (1) | FI943208A (en) |
HU (1) | HUT74170A (en) |
IL (1) | IL110175A (en) |
MX (1) | MX9405132A (en) |
NO (1) | NO305029B1 (en) |
NZ (1) | NZ266525A (en) |
PL (1) | PL312426A1 (en) |
RU (1) | RU2131876C1 (en) |
TW (1) | TW316904B (en) |
WO (1) | WO1995001980A1 (en) |
ZA (1) | ZA944844B (en) |
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JP4555547B2 (en) * | 2000-08-10 | 2010-10-06 | ファイザー イタリア ソシエタ ア レスポンサビリタ リミタータ | Bicyclic pyrazoles as kinase inhibitors, methods for preparing them and pharmaceutical compositions containing them |
US6960595B2 (en) * | 2001-03-23 | 2005-11-01 | Bristol-Myers Squibb Pharma Company | 5-6 to 5-7 Heterobicycles as factor Xa inhibitors |
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US7135469B2 (en) * | 2003-03-18 | 2006-11-14 | Bristol Myers Squibb, Co. | Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors |
KR20050115331A (en) | 2003-04-01 | 2005-12-07 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Inhibitors of phosphodiesterases in infertility |
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PE20081889A1 (en) * | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | INDOL CARBOXAMIDES AS INHIBITORS OF IKK2 |
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US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
CA2726917C (en) | 2008-06-04 | 2018-06-26 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
WO2010009319A2 (en) | 2008-07-16 | 2010-01-21 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
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-
1994
- 1994-06-16 KR KR1019960700019A patent/KR100228949B1/en not_active IP Right Cessation
- 1994-06-16 CZ CZ9636A patent/CZ3696A3/en unknown
- 1994-06-16 CN CN94193233A patent/CN1048015C/en not_active Expired - Fee Related
- 1994-06-16 AU AU68057/94A patent/AU695301B2/en not_active Ceased
- 1994-06-16 EP EP94916370A patent/EP0707585A1/en not_active Withdrawn
- 1994-06-16 WO PCT/IB1994/000156 patent/WO1995001980A1/en not_active Application Discontinuation
- 1994-06-16 JP JP7503938A patent/JP2944048B2/en not_active Expired - Lifetime
- 1994-06-16 PL PL94312426A patent/PL312426A1/en unknown
- 1994-06-16 NZ NZ266525A patent/NZ266525A/en unknown
- 1994-06-16 RU RU96103653A patent/RU2131876C1/en active
- 1994-06-16 HU HU9503934A patent/HUT74170A/en unknown
- 1994-06-16 CA CA002166721A patent/CA2166721C/en not_active Expired - Fee Related
- 1994-06-16 BR BR9406946A patent/BR9406946A/en not_active Application Discontinuation
- 1994-06-17 TW TW083105518A patent/TW316904B/zh active
- 1994-06-30 IL IL11017594A patent/IL110175A/en active IP Right Grant
- 1994-07-05 ZA ZA944844A patent/ZA944844B/en unknown
- 1994-07-05 EG EG40294A patent/EG20513A/en active
- 1994-07-05 FI FI943208A patent/FI943208A/en unknown
- 1994-07-05 MX MX9405132A patent/MX9405132A/en unknown
-
1996
- 1996-01-05 NO NO960056A patent/NO305029B1/en unknown
Also Published As
Publication number | Publication date |
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CA2166721A1 (en) | 1995-01-19 |
AU6805794A (en) | 1995-02-06 |
MX9405132A (en) | 1995-01-31 |
IL110175A (en) | 2000-01-31 |
TW316904B (en) | 1997-10-01 |
RU2131876C1 (en) | 1999-06-20 |
CN1048015C (en) | 2000-01-05 |
NO960056D0 (en) | 1996-01-05 |
HU9503934D0 (en) | 1996-03-28 |
FI943208A (en) | 1995-01-07 |
PL312426A1 (en) | 1996-04-29 |
EG20513A (en) | 1999-06-30 |
CN1129940A (en) | 1996-08-28 |
IL110175A0 (en) | 1994-10-07 |
JP2944048B2 (en) | 1999-08-30 |
WO1995001980A1 (en) | 1995-01-19 |
NZ266525A (en) | 1997-10-24 |
KR960703852A (en) | 1996-08-31 |
NO960056L (en) | 1996-01-05 |
AU695301B2 (en) | 1998-08-13 |
ZA944844B (en) | 1996-01-05 |
EP0707585A1 (en) | 1996-04-24 |
HUT74170A (en) | 1996-11-28 |
NO305029B1 (en) | 1999-03-22 |
FI943208A0 (en) | 1994-07-05 |
JPH08507084A (en) | 1996-07-30 |
KR100228949B1 (en) | 1999-11-01 |
BR9406946A (en) | 1996-08-06 |
CZ3696A3 (en) | 1997-06-11 |
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