U.S. patent application number 10/560386 was filed with the patent office on 2006-06-15 for pyridinylpyrazolopyrimidinone derivatives as pde 7 inhibitors.
This patent application is currently assigned to Daiichi Asubio Pharma Co., Ltd. Invention is credited to Yasuhiro Hayashi, Hidekazu Inoue, Hidenobu Murafuji.
Application Number | 20060128728 10/560386 |
Document ID | / |
Family ID | 33549403 |
Filed Date | 2006-06-15 |
United States Patent
Application |
20060128728 |
Kind Code |
A1 |
Inoue; Hidekazu ; et
al. |
June 15, 2006 |
Pyridinylpyrazolopyrimidinone derivatives as pde 7 inhibitors
Abstract
To provide the compounds inhibiting PDE 7 selectively, and
therefore, enhance cellular cAMP level. Consequently, the compound
is useful for treating various kinds of disease such as allergic
disease, inflammatory disease or immunologic disease. The compound
is pyridinylpyrazolopyrimidinone compound represented by the
following formula (IA) or (IB): especially, R.sup.1 is cyclohexyl
or cycloheptyl group, R.sup.2 is methyl; R.sup.3 is a group:
--NR.sup.5R.sup.6 or --S(O).sub.0-2R.sup.8; hydrogen atom; nitro
group; cyano group; a halogen atom; heteroaryl group; and R.sup.4
is methoxy or ethoxy group. ##STR1##
Inventors: |
Inoue; Hidekazu; (Osaka,
JP) ; Murafuji; Hidenobu; (Osaka, JP) ;
Hayashi; Yasuhiro; (Osaka, JP) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP;INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W.
SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Assignee: |
Daiichi Asubio Pharma Co.,
Ltd
9-11, Akasaka 2-chome, Minato-ku
Tokyo
JP
107-8541
|
Family ID: |
33549403 |
Appl. No.: |
10/560386 |
Filed: |
June 11, 2004 |
PCT Filed: |
June 11, 2004 |
PCT NO: |
PCT/JP04/08643 |
371 Date: |
December 13, 2005 |
Current U.S.
Class: |
514/262.1 ;
544/262 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
31/04 20180101; A61P 19/02 20180101; A61P 27/16 20180101; A61P 1/04
20180101; A61P 17/06 20180101; A61P 25/00 20180101; A61P 27/02
20180101; A61P 37/00 20180101; A61P 11/06 20180101; A61P 11/02
20180101; A61P 29/00 20180101; C07D 487/04 20130101; A61P 37/06
20180101; A61P 43/00 20180101; A61P 1/00 20180101; A61P 1/16
20180101; A61P 1/18 20180101; A61P 37/02 20180101; A61P 11/00
20180101; A61P 9/10 20180101; A61P 17/00 20180101; A61P 27/14
20180101; A61P 37/08 20180101 |
Class at
Publication: |
514/262.1 ;
544/262 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/02 20060101 C07D487/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 13, 2003 |
JP |
2003-170094 |
Claims
1. Pyridinylpyrazolopyrimidinone derivative represented by the
following formula (IA) or (IB): ##STR56## wherein: R.sup.1 is a
substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl group or
tert-butyl group; R.sup.2 is a hydrogen atom or C.sub.1-C.sub.3
alkyl group; R.sup.3 is a group: --NR.sup.5R.sup.1, --C(=O)R.sup.7
or --S(O).sub.0-2R.sup.8; R.sup.4 is a hydrogen atom or
C.sub.1-C.sub.3 alkoxyl group which is unsubstituted or substituted
by one or more fluorine atom(s); R.sup.5 and R.sup.6 are, same or
different from each other, a hydrogen atom, substituted or
unsubstituted C.sub.1-C.sub.6 alkyl group, substituted or
unsubstituted acyl group, substituted or unsubstituted
heterocycloalkyl group, and substituted or unsubstituted
heterocycloalkyl ring formed with a nitrogen atom which is binding
R.sup.5 and R.sup.6; R.sup.7 is a group: --OR.sup.9 or
--NR.sup.5R.sup.6; R.sup.8 is a hydrogen atom, a halogen atom, a
group: --NR.sup.5R.sup.6, substituted or unsubstituted
C.sub.1-C.sub.6 alkyl group, or substituted or unsubstituted aryl
group; R.sup.9 is a hydrogen atom or substituted or unsubstituted
C.sub.1-C.sub.6 alkyl group; or pharmaceutically acceptable salts
or solvates thereof.
2. The compound represented by the formula (IA) according to claim
1.
3. The compound represented by the formula (IB) according to claim
1.
4. The compound according to claim 1, in which R.sup.1 is a
cyclohexyl group or cycloheptyl group.
5. The compound according claim 1, in which R.sup.2 is a methyl
group.
6. The compound according to claim 1, in which R.sup.4 is a methoxy
or ethoxy group.
7. The compound according to claim 1, in which R.sup.3 is a group
--NR.sup.5R.sup.6.
8. A pharmaceutical composition comprising a compound according to
claim 1 or pharmaceutically acceptable salts or solvates thereof as
active ingredient.
9. A PDE 7 inhibitor comprising a compound according to claim 1 or
pharmaceutically acceptable salts or solvates thereof as active
ingredient.
Description
TECHNICAL FIELD
[0001] The present invention relates to
pyridinylpyrazolopyrimidinone compounds, pharmaceutically
acceptable salts and solvates thereof, having selective PDE 7
(phosphodiesterase VII) inhibiting effect. These compounds are
effective compounds for treating various kinds of disease such as
allergic disease, inflammatory disease and immunologic disease.
BACKGROUND ART
[0002] A cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an
intracellular second messenger substance, is decomposed and
inactivated by phosphodiesterase (PDE 1 to PDE 11). The PDE 7
selectively decomposes CAMP, and is characterized as an enzyme not
decomposed by rolipram. Rolipram is a selective inhibitor of PDE 4
which decomposes CAMP.
[0003] It is suggested that PDE 7 plays an important role for
activating T cells (Beavo, et al., Science, 283, 848 (1999)), and
well known that activating of T-cell is concerned with the
exacerbation of allergic disease, inflammatory disease or
immunologic disease. These diseases are for example bronchial
asthma, chronic bronchitis, chronic obstructive pulmonary disease,
allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, septicemia, Crohn's disease,
rejection for organ transplantation, graft versus host disease (GVH
disease), and restenosis after angioplasty. [J. Allergy Clin.
Immunol., 2000 Nov; 106(5 Suppl.): S221-6; Am. J. Respir. Crit.
Care Med., 1996 Feb; 153(2): 629-32; Am. J. Respir. Crit. Care
Med., 1999 Nov; 160(5 Pt 2): S33-7; Clin. Exp. Allergy, 2000 Feb;
30(2): 242-54; Hosp. Med., 1998 Jul; 59(7): 530-3; Int. Arch.
Allergy Immunol., 1998 Mar; 115(3): 179-90; J. Immunol., 1991 Feb
15; 146(4): 1169-74; Osteoarthritis Cartilage, 1999 Jul; 7(4):
401-2; Rheum. Dis. Clin. North Am., 2001 May; 27(2): 317-34; J.
Autoimmun., 2001 May; 16(3): 187-92; Curr. Rheumatol. Rep., 2000
Feb; 2(1): 24-31; Trends Immunol., 2001 Jan; 22(1): 21-6; Curr.
Opin. Immunol., 200 Aug; 12(4): 403-8; Diabetes Care, 2001 Sep;
24(9): 1661-7; J. Neuroimmunol., 2000 Nov 1; 111(1-2): 224-8; Curr.
Opin. Immunol., 1997 Dec; 9(6): 793-9; JAMA, 1999 Sep 15;
282(11):1076-82; Semin. Cancer Biol., 1996Apr; 7(2): 57-64; J.
Interferon Cytokine Res., 2001 Apr; 21(4): 219-21].
[0004] Therefore, it is considered that a compound having PDE 7
inhibiting effect is useful for treating various kinds of disease
such as allergic disease, inflammatory disease or immunologic
disease concerned with T cells.
[0005] There has been proposed many compounds selectively inhibit
PDE 7. These are for example, imidazopyridine derivatives
(International Patent Publication WO 01/34601), dihydropurine
derivatives (International Patent Publication WO 00/68203), pyrrole
derivatives (International Patent Publication WO 01/32618),
benzothiopyranoimidazolone derivatives (DE Patent 19950647),
heterocyclic compounds (International Patent Publications WO
02/88080; 02/87513), quinazoline and pyridopyrimidine derivatives
(International Patent Publication WO 02/102315), spiro tricyclic
compounds (International Patent Publication WO 02/74754), thiazole
and oxathiazole derivatives (International Patent Publication WO
02/28847), sulfonamide derivatives (International Patent
Publication Wo 01/98274), heterobiarylsulfonamide derivatives
(International Patent Publication WO01/74786), dihydroisoquinoline
derivatives (International Patent Publication WO 02/40450), guanine
derivatives (Bioorg. Med. Chem. Lett., 11(2001), 1081),
benzothiadiazine derivatives (J. Med. Chem., 43(2000), 683) and
benzothienothiadiazine derivatives (Eur. J. Med. Chem., 36(2001),
333). However, no curative medicines having PDE 7 inhibiting effect
as main pharmacological mechanism have developed up to now.
[0006] Though some pyrazolopyrimidinone derivatives as cGMP
specified PDE inhibitor have been known (For examples: EP 463756;
EP 526004; EP 349239; EP 636626; EP 995751; and Japanese Patent
Publication No. Hei8-25384), there is no suggestion that these
compounds have PDE 7 inhibiting effect.
[0007] Therefore, the purpose of the present invention is to
provide novel compounds having PDE 7 inhibiting effect, and PDE 7
inhibiting composition containing the same as an active
ingredient.
[0008] The compounds of the present invention inhibit PDE 7
selectively, and therefore, enhance cellular cAMP level.
Consequently, the compounds of the present invention are useful for
treating various kinds of disease such as allergic disease,
inflammatory disease or immunologic disease. For example, the
compounds of the present invention are useful for treating or
preventing the diseases such as bronchial asthma, chronic
bronchitis, chronic obstructive pulmonary disease, allergic
rhinitis, psoriasis, atopicdermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, septicemia, Crohn's disease,
rejection for organ transplantation, GVH disease, restenosis after
angioplasty.
DISCLOSURE OF INVENTION
[0009] Through extensive investigations of researching compounds
having the capabilities of inhibiting PDE 7, the present inventors
discovered that the compounds having pyridinylpyrazolopyrimidinone
skeleton in the molecular represented by the formula (IA) or (IB)
mentioned below possess potent and selective PDE 7 inhibiting
effect, and therefore, completed the present invention.
[0010] Accordingly, as one aspect of the present invention, it is
provided pyridinylpyrazolopyrimidinone compounds represented by the
following formula (IA) or (IB): ##STR2## wherein:
[0011] R.sup.1 is substituted or unsubsituted C.sub.3-C.sub.8
cycloalkyl group or tert-butyl group;
[0012] R.sup.2 is a hydrogen atom or C.sub.1-C.sub.3 alkyl
group;
[0013] R.sup.3 is a group: --NR.sup.5R.sup.6, --C(=O)R.sup.7 or
--S(O).sub.0-2R.sup.8;
[0014] R.sup.4 is a hydrogen atom or C.sub.1-C.sub.3 alkoxy group
which is unsubstututed or substituted by one or more fluorine
atom(s);
[0015] R.sup.5 and R.sup.6 are, same or different from each other,
a hydrogen atom, substituted or unsubsituted C.sub.1-C.sub.6 alkyl
group, substituted or unsubsituted acyl group, substituted or
unsubsituted heterocycloalkyl group, and substituted or
unsubsituted heterocycloalkyl ring is formed with nitrogen atom
which is binding R.sup.5 and R.sup.6;
[0016] R.sup.7 is a group: --OR.sup.9 or --NR.sup.5R.sup.6;
[0017] R.sup.8 is a hydrogen atom, a halogen atom, a group:
--NR.sup.5R.sup.6, substituted or unsubsituted C.sub.1-C.sub.6
alkyl group, or substituted or unsubsituted aryl group;
[0018] R.sup.9 is a hydrogen atom or substituted or unsubsituted
C.sub.1-C.sub.6 alkyl group;
or pharmaceutically acceptable salts or solvates thereof.
[0019] Still another aspect of the present invention, it is
provided PDE 7 inhibiting composition containing the
pyridinylpyrazolopyrimidinone compounds mentioned above, or
pharmaceutically acceptable salts or solvates thereof as an active
ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
[0020] The present invention will now be explained more
specifically as following.
[0021] The term "C.sub.1-C.sub.3 alkyl group" of the present
invention includes a straight or branched-chained alkyl group
having 1 to 3 carbon atoms, such as methyl, ethyl and propyl group,
and the term "C.sub.1-C.sub.6 alkyl group" of the present invention
means a straight or branched-chained alkyl group having 1 to 6
carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl
group. The term "C.sub.3-C.sub.8 cycloalkyl group" of the present
invention includes a cycloalkyl group having 3 to 8 carbon atoms
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cyclooctyl.
[0022] The term "heterocycloalkyl group" is 3 to 7 membered
heterocyclic group containing the same or different 1 to 4 hetero
atom(s) such as oxygen, nitrogen or sulfur atom(s), and examples
may include pyrrolidinyl, piperidinyl, piperazinyl,
homopiperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl
and azetidinyl.
[0023] The term "C.sub.1-C.sub.3 alkoxy group" means alkoxy group
having 1 to 3 carbon atoms and examples include methoxy, ethoxy and
propoxy. The term "acyl group" means acyl group having 1 to 8
carbon atoms, and examples include formyl, acetyl, propionyl,
butanoyl, pentanoyl, benzoylandtoluoyl. The "halogen atom" includes
fluorine, chlorine, bromine and iodine.
[0024] The term "aryl group" is phenyl, naphthyl, biphenyl group
which is consisted by 6 to 12 carbon atoms, and the term
"heteroaryl group" is 5 to 7 membered monocyclic or polycyclic
group thereof containing 2 to 8 carbon atoms and the same or
different 1 to 4 hetero atom(s) such as oxygen, nitrogen,
sulfuratom(s). The examples includepyrrole, furyl, thienyl,
imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl,
isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl pyridazinyl and
pyrimidinyl.
[0025] Examples of suitable substituent of "substituted or
unsubstituted C.sub.1-C.sub.6 alkyl group" include hydroxyl group
and halogen atom, and examples of suitable substituent of
"substituted or unsubstituted acyl group" include halogen atom and
nitro group. Further, examples of suitable substituent of
"substituted or unsubstituted aryl group" include C.sub.1-C.sub.3
alkyl, halogenatom, amino group, acylgroup, amidegroup, hydroxyl
group, acylamino group, carboxyl group and sulfonyl group. Examples
of suitable substituent of "substituted or unsubstituted C.sub.3-C8
cycloalkyl group" is C.sub.1-C.sub.3 alkyl, hydroxyl group and oxo
group, and examples of suitable substituent of "substituted or
unsubstituted heterocycloalkyl group" may include carboxy group,
acyl group, alkoxy group, amino group, alkylamino group, acylamino
group, hydroxyl group, oxo group, ethylenedioxy group, ethyl group,
ethyl group and hydroxyethyl group.
[0026] Preferable compounds of the formula (IA) and (IB) of the
present invention include the compounds wherein R.sup.1 is
cyclohexyl group or cycloheptyl group; R.sup.2 is methyl group;
R.sup.3 is the group --NR.sup.5R.sup.6 or --S(O).sub.0-2R.sup.8;
and R.sup.4 is methoxy or ethoxy group.
[0027] The compounds of the formula (IA) and (IB) of the present
invention may exist in the tautomeric mixtures, the tautomeric
isomers per se, and the mixture thereof. Furthermore, the radio
labelled compounds of the formula (IA) and (IB) shall be included
within the scope of the compounds of the present invention.
[0028] The compounds of the present invention may contain one or
more asymmetric carbon atom and therefore, the compounds of the
present invention may exist as optically isomer of (R)-form or
(S)-form, racemic forms, as well as diastereomers. Further, the
compounds of the present invention may exist as geometrical isomer
such as (Z)-form or (E)-form due to the double bond in the
substituent. Therefore, the compounds of the present invention
should include these isomers per se as well as the isomeric
mixtures thereof.
[0029] The compounds of the present invention may form acid
additional salt thereof with various acids. Examples of the acid
additional salt include the salts with inorganic acid such as
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,
nitric acid and phosphoric acid; salts with organic acid such as
formic acid, acetic acid, propionic acid, oxalic acid, malonic
acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic
acid, citric acid, tartaric acid, benzoic acid, picric acid,
methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,
trichloroacetic acid, trifluoroacetic acid, asparaginic acid and
glutamic acid.
[0030] The compounds of the present invention may form
pharmaceutically acceptable metal salts by treating with various
kinds of metal, especially alkali metal or alkali earth metal.
These salts may include sodium salt, potassium salt and calcium
salt. Further, the compounds of the present invention may include
hydrate or solvate with water, ethanol or isopropanol, and
polymorphisms thereof.
[0031] The following compounds are preferable
pyridinylpyrazolo-pyrimidinone compounds of the formula (IA) or
(IB). [0032]
1-cyclohexyl-5-{2-methoxy-6-[(4-methylphenyl)sulfanyl]-3-pyridiny-
l}-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0033]
1-cyclohexyl-5-{2-methoxy-6-[(4-methylphenyl)sulfonyl]-3-pyridinyl}-3-met-
hyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0034]
3-cyclohexyl-6-{2-methoxy-6-[(4-methylphenyl)sulfanyl]-3-pyridinyl}-1-met-
hyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0035]
3-cyclohexyl-6-{2-methoxy-6-[(4-methylphenyl)sulfonyl]-3-pyridinyl}-1-met-
hyl-l, 5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0036]
1-cyclohexyl-5-[2-methoxy-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3-methy-
l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0037]
1-cyclohexyl-5-[2-methoxy-6-(4-morpholinyl)-3-pyridinyl)-3-methyl-1,6-dih-
ydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0038]
1-cyclohexyl-5-[2-methoxy-6-(4-methyl-i,
4-diazepan-1-yl)-3-pyridinyl]-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-dlpyri-
midin-7-one; [0039]
1-cyclohexyl-5-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methoxy-3-pyridin-
yl]-3-methyl-1,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one; [0040]
1-cyclohexyl-5-[2-methoxy-6-(4-oxo-1-piperidinyl)-3-pyridinyl]-3-methyl-l-
, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0041]
1-cyclohexyl-5-[6-(4-hydroxy-1-piperidinyl)-2-methoxy-3-pyridinyl)-3-meth-
yl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0042]
1-cyclohexyl-5-{2-methoxy-6-[4-(methylamino)-1-piperidinyl]-3-pyridinyl}--
3-methyl-1,6-dihydro-7H-pyrazolo[4,3-dlpyrimidin-7-one; [0043]
1-cyclohexyl-5-{6-[4-(dimethylamino)-1-piperidinyl-2-methoxy-3-pyridinyl}-
-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0044]
6-[6-(4-amino-1-piperidinyl)-2-methoxy-3-pyridinyl]-1-cyclohexyl-3-methyl-
-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0045]
N-{1-[5-(1-cyclohexyl-3-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]-pyrim-
idin-5-yl)-6-methoxy-2-pyridinyl]-4-piperidinyl}acetamide; [0046]
1-cyclohexyl-5-(2-methoxy-3-pyridinyl)-3-methyl-1,6-dihydro-7H-pyrazolo[4-
,3-d]pyrimidin-7-one; [0047]
3-cyclohexyl-6-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methoxy-3-pyridin-
yl]-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-d]pyrimidin-4-one; [0048]
3-cyclohexyl-6-[2-methoxy-6-(4-oxo-1-piperidinyl)-3-pyridinyl]-1-methyl-1-
,5-dihydro-4H-pyrazolo[4,3-d]pyrimidin-4-one; [0049]
3-cyclohexyl-6-[6-(4-hydroxy-1-piperidinyl)-2-methoxy-3-pyridinyl]-1-meth-
yl-1, 5-dihydro-4H-pyrazolo[4, 3-d]pyrimidin-4-one; [0050]
3-cyclohexyl-6-(2-methoxy-6-[4-(methylamino)-1-piperidinyl]-3-pyridinyl)--
1-methyl-1,5-dihydro-4H-pyrazolo[4, 3-d]pyrimidin-4-one; [0051]
3-cyclohexyl-6-{6-[4-(dimethylamino)-1-piperidinyl]-2-methoxy-3-pyridinyl-
}-1-methyl-1,5-dihydro-4H-pyrazolo[4,3-d]pyrimidin-4-one; [0052]
6-[6-(4-amino-1-piperidinyl)-2-methoxy-3-pyridinyl]-3-cyclohexyl-1-methyl-
-1,5-dihydro-4H-pyrazolo[4,3-d]pyrimidin-4-one; [0053]
N-{1-[5-(3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-d]-pyrim-
idin-6-yl)-6-methoxy-2-pyridinyl]-4-piperidinyl}acetamide; [0054]
1-cyclohexyl-5-(2-methoxy-3-pyridinyl)-3-methyl-1,6-dihydro-7H-pyrazolo[4-
,3-d]pyrimidin-7-one; [0055]
3-cyclohexyl-6-[2-methoxy-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1-methy-
l-1, 5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0056]
3-cyclohexyl-6-[2-methoxy-6-(4-morpholinyl)-3-pyridinyl]-1-methyl-1,5-dih-
ydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0057]
3-cyclohexyl-6-[2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)-3-pyridinyl]-1-m-
ethyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0058]
3-cyclohexyl-6-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methoxy-3-pyridin-
yl]-1-methyl-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one; [0059]
3-cyclohexyl-6-[2-methoxy-6-(4-oxo-1-piperidinyl)-3-pyridinyl]-1-methyl-1-
,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0060]
3-cyclohexyl-6-[6-(4-hydroxy-1-piperidiny)-2-methoxy-3-pyridinyl]-1-methy-
l-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0061]
3-cyclohexyl-6-{2-methoxy-6-[4-(methylamino)-1-piperidinyl]-3-pyridinyl]--
1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0062]
3-cyclohexyl-6-{6-[4-(dimethylamino)-1-piperidinyl]-2-methoxy-3-pyridinyl-
}-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0063]
6-[6-(4-amino-1-piperidinyl)-2-methoxy-3-pyridinyl]-3-cyclohexyl-1-methyl-
-1, 5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; [0064]
N-{1-[5-(3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo(3,4-d]-pyrim-
idin-6-yl)-6-methoxy-2-pyridinyl]-4-piperidinyl}acetamide; [0065]
3-cyclohexyl-6-(2-methoxy-6-sulfanyl-3-pyridinyl)-1-methyl-1,5-dihydro-4H-
-pyrazolo[3,4-d]pyrimidin-4-one; [0066]
5-(3-cyclohexyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]-pyrilidin-6-
-yl)-6-methoxy-2-pyridinesulfonyl chloride; [0067]
3-cyclohexyl-6-{2-methoxy-6-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]-3-pyri-
dinyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
[0068]
1-cyclohexyl-5-{2-methoxy-6-[(4-methylphenyl)sulfinyl]-3-pyridinyl}-3-met-
hyl-1, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0069]
1-cyclohexyl-5-{2-ethoxy-6-[(4-methylphenyl)sulfanyl]-3-pyridinyl}-3-meth-
yl-1, 6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one; [0070]
1-cyclohexyl-5-{2-ethoxy-6-[(4-methylphenyl)sulfonyl]-3-pyridinyl}-3-meth-
yl-1, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0071]
1-cyclohexy-5-[2-ethoxy-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3-methyl--
1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0072]
1-cyclohexyl-5-[2-ethoxy-6-(4-methyl-1,4-diazepan-1-yl)-3-pyridinyl]-3-me-
thyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0073]
1-cyclohexyl-5-[6-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-2-ethoxy-3-pyridin-
yl]-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0074]
1-cyclohexyl-5-[2-ethoxy-6-(4-oxo-1-piperidinyl)-3-pyridinyl]-3-methyl-1,-
6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0075]
1-cyclohexyl-5-{6-[4-(dimethylamino)-1-piperidinyl]-2-ethoxy-3-pyridinyl}-
-3-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0076]
1-cyclohexyl-5-{2-ethoxy-6-[4-(methylamino)-1-piperidinyl)-3-pyridinyl}-3-
-methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; [0077]
1-cyclohexyl-5-[2-ethoxy-6-(4-hydroxy-1-piperidinyl)-3-pyridinyl)-3-methy-
l-1, 6-dihydro-7H-pyrazolo(4, 3-d]pyrimidin-7-one.
[0078] The compound of the formula (IA) of the present invention
can be synthesized by the following methods. ##STR3## ##STR4##
(wherein, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.8
have same meaning mentioned above; L is C.sub.1-C.sub.3 lower
alkyl, and Y is hydroxyl group or halogen atom, preferably chlorine
atom) First, the compound (IX) obtained from the compound (X) by
reacting with R'NHNH.sub.2 or salt thereof in accordance with the
known method. Namely, the compound (X) is reacted with 1 to 2
equivalent, preferably about 1 equivalent of R.sup.1NHNH.sub.2 or
salt thereof in the solvent or absent of the solvent at room
temperature to 120.degree. C. The solvent to be used in the
reaction is inorganic acid aqueous solution such as hydrochloric
acid or sulfuric acid; aromatic carbon hydrate such as benzene or
toluene; organic acid such as acetic acid; alcohols such as
methanol or ethanol; or the mixture solvent there of. After the
reaction is completed, inorganic base aqueous solution such as
sodium hydroxide aqueous solution is added to the reaction mixture
and the mixture is extracted wit an organic solvent, which is
nonmiscible solvent with water, and the organic layer is washed
sequentially with water and saturated saline solution. Then, the
compound (IX) can be obtained by removal of the solvent. This
compound (IX) can be purified by recrystallization, if
necessary.
[0079] The compound (X) to be used in this reaction can be
commercially available or can be easily prepared from known
compounds by using common methods. Further, the compound represent
by the formula R.sup.1NHNH.sub.2 or salt thereof can also be
commercially available or can be easily prepared from known
compounds by using common methods (For example: J. Org. Chem.,
1981, 46, 5414-5415).
[0080] Then, the compound (IX) is converted to the compound (VIII)
in accordance with the common method. Namely, the reaction can be
conducted by reacting the compound (IX) with 1 to 5 equivalent of
halogenate reagent such as phosphorus oxychloride or thionyl
chloride in aromatic hydrocarbon solvent such as benzene or
toluene, or the absence of the solvent, at room temperature to
refluxing temperature of the solvent. After the reaction is
completed, the compound (VIII) can be obtained by removal of the
solvent.
[0081] The obtained compound (VIII) is converted, without further
purification, to the compound (VII) by nitration in accordance with
the common method. The nitration can be conducted by using nitric
acid with sulfuric acid or acetic anhydride at the temperature from
-20.degree. to room temperature. After the reaction is completed,
the reaction mixture is poured into ice and the resulting
precipitate is collected to obtain the purpose compound (VII). This
compound (VII) can be purified by recrystallization, if
necessary.
[0082] Next, the obtained compound (VII) is converted to the
compound (VI) in accordance with the common method. Namely, the
reaction can be conducted by reacting the compound (VII) with 1 to
3 equivalent metal cyanide such as potassium cyanide or sodium
cyanide in a polar solvent such as N,N-dimethylformamide at room
temperature to 120.degree. C. After the reaction is completed,
water is added to the reaction mixture and the mixture is extracted
with an organic solvent, which is nonmiscible solvent with water,
and the organic layer is washed sequentially with water and
saturated saline solution. Then, the compound (VI) can be obtained
by removal of the solvent. This compound (VI) can be purified by
chromatography, if necessary.
[0083] The obtained compound (VI) is converted to the compound (V)
in accordance with the common method. This reaction is hydrolysis
reaction of nitrile group converting to the corresponding acid
amide group, and various methods are applied. For example, the
reaction can be conducted by reacting the compound (VI) with
hydrogen peroxide in the presence of base such as sodium hydroxide
or potassium carbonate in a solvent at 0.degree. C. to the room
temperature. The solvent to be used is water, alcohols such as
methanol or ethanol, ethers such as 1,4-dioxane or tetrahydrofuran,
or the mixture thereof. After the reaction is completed, the
reaction mixture is extracted with an organic solvent, which is
nonmiscible solvent with water, and the organic layer is washed
sequentially with water and saturated saline solution. Then, the
compound (V) can be obtained by removal of the solvent. This
compound (V) can be purified by recrystallization, if
necessary.
[0084] Then, the obtained compound (V) is converted to the compound
(III) in accordance with the common method. This reaction is
reduction of nitro group converting to the corresponding amino
group, and various methods are applied. For example, the reaction
can be conducted by reacting the compound (V) with 2 to 10
equivalent of tin(II) chloride in the presence of inorganic acid
such as hydrochloric acid at 0.degree. C. to the refluxing
temperature. After the reaction is completed, the reaction mixture
is neutralized by inorganic base such as sodium hydroxide, and
filtrate by Celite.RTM.. The obtained filtrate is extracted with an
organic solvent, which is nonmiscible solvent with water, and the
organic layer is washed sequentially with water and saturated
saline solution. Then, the compound (III) can be obtained by
removal of the solvent. This compound (III) can be purified by
chromatography, if necessary.
[0085] The obtained compound (III) is, then, converted to the
compound (II) in accordance with the common method. This reaction
can be conducted by the reaction of the amine compound (III) with
carboxylic compound (IV) to obtain the corresponding acid amide
compound (II), and various methods are applied. For example, in the
case of the compound (IV) in which Y is halogen atom, preferably
chlorine atom, the reaction can be conducted by reacting the
compound (III) with 1.0 to 1.5 equivalent, preferably 1.2
equivalent of the compound (IV) in the presence of 1 to 5
equivalent, preferably 2.5 equivalent of tertiary amine such as
triethylamine, based on the compound (III), and if necessary in the
presence of the catalyst such as 4-dimethylaminopyridine. The
reaction can be carried out in the presence of inert solvent such
as dichloromethane at 0.degree. C. to the room temperature.
[0086] Furthermore, in the case of the compound (IV) in which Y is
hydroxyl group, the reaction can be conducted by reacting the
compound (III) with 1.0 to 1.5 equivalent, preferably 1.2
equivalent of the compound (IV) 15 in the presence of 1 to 5
equivalent, preferably 1.2 equivalent of the condensing agent such
as 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride,
based on the compound (III), and if necessary in the presence of
the catalyst such as 4-dimethylaminopyridine in the inert solvent
such as dichloromethane.
[0087] After the reaction is completed, the reaction mixture is
diluted with an organic solvent, which is nonmiscible solvent with
water, and the organic layer is washed sequentially with water and
saturated saline solution, then, the solvent is removed to give the
purpose compound (II). This compound can be purified by column
chromatography, if necessary.
[0088] Then, the obtained compound (II) is converted to the
compound (IA') by pyrimidine ring formation reaction. This ring
formation reaction can be carried out by heating the compound (II)
with base such as sodium hydroxide, potassium t-butoxide or
potassium carbonate in ethanol/water in the seal tube at 120 to
140.degree. C. Further, the reaction can be carried out in high
boiling solvent such as methoxyethanol in the presence of base such
as potassium t-butoxide at 120 to 140.degree. C. After the reaction
is completed, the reaction mixture is diluted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (IA') can be obtained by removal of
the solvent. This compound (IA') can be purified by chromatography
or recrystallization, if necessary.
[0089] The compound (IA'') can be obtained from the obtained
compound (IA') by the function group converting reaction with per
acid such as m-chloroperbenzoic acid or magnesium
mono-peroxyphthalate in chloroform or dichloromethane or chloroform
at .degree. C. to the room temperature.
[0090] Further, the compound (IA''') can be obtained by reacting
the compound (IA'') with lithium amide, which is obtained by
reacting the amine compound with n-butyllithium. For example, to 2
to 5 equivalent of amine compound based on the compound (IA'') in
ethers such as 1,4-dioxan or tertahydrofuran is added by dripping
same equivalent of n-butyl lithium to obtain corresponding lithium
amide at -78.degree. C. to 0.degree. C., and then the compound
(IA'') is added to this mixture of lithium amide solution to obtain
the compound (IA'''). After the reaction is completed, water is
added to the reaction mixture and the mixture is extracted with an
organic solvent, which is nonmiscible solvent with water, and the
organic layer is washed sequentially with water and saturated
saline solution, then, the solvent is removed to give the purpose
compound (IA''').
[0091] The carboxylic compound (IV) to be used in the above
reaction can be obtained by the following reaction scheme. ##STR5##
(wherein, L, Y, R.sup.4 and R.sup.6 have same meaning mentioned
above; and X is a halogen atom)
[0092] Namely, the compound (XII) is obtained from the compound
(XIII) in accordance with the known method (e.g., Chem. Pharm.
Bull., 48(12), 1847-1853 (2000)). For example, the reaction can be
conducted by reacting the compound (XIII) with about 1 equivalent
thiol compound such as ethanethiol or benzenethiol in the presence
of base such as potassium t-butoxide, in polar solvent such as
N,N-dimethylformamide at the room temperature to -30.degree. C.,
preferably -30.degree. C. After the reaction is completed, water is
added to the reaction mixture and the mixture is extracted with an
organic solvent, which is nonmiscible solvent with water, and the
organic layer is washed sequentially with water and saturated
saline solution. Then, the compound (XII) can be obtained by
removal of the solvent. This compound (XII) can be purified by
recrystallization, if necessary.
[0093] Then, obtained compound (XII) is converted to the compound
(XI) in accordance with common method. For example the reaction is
conducted by reacting the compound (XII) with small excess of metal
alcoholate such as sodium methylate in ethers solvent such as
1,4-dioxan or tetrahydrofuran at the room temperature to refluxing
temperature. After the reaction is completed, water is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (XI) can be obtained by removal of the
solvent. This compound (XI) can be purified by recrystallization,
if necessary.
[0094] The obtained compound (XI) is converted to the compound (IV)
in accordance with common method. This reaction is hydrolysis
reaction of ester compound and various methods are applied. For
example the reaction is conducted by reacting the compound (XI)
with base such as sodium hydroxide in the alcohol solvent such as
methanol or water, as well as a mixture thereof at the room
temperature to refluxing temperature. After the reaction is
completed, the reaction mixture is condensed and the residue is
neutralized to give the compound (IV).
[0095] All reaction mentioned above are well known, and the
reagents to be used or the reaction conditions to be applied can be
easily established in accordance with the standard text book and
the examples mentioned later. Further, the other methods or
modified methods for obtaining the compound (IA) of the present
invention can be easily selected by the person skilled in this
field.
[0096] The compound of the formula (IB) of the present invention
may be synthesized by the following methods. ##STR6## (wherein,
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have same meaning mentioned
above; and Y is hydroxyl group or halogen atom, preferably chlorine
atom)
[0097] At the beginning, to carry out the method described above,
the compound (XIX) is obtained from the compound (XX) in accordance
with the known method (e.g., J. Chem. Soc, Perkin Trans. I, 1996,
1545-1552). This method can be conducted by the reaction of the
compound (XX) with 1 to 1.5 equivalent of the compound (XXI) based
on the compound (XX), in the presence of the 2 to 2.5 equivalent of
alkali metal hydride such as sodium hydride and potassium hydride,
or tertiary amine such as triethlyamine based on the compound (XX).
The reaction can be carried out in an appropriate solvent and these
are halogenated hydrocarbons such as dichloromethane; aromatic
hydrocarbon such as toluene and benzene; ethers solvent such as
diethyl ether tetrahydrofuran; or a mixture of solvent thereof. The
reaction temperature is a range from 0.degree. C. to the room
temperature. After the reaction is completed, the reaction mixture
is diluted with an organic solvent, which is nonmiscible solvent
with water, and the organic layer is washed sequentially with water
and saturated saline solution. Then, the compound (XIX) can be
obtained by removal of the solvent. This compound (XIX) can be
purified by chromatography, if necessary.
[0098] Then, the obtained compound (XIX) is converted to the
compound (XVIII) in accordance with the common method (e.g., J.
Chem. Soc, Perkin Trans. I, 1996, 1545-1552). For example, the
reaction can be carried out by the reacting the compound (XIX) with
5 to 10 equivalent of the methylation reagent such as dimethyl
sulfate in an appropriate solvent. The solvent to be used in this
reaction may include halogenated hydrocarbons such as
dichloromethane; aromatic hydrocarbon such as toluene and benzene;
ethers solvent such as diethyl ether tetrahydrofuran; or a mixture
of solvent thereof, and the reaction temperature is from the room
temperature to the refluxing temperature of the solvent. After the
reaction is completed, the reaction mixture is diluted with an
organic solvent, which is nonmiscible solvent with water, and the
organic layer is washed sequentially with water and saturated
saline solution. Then, the compound (XVIII) can be obtained by
removal of the solvent. This compound (XVIII) can be purified by
chromatography, if necessary.
[0099] Next, the obtained compound (XVIII) is converted to the
compound (XVI) in accordance with the common method (e.g., J. Chem.
Soc, Perkin Trans. I, 1996, 1545-1552). For example, the reaction
can be carried out by the reacting the compound (XVIII) with 1 to
1.5 equivalent of the compound XVII) based on the compound (XVIII)
in an appropriate solvent. The solvent to be used in this reaction
may include halogenated hydrocarbons such as dichloromethane;
aromatic hydrocarbon such as toluene and benzene; ethers solvent
such as diethyl ether tetrahydrofuran; or a mixture solvent
thereof, and the reaction temperature is from the room temperature
to the refluxing temperature of the solvent. After the reaction is
completed, the solvent is removed to give the compound (XVI). This
compound (XVI) can be purified by chromatography, if necessary.
[0100] Then, the obtained compound (XVI) is converted to the
compound (XV) in accordance with the common method. This reaction
is hydrolysis reaction of nitrile group converting to the
corresponding acid amide group, and various methods are applied.
For example, the reaction can be conducted by treating the compound
(XVI) with catalyst such as sulfuric acid or hydrochloric acid in
an appropriate solvent at the room temperature to 100.degree. C.
The solvent to be used is water, alcohols such as methanol or
ethanol, ethers such as diethyl ether, tetrahydrofuran or dioxane,
or the mixture thereof. After the reaction is completed, the pH of
reaction mixture is adjusted to alkali side, and the reaction
mixture is extracted with an organic solvent, which is nonmiscible
solvent with water, and the organic layer is washed sequentially
with water and saturated saline solution. Then, the compound (XV)
can be obtained by removal of the solvent. This compound (XV) can
be purified by recrystallization, if necessary.
[0101] The obtained compound (XV) is, then, converted to the
compound (XIV) in accordance with the common method. This reaction
can be conducted by the reaction of the compound (XV) with compound
(IV) to obtain the corresponding acid amide compound (XIV). For
example, in the case of the compound (IV) in which Y is halogen
atom, preferably chlorine atom, the reaction can be conducted by
reacting the compound (XV) with 1.0 to 2.0 equivalent, preferably
about 1.4 equivalent of the compound (IV) in the presence of 1 to 5
equivalent, preferably 2.5 equivalent of tertiary amine such as
triethylamine, based on the compound (XV), and if necessary in the
presence of the catalyst such as 4-dimethylaminopyridine. The
reaction can be carried out in the presence of inert solvent such
as dichloromethane at 0.degree. C. to the room temperature.
[0102] Furthermore, in the case of the compound (IV) in which Y is
hydroxyl group, the reaction can be conducted by reacting the
compound (XV) with 1.0 to 1.5 equivalent, preferably about 1.2
equivalent of the compound (IV) in the presence of 1 to 5
equivalent, preferably about 1.2 equivalent of the condensing agent
such as 1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide
hydrochloride, based on the compound (XV), and if necessary in the
presence of the catalyst such as 4-dimethylaminopyridine in the
inert solvent such as dichloromethane.
[0103] After the reaction is completed, the reaction mixture is
diluted with an organic solvent, which is nonmiscible solvent with
water, and the organic layer is washed sequentially with water and
saturated saline solution, then, the solvent is removed to give the
purpose compound (XIV).
[0104] Then, the obtained compound (XIV) is used for the next
reaction without further purification, and is converted to the
compound (IB) by pyrimidine ring formation reaction by mean of the
known method (e.g., J. Med. Chem., 39 1635-1644 (1996)). This ring
formation reaction can be carried out by heating the compound (XIV)
with base such as sodium hydroxide, potassium t-butoxide or
potassium carbonate in ethanol/water in the seal tube at 120 to
140.degree. C. Further, the reaction can be carried out in high
boiling solvent such as methoxyethanol in the presence of base such
as potassium t-butoxide at 120 to 140.degree. C. After the reaction
is completed, the reaction mixture is diluted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (IB) can be obtained by removal of the
solvent. This compound (IB) can be purified by chromatography or
recrystallization, if necessary.
[0105] All reaction mentioned above are well known, and the
reagents to be used or the reaction conditions to be applied can be
easily established in accordance with the standard text book and
the examples mentioned later. Further, the other methods or
modified methods for obtaining the compound (IB) of the present
invention can be easily selected by the person skilled in this
field.
EXAMPLES
[0106] The present invention is illustrated in more detail by way
of the following Biological Test and Examples, but it is to be
noted that the present invention is not limited by those Examples
in any way.
[0107] The synthesis of the compounds of the present invention and
intermediate compounds to be used in the synthesis are illustrated
in the Example mentioned later. Further, the physicochemical data
and chemical structure of the compounds and intermediate compounds
obtained by the Examples are summarized in the Tables mentions
later.
[0108] The compound numbers in the Examples are identical to those
in the Tables.
[0109] The PDE 7 (phosphodiesterase VII) inhibiting effect of the
compounds of the present invention obtained in the later mentioned
Examples was evaluated by mean of the following Biological
Tests.
Biological Test 1:
Methods for Evaluating the PDE 7 Inhibiting Effect
[0110] The PDE 7 (phosphodiesterase VII) inhibiting effect of the
compounds of the present invention was performed by the following
method, which was modified assay method described in Biochemical.
Pharmacol. 48(6), 1219-1223 (1994). [0111] (1) The active fraction
of PDE 7 (phosphodiesterase VII) was obtained. That is, MOLT-4
(obtainable from ATCC as ATCC No. CRL-1582), which was cell line of
human acute lymphoblastic lymphoma T cells, was incubated in RPMI
1640 culture medium containing 10% fetal bovine serum to obtain
5.times.10.sup.8 MOLT-4 cells. The cells were collected by
centrifugation and suspended with 10 mL of buffer solution A [25 mM
of tris-HCl, 5 mM of 2-mercaptoethnol, 2 mM of benzamidine, 2 mM of
EDTA, 0.1 mM of 4-(2-aminoethyl) benzensulfonyl hydrochloride; pH
7.5], then homogenized by Polytron.RTM. homogenizer. The homogenate
were centrifuged under 25,000.times.G for 10 minutes at 4.degree.
C. The supernatant was separated and thus obtained supernatant was
further centrifuged under 100,000.times.G for 60 minutes at
4.degree. C., and then filtrated with 0.2 .mu.m filter to obtain
the soluble fraction. [0112] (2) The obtained soluble fraction was
filled in equilibrium HiTrap Q column (5 mL.times.2) with buffer
solution A, and phosphodiesterase fractions were eluted by 300 mL
of buffer solution A with linear gradient from 0 to 0.8 M NaCl
concentration. 5 ml each of 60 eluents were collected, and each
eluents were examined for cyclic AMP metabolic activities of
phosphodiesterase. The fraction eluting with about 350 mM NaCl
concentration parts, where metabolic activities were not
inactivated by 10 .mu.M of rolipram (selective inhibitor for
phosphodiesterase IV) and 10 .mu.M of milrinone (selective
inhibitor for phosphodiesterase III), were collected as storage
solution for using to test PDE 7 inhibiting effect. [0113] (3) The
tested compound having desired concentration was reacted in the
solution of20 mM tris-HCl (pH7.5), 1 mM of MgCl.sub.2, 100 .mu.M of
EDTA, 330 .mu.g/mL of bovine serum albumin, 4 .mu.g/mL of
5'-nucleotidase, 0.1 .mu.Ci of .sup.3H-cAMP (0.064 .mu.M of CAMP),
10 .mu.M of rolipram in storage solution of PDE 7 for 2 hours at
25.degree. C. After the reaction, suspension of Sephadex(-QAE in 10
.mu.mM of HEPES-Na (pH 7.0) was added to the reaction mixture, and
the mixture was left at rest for 5 minutes. Further, Sephadex-QAE
was added to the obtained supernatant and the mixture was leaved at
rest for 5 minutes, then, the radioactivity of the solution was
measured. [0114] (4) IC.sub.50 was calculated as 50% inhibiting
concentration of the metabolic activities of phosphodiesterase VII
of the tested compound. PDE 7 Inhibiting Effect of the Each Tested
Compounds:
[0115] The following compounds showed no more than 0.1 .mu.M of
IC.sub.50 values. Compounds NO. 16, 17, 18, 20, 21, 22, 25, 26, 27,
28, 29, 32, 33, 36, 37, 43, 44, 47, 48, 49.
[0116] Further, the following are PDE 7 inhibiting activities of
the tested compounds. [0117] Compound 26: IC.sub.50=0.0026 .mu.M;
[0118] Compound 32: IC.sub.50=0.00321 .mu.M;
[0119] As described above, the compounds of the present invention
showed significant PDE 7 inhibiting effect.
[0120] The compounds of the present invention selectively inhibit
PDE 7 and their selectivities are more than 10 times compared to
PDE 4 (phosphodiesterase IV), which is similar to the PDE 7.
Therefore, it is expected that the side effect of the compounds of
the present invention caused by PDE 4 to be less. The selectivity
against PDE 4 (phosphodiesterase IV) of the compounds of the
present invention was affirmed by means of the following Biological
Test.
Biological Test 2:
Methods for Evaluating the PDE 4 Inhibiting Effect
[0121] The PDE 4 (phosphodiesterase IV) inhibiting effect of the
compounds of the present invention was performed by the following
method, which was modified assay method described in Biochemical.
Pharmacol. 48(6), 1219-1223 (1994). [0122] (1) The active fraction
of PDE 4 (phosphodiesterase IV) was obtained. That is, the livers
obtained from three Balb/c mice (male, 12 weeks: obtainable from
CLEA Japan, Inc.) were suspended with 30 mL of buffer solution B
[20 mM of bis-tris, 5 mM of 2-mercaptoethnol, 2 mM of benzamidine,
2 mM of EDTA, 0.1 mM of 4-(2-aminoethyl) benzensulfonyl
hydrochloride, 50 mM of sodium acetate; pH 6.5], then homogenized
by Polytron.RTM. homogenizer. The homogenate were centrifuged under
25,000.times.G for 10 minutes at 4.degree. C. The supernatant was
separated and thus obtained supernatant was further centrifuged
under 100,000.times.G for 60 minutes at 4.degree. C., and then
filtrated with 0.2 .mu.m filter to obtain the soluble fraction.
[0123] (2) The obtained soluble fraction was filled in equilibrium
DEAE sepharosecolumn (1.times.10 cm) with buffer solution B, and
phosphodiesterase fractions were eluted by 120 mL of buffer
solution B with linear gradient from 0.05 to 1M sodium acetate
concentration. 5 ml each of 24 eluents were collected, and each
eluents were examined for cyclic AMP metabolic activities of
phosphodiesterase. The fraction eluting with about 620 mM of
soadium acetate concentration parts, where metabolic activities
were inactivated by 30 .mu.M of rolipram (selective inhibitor for
phosphodiesterase IV), were collected as storage solution to test
PDE 4 inhibiting effect. [0124] (3) The tested compound having
desired concentration was reacted in the solution of 20 mM tris-HCl
(pH 7.5), 1 mM of MgCl.sub.2, 100 .mu.mM of EDTA, 330 .mu.g/mL of
bovine serum albumin, 4 .mu.g/mL of 5'-nucleotidase, 0.1 .mu.Ci of
.sup.3H-cAMP (0.064 .mu.M of cAMP), and storage solution of PDE 4
for 2 hours at 25.degree. C. After the reaction, suspension of
Sephadex-QAE in 10 mM of HEPES-Na (pH 7.0) was added to the
reaction mixture, and the mixture was left at rest for 5 minutes.
Further, Sephadex.RTM.-QAE was added to the obtained supernatant
and the mixture was left at rest for 5 minutes, then, the
radioactivity of the solution was measured. [0125] (4) IC.sub.50
was calculated as 50% inhibiting concentration of the metabolic
activities of phosphodiesterase IV of the tested compound.
[0126] As the results of the mentioned above Biological Test 2, the
IC.sub.50 of the compounds of the present invention was more than
10 times weaker than that of PDE 7 inhibiting effect.
[0127] The following are PDE 4 inhibiting activities of the tested
compounds. [0128] Compound 26: IC.sub.50 1.2 .mu.M;
[0129] Compound 32: IC.sub.50 0.98 .mu.M;
[0130] The compounds of the present invention inhibit PDE 7
selectively, and therefore, enhance cellular cAMP level.
Consequently, the compounds of the present invention are useful for
treating various kinds of disease such as allergic disease,
inflammatory disease or immunologic disease. For example, the
compounds of the present invention are useful for treating or
preventing the diseases such as bronchial asthma, chronic
bronchitis, chronic obstructive pulmonary disease, allergic
rhinitis, psoriasis, atopic dermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, septicemia, CrohnIs disease,
rejection for organ transplantation, GVH disease, and restenosis
after angioplasty.
[0131] The compounds of the present invention can be used for
preparation of the pharmaceutical composition or PDE 7 inhibitor.
As an active ingredient, one or more compounds may be administered
in the appropriated formulation. The formulation for oral
administration may include for example, capsules, granules, fine
granules, syrups, dry syrups or the like; the formulation for
parenteral administration may include, for example injectable
solution, suppository formulation such as rectal suppository or
vaginal suppository, nasal administration such as sprays, or
percutaneous absorption formulation such as ointment and tapes, and
the like.
[0132] The administration dose may vary depending on the various
kinds of factors. These factors may be the condition of the
patients, the severity of the disease, ages, existence of a
complication, as well as formulation. A usual recommended daily
dose for oral administration is within the range of 0.1-1,000
mg/day/adult, preferably 0.1-500 mg/day/adult, and more
preferably1-100 mg/day/adult. In the case of parenteral
administration, a usual recommended daily dose is within the range
of 1/1000 to 1/2 based on dose of oral administration. These doses
can be adjusted depending on age, as well as the patient's
condition.
[0133] The toxicological properties of the compounds of the present
invention is low, therefore, the compounds of the present invention
is expected to have high safety margin.
Manufacturing Examples and Examples
[0134] The synthesis of the compounds of the present invention is
illustrated in the following Examples.
[0135] The physicochemical data and chemical structure of the
compounds are summarized in the Tables mentions later. The compound
numbers in the Examples are identical to those in the Tables.
Example 1
2-Cyclohexyl-5-Methyl-2,4-Dihydro-3H-Pyrazol-3-One
[0136] A mixture solution of 14.5 mL(0.134 mol) of methyl
acetoacetate and 20.2 g (0.134 mol) of cyclohexylhydrazine
hydrochloride was stirred for 2 hours at 120.degree. C., and the
mixture was cooled. Then, the reaction mixture was neutralized with
30 mL of 4M-sodium hydroxide solution and extracted with ethyl
acetate. The organic layer was washed with water and saturated
saline solution and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure, and the resulting
residue was treated with hexane. The resulting precipitate was
collected to give 19.0 g (79%) of the titled compound.
Example 2
5-Chloro-1-Cyclohexyl-3-Methyl-4-Nitro-1H-Pyrazole
[0137] To 9.3 g (51.6 mmol) of the compound obtained by the Example
1 was added 10 mL (107 mmol) of phosphorus oxychloride, and the
mixture was stirred for 10 hours at 120.degree. C. The reaction
mixture was cooled to the room temperature and excess phosphorus
oxychloride was removed off under reduced pressure. The resulting
residue was dissolved in 45 mL of acetic anhydride, and to this
mixture was gradually added by dripping 9 mL of fuming nitric acid
under ice cooling and the mixture was stirred for 2 hours at the
same temperature. Then, the mixture was poured into ice and the
resulting precipitate was collected and dissolved in
dichloromethane. The organic layer was washed with sodium hydrogen
carbonate aqueous solution, water and saturated saline solution,
and dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure, and the residue was recrystallized from
hexane to give 6.28 g (50%) of the title compound. Further, the
filtrate was removed off under reduced pressure and the resulting
residue was purified by silica gel column chromatography (eluent:
hexane/ethyl acetate= 6/1) to give 4.21 g (33%) of the title
compound.
Example 3
1-Cyclohexyl-3-Methyl-4-Nitro-1H-Pyrazole-5-Carbonitrile
[0138] To a solution of 10.3 g (42.2 mmol) of the compound obtained
in the Example 2 in 90 mL of N,N-dimethylformamide was added 4.2 g
(84.9 mmol) of sodium cyanide, and the mixture was stirred for 1.5
hours at 80.degree. C. After the reaction mixture was cooled to the
room temperature, the reaction mixture was treated with water and
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution, and dried over an hydrous
sodium sulfate. The solvent was removed under reduced pressure and
the resulting residue was purified by silica gel column
chromatography (eluent: hexane/ethyl acetate= 6/1) to give 9.18 g
(93%) of the title compound.
Example 4
4-Amino-1-Cyclohexyl-3-Methyl-1H-Pyrazole-5-Carbonitrile
[0139] To a solution of 1.0 g (4.27 mmol) of the compound obtained
in the Example 3 in 10 mL of methanol and 10 mL of concentrated
hydrochloric acid was added 1.2 g (21.4 mmol) of iron powder, and
the mixture was refluxed for2 hours. Then, the reaction mixture was
cooled to the room temperature, neutralized by sodium hydrogen
carbonate aqueous solution, and filtrated with Celite.RTM.. The
filtrate was extracted with dichloromethane, and the organic layer
was washed with water and saturated saline solution and dried over
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the resulting residue was purified by silica gel
column chromatography (eluent: hexane/ethyl acetate= 7/1) to give
0.75 g (87%) of the title compound.
Example 5
1-Cyclohexyl-3-Methyl-4-Nitro-1H-Pyrazole-5-Carboxamide
[0140] To a solution of 9.0 g (38.5 mmol) of the compound obtained
in the Example 3 in 25 mL of methanol were added 12 mL of 30%
hydrogen peroxide aqueous solution and 30 mL of 3M-sodium hydroxide
aqueous solution, and the mixture was stirred at room temperature
for 1.5 hours. Then, water was added to the reaction mixture and
the mixture was extracted with dichloromethane. The organic layer
was washed with water and saturated saline solution, and dried over
anhydrous sodium sulfate. The solvent was removed to give 7.8 g
(80%) of the title compound.
Example 6
4-Amino-1-Cyclohexyl-3-Methyl-1H-Pyrazole-5-Carboxamide
[0141] To a suspension of 7.7 g (30.66 mmol) of the compound
obtained in the Example 5 in 180 mL of concentrated hydrochloric
acid was added 27.6 g (122 mmol) of zinc chloride dihydrate, and
the mixture was stirred for 1.5 hours at 80.degree. C. Then, the
reaction mixture was cooled to the room temperature and neutralized
with sodium hydroxide aqueous solution. After filtrated by
Celite.RTM., the filtrate was extracted with dichloromethane, and
the organic layer was washed with water and saturated saline
solution, and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent: ethyl acetate) to give
6.05 g (89%) of the title compound.
Example 7
2-Methoxy-6-[(4-Methylphenyl)Sulfanyl]Nicotinic Acid
[0142] To a suspension of 9.25 g (31.96 mmol) of methyl
2-methoxy-6-(4-methyl benzylthio)pyridine-3-carboxylate in 80 ML of
methanol was added 38.36 mL (38.36 mmol) of 1N-sodium hydroxide
aqueous solution, and the mixture was refluxed for 1 hour. After
the reaction mixture was cooled to the room temperature, the
solvent was removed under reduced pressure and the residue was
diluted with water. Then 2N-HCl was added to the solution and the
resultant precipitate was collected to obtain 8.92 g (quantitative)
of the title compound.
Example 8
1-Cyclohexyl-5-(2-Methoxy-6-[(4-Methylpheny)Sulfanyl]-3-Pyridinyl}-3-Met-
hyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0143] To a suspension of 3.03 g (11 mmol) of the compound obtained
in the Example 7 in 30 mL of 1,2-dichloroethane was added 1.60 mL
(22 mmol) of thionyl chloride, and the mixture was refluxed for 1.5
hours. After the reaction mixture was cooled to the room
temperature, the solvent was removed under reduced pressure to give
the corresponding acid chloride.
[0144] To a solution of 2.22 g (10 mmol) of the compound obtained
in the Example 6 in 30 mL of chloroform were added above acid
chloride in 20 mL of chloroform, 3.48 mL (25 mmol) of triethylamine
and 5 mg of dimethyl-aminopyridine, and the mixture was stirred
over night. Then, water was added to the reaction mixture and the
mixture was extracted with chloroform. The organic layer was washed
with saturated saline solution and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure to give the
corresponding amide compound as pale yellowish solid.
[0145] The obtained amide compound was suspended in 50 mL of
methoxyethanol and to this mixture was added 2.81 g (25 mmol) of
potassium tert-butoxide and the mixture was stirred for 40 minutes
at 130.degree. C. After the reaction mixture was cooled to the room
temperature, the solvent was removed under reduced pressure. The
resulting residue was diluted with water and 26 mL of 1N-HCl was
added. The mixture was extracted with chloroform and the organic
layer was dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the resulting residue was
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate= 3/1) to give 3.64 g (79%) of the title compound.
Example 9
1-Cyclohexyl-5-{2-Methoxy-6-[(4-Methylphenyl)Sulfonyl]-3-Pyridinyl}-3-Me-
thyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0146] To a solution of 1.5 g (3.25 mmol) of the compound obtained
in the Example 8 in 40 mL of dichloromethane was added 1.54 g (7.15
mmol) of m-chloro-perbenzoic acid at 0.degree. C., and the mixture
was stirred for 2 hours. Then, saturated sodium hydrogen carbonate
aqueous solution was added to the mixture and the mixture was
extracted with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate and the solvent was removed under reduced
pressure to give 1.75 g (quantitative) of the title compound. This
compound was used for the next reaction without further
purification.
Example 10
2-[Cyclohexyl(Hydroxyl)Methylene]Malononitrile
[0147] To a solution of 3.96 g (0.06 mol) of malononitrile in 60 mL
of tetrahydrofuran was added 4.8 g (60% dispersion in mineral oil;
0.12 mol) of sodium hydride in 4 separate times at 0.degree. C.,
and the mixture was stirred for 30 minutes at the same temperature.
Then, to this mixture was added by dripping cyclohexanecarboxylic
chloride and the mixture was stirred for 30 minutes at room
temperature. 150 mL of 1M-HCl was added slowly to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and the
solvent was removed under reduces pressure. The resulting residue
was recrystallized from diisopropyl ether to give 8.16 g (77%) of
the title compound.
Example 11
2-[Cyclohexyl(Methoxy)Methylenelmalononitrile
[0148] To a mixture of 2.64 g (15 mmol) of the compound obtained in
the Example 10 in 24 mL of 1,4-dioxane and 4 mL of water was added
10 g of sodium hydrogen carbonate and 10 mL of dimethyl sulfate was
added by dripping for 5 minutes to this mixture. After the mixture
was heated for 2.5 hours at 85.degree. C., the reaction mixture was
cooled to the room temperature and water was added to the reaction
mixture. The mixture was extracted with diethyl ether and the
extract was dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the resulting residue was
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate= 3/1) to give 2.35 g (82%) of the title compound.
Example 12-1
5-Amino-3-Cyclohexyl-1-Methyl-1H-Pyrazole-4-Carbonitrile
[0149] To a solution of 2.3 g (12.1 mmol) of the compound obtained
in the Example 11 in 20 mL of ethanol was added 0.643 mL (12.1
mmol) of methylhydrazine, and the mixture was refluxed for 5 hours.
After the mixture was cooled to the room temperature, the solvent
was removed under reduced pressure. The resulting residue was
purified by silica gel column chromatography (eluent:
dichloromethane/methanol= 50/1) to give 1.48 g (60%) of the title
compound.
Example 12-2
5-Amino-3-Cyclohexyl-1-Methyl-1H-Pyrazole-4-Carbonitrile
[0150] To a solution of 17.2 g (260 mmol) of malononitrile in 260
mL of tetrahydrofuran was added slowly to 20.8 g (60% dispersion in
mineral oil; 520 mmol) of sodium hydride at 0.degree. C., then, to
this mixture was added by dripping 35 mL (260 mmol) of
cyclohexanecarbonyl chloride at the same temperature and the
mixture was stirred for 1.5 hours at room temperature. Then, 30 mL
(312 mmol) of dimethyl sulfate was added to the reaction mixture
and the mixture was refluxed for 3 hours. Then, 17.4 mL (125 mmol)
of triethylamine and 13.8 mL (260 mmol) of methylhydrazine were
added to the reaction mixture under ice cooling and the mixture was
refluxed for 1 hour. After the mixture was cooled to the room
temperature, the solvent was removed under reduce pressure. Water
was added to the residue and the mixture was extracted with ethyl
acetate and the organic layer was washed with water, and saturated
saline solution, then, dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the resulting
residue was purified by silica gel column chromatography (eluent:
chloroform/methanol= 30/1 to 20/1). The obtained crude crystalline
was further purified by recrystallization (hexane-ethyl acetate) to
give 20.7 g (39%) of the title compound. The filtrate was further
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate=2:1) to give 11.3 g (21%) of the title compound.
Example 13
5-Amino-3-Cyclohexyl-1-Methyl-1H-Pyrazole-4-Carboxamide
[0151] 75 mL of concentrated. HCl was added to25.3 g (124 mmol) of
thecompound obtained in the Example 12, and the mixture was stirred
for 15 minutes at room temperature and for 1 hour at 60.degree. C.
Then, the reaction mixture was poured into ice, neutralized by
sodium hydroxide aqueous solution and extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the resulting
residue was recrystallized from ethyl acetate to give 20.2 g (73%)
of the title compound.
Example 14
3-Cyclohexyl-6-{2-Methoxy-6-((4-Methylphenyl)Sulfanyl]-3-Pyridinyl}-1-Me-
thyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One
[0152] To a suspension of 2.70 g (9.81 mmol) of the compound
obtained in the Example 7 in 30 mL of 1,2-dichloroethane was added
1.43 mL (19.6 mmol) of thionyl chloride, and the mixture was
refluxed for 2 hours. Then, the reaction mixture was cooled to the
room temperature and the solvent was removed under reduced pressure
to give the corresponding acid chloride as yellowish solid.
[0153] To the solution of the obtained acid chloride in 30 mL of
pyridine were added 1.82 g (8.17 mmol) of the compound obtained in
the Example 13 and 5 mg of dimethylaminopyridine, and the mixture
was stirred for 20 hours at room temperature. Then, saturated
sodium hydrogen carbonate aqueous solution was added to the
reaction mixture and the mixture was extracted with chloroform. The
organic layer was washed with water and saturated saline solution,
and dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure to give the corresponding amide compound as
pale yellowish solid.
[0154] The obtained amide compound was suspended in 50 mL of
methoxyethanol and to this suspension was added 2.30 g (20.4 mmol)
of potassium t-butoxide, then the mixture was stirred for 2 hours
at 140.degree. C. After the reaction mixture was cooled to the-room
temperature, the mixture was condensed under reduced pressure and
water was added to the residue. Further added 21 mL of 1N-HCl to
the mixture, the mixture was extracted with chloroform. The organic
layer was washed with water and saturated saline solution, and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the resulting residue was purified by silica
gel column chromatography (eluent: dichloromethane/methanol=
100/1), and resultant product was further purified by silica gel
column chromatography (eluent: hexane/ethyl acetate= 2/1) and
recrystallized from ethyl acetate to give 1.12 g (30%) of the title
compound.
Example 15
3-Cyclohexyl-6-{2-Methoxy-6-[(4-Methylphenyl)Surfonyl]-3-Pyridinyl}-1-Me-
thyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One
[0155] The title compound 1.02 g (87%) was obtained in a manner
similar to the Example 9 by using the compound obtained in the
Example 14, instead of the compound obtained in the Example 8.
Example 16
1-Cyclohexyl-5-[2-Methoxy-6-(4-Methyl-1-Piperazinyl)-3-Pyridinyl]-3-Meth-
yl-1,6-Dihydro-7H-Pyrazolo([4,3-d]Pyrimidin-7-One
[0156] To a solution of 134 .mu.L (1.22 mmol of N-methylpiperazine
in 5 mL of etrahyrofuran was added by dripping 779 .mu.L of
n-butyllithium in hexane solution (1.56 M hexane solution: 1.22
mmol) at -30.degree. C., and the mixture was stirred for 15 minutes
at the same temperature. Then, to this mixture was added the
compound obtained in the Example 9 at -30.degree. C., and the
mixture was stirred for 15 minutes. After adding water to the
mixture and the temperature of the reaction mixture was raised to
the room temperature, and the mixture was extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate,
and the solvent was removed under reduced pressure. The resulting
residue was purified by silica gel column chromatography (eluent:
dichloromethane/methanol= 30/1) to give 123 mg (93%) of the title
compound.
Example 17
1-Cyclohexyl-5-[2-Methoxy-6-(4-Morpholinyl)-3-Pyridinyl]-3-Methyl-1,6-Di-
hydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0157] The title compound 72 mg (56%) was obtained in a manner
similar to the Example 16 using morpholine, instead of
N-methylpiperazine.
Example 18
1-Cyclohexyl-5-[2-Methoxy-6-(4-Methyl-1,4-Diazepan-1-yl)-3-Pyridinyl]-3--
Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0158] The title compound 16 mg (12%) was obtained in a manner
similar to the Example 16 by using N-methyl-homopiperazine, instead
of N-methylpiperazine.
Example 19
1-Cyclohexyl-5-(2-Methoxy-3-Pyridinyl)-3-Methyl-1,6-Dihydro-7H-Pyrazolo[-
4,3-d]Pyrimidin-7-One
[0159] To a solution of 200 mg (0.90 mmol) of the compound obtained
in the Example 6 in 3 mL of dichloromethane were added to 165 mg
(1.08 mmol) of 2-methoxynicotinic acid and 207 mg (1.08 mmol) of
1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride, and
the mixture was stirred for over night at room temperature. After
adding saturated sodium hydrogen carbonate aqueous solution, the
mixture was extracted with dichloromethane.
[0160] The organic layer was washed with water and saturated saline
solution, and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, then, 6 mL of ethanol and 3 mL of
sodium hydroxide aqueous solution were added to the residue, and
the mixture was refluxed for 9 hours. After the reaction mixture
was cooled to the room temperature, water was added and the mixture
was extracted with dichloromethane. The organic layer was washed
with water and saturated saline solution, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (eluent: hexane/ethylacetate= 2/1).
Theobtainedproduct was recrystallized from the mixture solvent of
ethyl acetate-hexane to give 78 mg (26%) of the title compound.
Example 20
3-Cyclohexyl-6-[2-Methoxy-6-(4-Methyl-1-Piperazinyl)
-3-Pyridinyl]-1-Methyl-1,5-Dihydro-4H-Pyrazolo
[3,4-d]Pyrimidin-4-One
[0161] The title compound 86 mg (65%) was obtained in a manner
similar to the Example 16 using the compound obtained in the
Example 15, instead of the compound obtained in the Example 9.
Example 21
3-Cyclohexyl-6-[2-Methoxy-6-(4-Morpholinyl)-3-Pyridinyl]-1-Methyl-1,5-Di-
hydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One
[0162] The title compound 58 mg (45%) was obtained in a manner
similar to the Example 16 using morpholine and the compound
obtained in the Example 15, instead of N-methylpiperazine and the
compound obtained in the Example 9, respectively.
Example 22
[0163]
3-Cyclohexyl-6-[2-Methoxy-6-(4-Methyl-1,4-Diazepan-1-yl)-3-Pyridin-
yl]-1-Methyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One The
title compound 115 mg (84%) was obtained in a manner similar to the
Example 16 using N-methyl-homopirerazine and the compound obtained
in the Example 15, instead of N-methylpiperazine and the compound
obtained in the Example 9, respectively.
Example 23
3-Cyclohexyl-6-[6-(1,4-Dioxa-8-Azaspiro[4.5]Dec-8-yl)-2-Methoxy-3-Pyridi-
nyl]-1-Methyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One
[0164] The title compound 776 mg (quantitative) was obtained in a
manner similar to the Example 16 using
1,4-dioxa-8-azaspiro[4.5]decane and the compound obtained in the
Example 15, instead of N-methylpiperazine and the compound obtained
in the Example 9, respectively.
Example 24
3-Cyclohexyl-6-[2-Methoxy-6-(4-Oxo-1-Piperidinyl)-3-Pyridinyl]-1-Methyl--
1,5-Dihydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One
[0165] To a suspension of 743 mg (1.55 mmol) of the compound
obtained in the Example 23 in 30 mL of acetone and 3 mL of water
was added 353 mg (1.86 mmol) of p-toluenesulfonic acid hydrate, and
the mixture was refluxed for 5 hours. After the reaction mixture
was cooled to the room temperature, the solvent was removed under
reduced pressure, saturated sodium hydrogen carbonate aqueous
solution was added to the reactionmixture and the mixture was
extracted with dichloromethane. The organic layer was washed with
saturated saline solution and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the residue was
recrystallized from mixture solvent of ethyl acetate-ethanol to
give 405 mg (93%) of the title compound.
Example 25
3-Cyclohexyl-6-[6-(4-Hydroxy-1-Piperidinyl)-2-Methoxy-3-Pyridinyl]-1-Met-
hyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]Pyrimidin-4-One
[0166] To a suspension of 120 mg (0.28 mmol) of the compound
obtained in the Example 24 in 3 mL of methanol was added 12.5 mg
(0.33 mmol) of sodium borohydride, and the mixture was stirred for
2.5 hours at room temperature. Then, acetone was added to the
reaction mixture and the solvent was removed under reduced
pressure. Water was added to the residue and the mixture was
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
resulting residue was purified by silica gel column chromatography
(eluent: dichloromethane/ethyl acetate= 2/1 to 1/2), and the
obtained crude product was recrystallized from ethanol to give 85
mg (70%) of the title compound.
Example 26
3-Cyclohexyl-6-{2-Methoxy-6-[4-(Methylamino)-1-Piperidinyl]-3-Pyridinyl}-
-1-Methyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]-Pyrimidin-4-One
[0167] To a suspension of 120 mg (0.28 mmol) of the compound
obtained in the Example 24 in 2 mL of 1,2-dichloromethane were
added to 57 .mu.M (30% ethanol solution; 0.55 mmol) of methylamine,
10 M of acetic acid and 87 mg (0.41 mmol) of sodium
triacetoxyborohydride, and the mixture was stirred for 2 hours at
room temperature. Then, saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture and the mixture was
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
resulting residue was purified by silica gel column chromatography
(eluent: dichloromethane/ethyl acetate/methanol= 10/10/1). The
obtained crude product was recrystallized from the mixture solvent
of ethyl acetate-hexane to give 87 mg (70%) of the title
compound.
Example 27
3-Cyclohexyl-6-(6-[4-(Dimethylamino)-1-Piperidinyl]-2-Methoxy-3-Pyridiny-
l}-1-Methyl-1,5-Dihydro-4H-Pyrazolo[3,4-d]-Pyrimidin-4-One
[0168] The title compound 103 mg (80%) was obtained in a manner
similar to the Example 26 using dimethylamine, instead of
methylamine.
Example 28
6-[6-(4-Amino-1-Piperidinyl)
-2-Methoxy-3-Pyridinyl]-3-Cyclohexyl-1-Methyl-1,5-Dihydro-4H-Pyrazolo[3,4-
-d]Pyrimidin-4-One
[0169] To a mixture of 240 mg (0.55 mmol) of the compound obtained
in the Example 24 in 10 mL of 4M-ammnonia-etanol solution was added
24 mg of 5% palladium-carbon and the mixture was stirred for 24
hours under hydrogen gas atmosphere at normal pressures. After the
reaction, the mixture was filtrated by Celite.RTM. and filtrate was
removed under reduced pressure. The resulting residue was purified
by alkaline silica gel column chromatography (eluent:
dichloromethane/ethyl acetate/methanol= 10/10/1) and obtained crude
product was recrystallized from ethanol to give 169 mg (70%) of the
title compound.
Example 29
N-{1-[5-(3-Cyclohexyl-1-Methyl-4-Oxo-4,5-Dihydro-1H-Pyrazolo[3,4-d]-Pyri-
midin-6-yl)-6-Methoxy-2-Piridinyl]-4-Piperidinyl}Acetamide
[0170] To a solution of 80 mg (0.18 mmol) of the compound obtained
in the Example 28 in 2 mL of dichloromethane were added 21 .mu.L
(0.22 mmol) of acetic anhydride and 38 .mu.L of triethylamine, and
the mixture was stirred for 1.5 hours at room temperature. Then,
saturated sodium hydrogen carbonate aqueous solution was added to
the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the residue was
recrystallized from ethanol to give 79 mg (90%) of the title
compound.
Example 30
1-Cyclohexyl-5-[6-(1,4-Dioxa-8-Axaspiro[4.5]Dec-8-yl)-2-Methoxy-3-Pyridi-
nyl]-3-Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0171] The title compound 588 mg (86%) was obtained in a manner
similar to the Example 16 using 1,4-dioxa-8-axaspiro[4.5]decane
instead of N-methylpiperazine.
Example 31
1-Cyclohexyl-5-[2-Methoxy-6-(4-Oxo-1-Piperidinyl)-3-Pyridinyl]-3-Methyl--
1,6-Dihydro-7H-Pyrazolo[4,3-D]-Pyrimidin-7-One
[0172] The title compound 255 mg (50%) was obtained in a manner
similar to the Example 24 using the compound obtained in the
Example 30 instead of the compound obtained in the Example 23.
Example 32
1-Cyclohexyl-5-{2-Methoxy-6-[(4-(Methylamino)-1-Piperidinyl)-3-Pyridinyl-
}-3-Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]-Pyrimidin-7-One
[0173] The title compound 68 mg (55%) was obtained in a manner
similar to the Example 26 using the compound obtained in the
Example 31 instead of the compound obtained in the Example 24.
Example 33
1-Cyclohexyl-5-{-6-[4-(Dimethylamino)-1-Piperidinyl)-2-Methoxy-3-Pyridin-
yl]-3-Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]-Pyrimidin-7-One
[0174] The title compound 102 mg (94%) was obtained in a manner
similar to the Example 26 using the compound obtained in the
Example 31 and dimethylamine instead of the compound obtained in
the Example 24 and methylamine, respectively.
Example 34
3-Cyclohexyl-6-(2-Methoxy-6-Sulfanyl-3-Piridinyl)-1-Methyl-1,5-Dihydro-4-
H-Pyrazolo[3,4-d]-pyrimidin-4-One
[0175] To a suspension of 230 mg (0.47 mmol) of the compound
obtained in the Example 15 in 5 mL of methanol was added 100 mg of
sodium hydrosulfide, and the mixture was refluxed for 4 hours.
After cooling, 1M-HCl was added to the reaction mixture and the
precipitate was collected. The obtained solid was purified by
silica gel column chromatography (eluent: dichloromethane/methanol=
20/1) to give 132 mg (76%) of the title compound.
Example 35
5-(3-Cyclohexyl-1-Methyl-4-Oxo-4,5-Dihydro-1H-Pyrazolo-[3,4-D]Pyrimidin--
6-yl)-6-Methoxy-2-Pyridinesulfonyl Chloride
[0176] To a suspension of 120 mg (0.32 mmol) of the compound
obtained in the Example 34 in 3 mL of acetonitrile was added 82 mg
(0.8 mmol) of potassium nitrate and to this mixture was added 65
.mu.L (0.81 mmol) of sulfuryl chloride at 0.degree. C. The mixture
was stirred for 2 hours at room temperature, then, water was added
to the reaction mixture. The precipitate was collected to give 114
mg (81%) of the title compound.
Example 36
3-Cyclohexyl-6-{2-Methoxy-6-[(4-Methyl-1,4-Diazepan-1-yl)Sulfony]-3-Pyri-
dinyl-1-Methyl-1,5-Dihydro-4H-Pyrazolo[3, 4-d]Pyrimidin-4-One
[0177] To a solution of 104 mg (0.24 mmol) of the compound obtained
in the Example 35 in 2 mL of dichloromethane were added 35 pL (0.29
mmol) of N-methyl-homopiperazine and 83 pL (0.59 mmol) of
triethylamine, and the mixture was stirred for 1 hour at room
temperature. Then, saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture and the mixture was
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution, and dried over an hydrous
sodium sulfate. The solvent was removed under reduced pressure and
the resulting residue was purified by alkaline silica gel column
chromatography (eluent:ethylacetate). The obtained crude solid was
recrystallized from ethyl acetate-hexane to give 68 mg (56%) of the
title compound.
Example 37
1-Cyclohexyl-5-[6-(4-Hydroxy-1-Piperidinyl)-2-Methoxy-3-Pyridinyl]-3-Met-
hyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0178] The title compound 733 mg (60%) was obtained in a manner
similar to the Example 25 using the compound obtained in the
Example 31 instead of the compound obtained in the Example 24.
Example 38
1-Cyclohexyl-5-{2-Methoxy-6-[(4-Methylphenyl)Sulfinyl]-3-Pyridinyl)-3-Me-
thyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0179] To a solution of 1.5 g (3.25 mmol) of the compound obtained
in the Example 8 in 30 mL of dichloromethane was added 701 mg (3.25
mmol) of m-chloroperbenzoic acid at 0.degree. C., and the mixture
was stirred for 40 minutes. Then, saturated sodium hydrogen
carbonate aqueous solution was added to the reaction mixture and
the mixture was extracted with dichloromethane. After the solvent
was dried over anhydrous sodium sulfate, the solvent was removed
under reduced pressure. The residue was recrystallized from
2-butanone to give 1.0 g (64%) of the title compound.
Example 39
Ethyl 2-Ethoxy-6-[(4-Methylphenyl)Sulfanyl]Nicotinate
[0180] To a solution of 11.5 g (92.4 mmol) in 55 mL of
N,N-dimethylformamide was added 10.8 g (96.0 mmol) of potassium
tert-butoxide at 0.degree. C., and the mixture was stirred for 15
minutes at room temperature. This mixture was added by dripping to
a solution of 19.56 g (88.9 mmol) of ethyl 2,6-dichloronicotinate
in 150 mL of N,N-dimethylformamide at -30.degree. C. for 15
minutes, and the mixture was stirred for 1 hour at the same
temperature. Then, the reaction mixture was poured into ice water
and extracted with a mixture solution of ethyl acetate/hexane (
2/1). The organic layer was washed with water and saturated saline
solution, then, dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure to give ethyl
2-chloro-6-[(4-methylphenyl)sulfanyl]nicotinate intermediate as
pale brown oil.
[0181] Then, this compound was dissolved in 180 mL of
tetrahydrofuran and 31.4 g (92.4 mmol) of 20% sodium
ethoxide-ethanol solution was added to this solution, and the
mixture was refluxed for 2 hours. After the reaction mixture was
cooled to the room temperature, the mixture was filtrated, and the
filtrate was removed under reduced pressure. The residue was
diluted with chloroform and the organic layer was washed with water
and saturated saline solution, then, dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography (eluent:
hexane/ethyl acetate=5/1) to give 23.4 g (83%) of the title
compound.
Example 40
2-Ethoxy-6-[(4-Methylphenyl)Sulfanyl]Nicotinic Acid
[0182] The title compound 20.16 g (97%) was obtained in a manner
similar to the Example 7 using the compound obtained in the Example
39 instead of methyl
2-methoxy-6-(4-methylbenzylthio)pyridine-3-carboxylate.
Example 41
1-Cyclohexyl-5-{2-Ethoxy-6-[(4-Methylphenyl)Sulfanyl]-3-Pyridinyl}-3-Met-
hyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0183] To a suspension of 3.18 g (11 mmol) of the compound obtained
in the Example 40 in 30 mL of 1,2-dichloromethane was added 1.60 mL
of thionyl chloride, and the mixture was refluxed for 2 hours.
Then, the reaction mixture was cooled to the room temperature and
the solvent was removed under reduced pressure to give the
corresponding acid chloride as pale yellow solid. Then, this acid
chloride was dissolved in 30 mL of dichloromethane and to this
solution were added 3.48 mL (25 mmol) of triethylamine, 2.22 g (10
mmol) of the compound obtained in the Example 6, and 50 mL of
dichloromethane, and then, the mixture was stirred for 2 hours at
room temperature. Saturated sodium hydrogen carbonate aqueous
solution was added the reaction mixture and the mixture was
extracted with chloroform. The organic layer was washed with water
and saturates saline solution, dried over anhydrous sodium sulfate,
and removed under reduced pressure to give the corresponding amide
compound as intermediate. Then, this amide compound was suspended
in 100 mL of ethanol and to this suspension was added 2.81 g (25
mmol) of potassium tert-butoxide, and the mixture was refluxed for
14 hours. After the reaction mixture was cooled to the room
temperature, the solvent was removed under reduced pressure. The
residue was diluted with water and 20 mL of 2N-HCl was added, and
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution, and dried over anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent: dichloromethane/hexane/ethyl acetate=10/20/1 to 10/10/1)
to give 3.48 g (73%) of the title compound.
Example 42
1-Cyclohexyl-5-(2-Ethoxy-6-[(4-Methylphenyl)Sulfonyl]-3-Pyridinyl}-3-Met-
hyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0184] The title compound 2.97 g (93%) was obtained in a manner
similar to the Example 9 using the compound obtained in the Example
41 instead of the compound obtained in the Example 8.
Example 43
1-Cyclohexyl-5-[2-Ethoxy-6-[(4-Methyl-Piperazinyl)-3-Pyridinyl]-3-Methyl-
-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0185] The title compound 131 mg (98%) was obtained in a manner
similar to the Example 16 using the compound obtained in the
Example 42 instead of the compound obtained in the Example 9.
Example 44
1-Cyclohexyl-5-[2-Ethoxy-6-(4-Methyl-1,4-Diazepan-1-yl)-3-Pyridinyl]-3-M-
ethyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0186] The title compound 128 mg (93%) was obtained in a manner
similar to the Example 16 using N-methylhomopiperazine and the
compound obtained in the Example 42, instead of N-methylpiperazine
and the compound obtained in the Example 9, respectively.
Example 45
1-Cyclohexyl-5-[6-(1,4-Dioxa-8-Azaspiro[4.5]Dec-8-yl)-2-Ethoxy-3-Pyridin-
yl]-3-Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0187] The title compound 934 mg (96%) was obtained in a manner
similar to the Example 16 using 1,4-dioxa-8-azaspiro[4.5]decane and
the compound obtained in the Example 42, instead of
N-methylpiperazine and the compound obtained in the Example 9,
respectively.
Example 46
1-Cyclohexyl-5-[2-Ethoxy-6-(4-Oxo-1-Piperidinyl)
-3-Pyridinyl]-3-Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-D]pyrimidin-7-One
[0188] The title compound 791 mg (97%) was obtained in a manner
similar to the Example 24 using the compound obtained in the
Example 45 instead of the compound obtained in the Example 23.
Example 47
1-Cyclohexyl-5-{6-[4-(Dimethylamino)-1-Piperidinyl]-2-Ethoxy-3-Pyridinyl-
]-3-Methyl-1,6-Dihydro-7H-Pyrazolo[4,3-d]Pyrimidin-7-One
[0189] The title compound 122 mg (86%) was obtained in a manner
similar to the Example 26 using dimethylamine and the compound
obtained in the Example4 6, instead of methylamine and the compound
obtained in the Example 24, respectively.
Example 48
1-Cyclohexyl-5-{2-Ethoxy-6-[4-(Methylamino)-1-Piperidinyl]-3-Pyridinyl}--
3-Methyl-1,6-Dihydro-7H-Pyrazolo[4, 3-d]Pyrimidin-7-One
[0190] The title compound 103 mg (83%) was obtained in a manner
similar to the Example 26 by using the compound obtained in the
Example 46 instead of the compound obtained in the Example 24.
Example 49
1-Cyclohexyl-5-[2-Ethoxy-6-(4-Hydroxy-1-Piperidinyl)-3-Pyridinyl]-3-Meth-
yl-1,6-Dihydro-7H-Pyrazolo[4, 3-d]Pyrimidin-7-One
[0191] The title compound 92 mg (76%) was obtained in a manner
similar to the Example 25 using the compound obtained in the
Example 46 instead of the compound obtained in the Example 24.
[0192] Physicochemical data of the compounds obtained by the
above-mentioned examples are summarized in the following Tables.
TABLE-US-00001 TABLE 1 Properties Example m.p. (.degree. C.) MS
(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 1 ##STR7## colorless solid 147.6-150.4 CDCl.sub.3
1.21-1.36 (1H, m), 1.39-1.52 (2H, m), 1.71-1.98 (7H, m), 2.09 (3H,
s), 3.20 (2H, s), 3.95-4.02 (1H, m) 181 2 ##STR8## colorless solid
104.8-105.2 (hexane) CDCl.sub.3 1.22-1.50 (3H, m), 1.70-1.79 (1H,
m), 1.88-2.01 (6H, m), 2.54 (3H, 2), 4.23-4.33 (1H, m) 244 3
##STR9## colorless solid 109.0-110.2 (hexane/AcOEt) CDCl.sub.3
1.22-1.37 (1H, m), 1.39-1.54 (2H, m), 1.72-1.82 (1H, m), 1.91-2.10
(6H, m), 2.58 (3H, s), 4.32-4.43 (1H, m) 235 4 ##STR10## pale
yellow solid 85.5-87.0 (haxane) CDCl.sub.3 1.18-1.31 (1H, m),
1.32-1.48 (2H, m), 1.66-1.75 (1H, m), 1.79-2.03 (6H, m), 2.16 (3H,
s), 3.33 (2H, brs), 4.02-4.14 (1H, m) 205
[0193] TABLE-US-00002 TABLE 2 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 5 ##STR11## colorless solid 148.1-149.0 (AcOEt/hexane)
CDCl.sub.3 1.19-1.48 (3H, m), 1.64-1.77 (1H, m), 1.84-2.07 (6H, m),
2.52 (3H, s), 4.41-4.54 (1H, m), 6.04 (1H, brs), 6.77 (1H, brs) 253
6 ##STR12## colorless solid 193-194 (AcOEt) CDCl.sub.3 1.18-1.31
(1H, m), 1.38-1.52 (2H, m), 1.63-1.74 (1H, m), 1.79-2.01 (6H, m),
2.21 (3H, s), 2.80 (2H, s), 5.18-5.29 (1H, m) 223 7 ##STR13##
colorless solid 174-175 CDCl.sub.3 2.41 (3H, s), 4.03 (3H, s), 6.58
(1H, d, J=8.1Hz), 7.26-7.31 (2H, m), 7.46-7.51 (2H, m), 8.14 (1H,
d, J=8.1Hz) 276 8 ##STR14## colorless solid 165-168 CDCl.sub.3
1.21-1.35 (1H, m), 1.40-1.52 (2H, m), 1.65-1.74 (1H, m), 1.83-2.06
(6H, m), 2.41 (3H, s), 2.47 (3H, s), 4.02 (3H, s), 4.95-5.05 (1H,
m), 6.64 (1H, d, J=8.3Hz), 7.23-7.27 (2H, m), 7.47-7.51 (2H, m),
8.56 (1H, d, J=8.3Hz), 10.72 (1H, brs) 462
[0194] TABLE-US-00003 TABLE 3 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 9 ##STR15## colorless solid 213-215 CDCl.sub.3 1.21-1.34
(1H, m), 1.40-1.53 (2H, m), 1.67-1.75 (1H, m), 1.83-2.06 (6H, m),
2.43 (3H, s), 2.53 (3H, s), 4.11 (3H, s), 4.95-5.05 (1H, m),
7.31-7.36 (2H, m), 7.91-7.97 (3H, m), 8.99 (1H, d, J=8.0Hz), 10.63
(1H, brs) 494 10 ##STR16## pale yellow solid 124-129 (di-isopropyl
ethr) CDCl.sub.3 1.12-1.41 (3H, m), 1.45-1.58 (2H, m), 1.68-1.89
(5H, m), 2.77-2.86 (1H, m) 177 11 ##STR17## pale yellow solid 58-59
CDCl.sub.3 1.12-1.51 (5H, m), 1.66-1.85 (5H, m), 2.77-2.86 (1H, m),
4.34 (1H, s) 191 12 ##STR18## colorless solid 139-141 CDCl.sub.3
1.20-1.41 (3H, m), 1.48-1.62 (2H, m), 1.65-1.73 (1H, m), 1.77-1.85
(2H, m), 1.88-1.97 (2H, m), 2.57-2.66 (1H, m), 3.58 (3H, s), 4.13
(2H, br-s) 205
[0195] TABLE-US-00004 TABLE 4 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Strucure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 13 ##STR19## colorless solid 172-173.5 CDCl.sub.3
1.20-1.40 (3H, m), 1.52-1.66 (2H, m), 1.71-1.78 (1H, m), 1.83-1.92
(2H, m), 1.98-2.06 (2H, m), 2.54-2.63 (1H, m), 3.56 (3H, s), 5.30
(2H, br-s), 5.41 (2H, br-s) 223 14 ##STR20## colorless solid
181-183 (AcOEt) CDCl.sub.3 1.27-1.49 (3H, m), 1.67-1.87 (5H, m),
1.94-2.02 (2H, m), 2.41 (3H, s), 3.01-3.12 (1H, m), 3.90 (3H, s),
4.02 (3H, s), 6.65 (1H, d, J=8.2Hz), 7.22-7.29 (2H, m), 7.47-7.53
(2H, m), 8.58 (1H, d, J=8.2Hz), 10.62 (1H, brs) 462 15 ##STR21##
colorless solid 215-216.5 CDCl.sub.3 1.22-1.50 (3H, m), 1.66-1.88
(5H, m), 1.93-2.04 (2H, m), 2.44 (3H, s), 3.01-3.11 (1H, m), 3.97
(3H, s), 4.11 (3H, s), 7.31-7.39 (2H, m), 7.91-8.00 (3H, m), 9.41
(1H, d, J=7.9Hz), 10.50 (1H, brs) 494 16 ##STR22## pale yellow
solid 213-215 CDCl.sub.3 1.21-1.36 (1H, m), 1.41-1.59 (2H, m),
1.67-1.76 (1H, m), 1.84-2.09 (6H, m), 2.35 (3H, s), 2.48-2.55 (7H,
s), 3.65-3.70 (4H, m), 4.09 (3H, s), 4.95-5.05 (1H, m), 6.34 (1H,
d, J=8.7Hz), 8.58 (1H, d, J=8.7Hz), 10.81 (1H, brs) 438
[0196] TABLE-US-00005 TABLE 5 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 17 ##STR23## colorless solid 220-223 CDCl.sub.3 1.22-1.35
(1H, m), 1.41-1.57 (2H, m), 1.67-1.75 (1H, m), 1.84-2.08 (6H, m),
2.52 (3H, s), 3.59-3.64 (4H, s), 3.80-3.85 (4H, m), 4.09 (3H, s),
4.95-5.05 (1H, m), 6.34 (1H, d, J=8.7Hz), 8.61 (1H, d, J=8.7Hz),
10.80 (1H, brs) 425 18 ##STR24## colorless solid 135-138 CDCl.sub.3
1.22-1.36 (1H, m), 1.41-1.57 (2H, m), 1.67-1.75 (1H, m), 1.84-2.07
(8H, m), 2.39 (3H, s), 2.51 (3H, s), 2.54-2.59 (2H, s), 2.70-2.75
(2H, m), 3.65-3.72 (2H, m), 3.81-3.88 (2H, m), 4.08 (3H, s),
4.95-5.04 (1H, m), 6.23 (1H, d, J=8.7Hz), 8.55 (1H, d, J=8.7Hz),
10.82 (1H, brs) 452 19 ##STR25## colorless solid 172-174
(AcOEt/hexane) CDCl.sub.3 1.21-1.38 (1H, m), 1.44-1.58 (2H, m),
1.68-1.79 (1H, m), 1.85-2.09 (6H, m), 2.55 (3H, s), 4.19 (3H, S),
4.98-5.09 (1H, m), 7.13 (1H, dd, J=4.9 and 7.7Hz), 8.31 (1H, dd,
J=1.9 and 4.9Hz), 8.83 (1H, dd, J=1.9 and 7.7Hz), 10.86 (1H, brs)
340 20 ##STR26## colorless solid 229.5-232 (EtOH) CDCl.sub.3
1.26-1.51 (3H, m), 1.68-1.87 (5H, m), 1.95-2.03 (2H, m), 2.35 (3H,
s), 2.46-2.54 (4H, m), 3.01-3.11 (1H, m), 3.64-3.74 (4H, m), 3.92
(3H, s), 4.09 (3H, s), 6.35 (1H, d, J=8.8Hz), 8.59 (1H, d,
J=8.8Hz), 10.65 (1H, brs) 438
[0197] TABLE-US-00006 TABLE 6 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 21 ##STR27## green/yellow solid 251.5-255 (EtOH)
CDCl.sub.3 1.26-1.51 (3H, m), 1.69-1.88 (5H, m), 1.96-2.04 (2H, m),
3.01-3.11 (1H, m), 3.60-3.69 (4H, m), 3.78-3.86 (4H, m), 3.92 (3H,
s), 4.09 (3H, s), 6.34 (1H, d, J=8.7Hz), 8.62 (1H, d, J=8.7Hz),
10.64 (1H, brs) 425 22 ##STR28## colorless solid 179.5-180.5
CDCl.sub.3 1.28-1.51 (3H, m), 1.68-1.87 (5H, m), 1.96-2.09 (4H, m),
2.39 (3H, s), 2.52-2.61 (2H, m), 2.69-2.79 (2H, m), 3.01-3.11 (1H,
m), 3.63-3.77 (2H, m), 3.80-3.96 (2H, m), 3.91 (3H, s), 4.08 (3H,
s), 6.24 (1H, d, J=8.7Hz), 8.57 (1H, d, J=8.7Hz), 10.65 (1H, brs)
452 23 ##STR29## colorless solid 232.5-234 CDCl.sub.3 1.28-1.50
(3H, m), 1.69-1.89 (9H, m), 1.95-2.05 (2H, m), 3.01-3.11 (1H, m),
3.73-3.83 (4H, m), 3.92 (3H, s), 4.00 (4H, s), 4.08 (3H, s), 6.36
(1H, d, J=8.9Hz), 8.58 (1H, d, J=8.9Hz), 10.65 (1H, brs) 481 24
##STR30## colorless solid 284-286 (AcOEt/EtOH) CDCl.sub.3 1.28-1.51
(3H, m), 1.68-1.88 (5H, m), 1.96-2.05 (2H, m), 2.53-2.62 (4H, m),
3.01-3.11 (1H, m), 3.93 (3H, s), 3.98-4.07 (4H, m), 4.12 (3H, s),
6.45 (1H, d, J=8.8Hz), 8.66 (1H, d, J=8.8Hz), 10.62 (1H, brs)
437
[0198] TABLE-US-00007 TABLE 7 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 25 ##STR31## colorless solid 205-206.5 (EtOH) CDCl.sub.3
1.28-1.50 (3H, m), 1.53-1.65 (2H, m), 1.69-1.88 (5H, m), 1.94-2.04
(4H, m), 3.00-3.10 (1H, m), 3.30-3.40 (2H, m), 3.92 (3H, s),
3.94-4.03 (1H, m), 4.06-4.17 (2H, m), 4.09 (3H, s), 6.38 (1H, d,
J=8.8Hz), 8.58 (1H, d, J=8.8Hz), 10.65 (1H, brs) 439 26 ##STR32##
colorless solid 202-203.5 (AcOEt/hexane) CDCl.sub.3 1.28-1.63 (5H,
m), 1.68-1.87 (5H, m), 1.93-2.03 (4H, m), 2.47 (3H, s), 2.60-2.71
(1H, m), 3.00-3.13 (3H, m), 3.91 (3H, s), 4.08 (3H, s), 4.29-4.39
(2H, m), 6.36 (1H, d, J=8.8Hz), 8.57 (1H, d, J=8.8Hz), 10.66 (1H,
brs) 452 27 ##STR33## colorless solid 178.5-180 (EtOH) CDCl.sub.3
1.28-1.58 (5H, m), 1.68-1.88 (5H, m), 1.90-2.03 (4H, m), 2.30 (6H,
s), 2.38-2.48 (1H, m), 2.91-3.11 (3H, m), 3.91 (3H, s), 4.08 (3H,
s), 4.40-4.50 (2H, m), 6.36 (1H, d, J=8.8Hz), 8.57 (1H, d,
J=8.8Hz), 10.65 (1H, brs) 466 28 ##STR34## colorless solid
206-208.5 (EtOH)) CDCl.sub.3 1.27-1.66 (5H, m), 1.69-1.87 (5H, m),
1.90-2.04 (4H, m), 2.93-3.11 (4H, m), 3.92 (3H, s), 4.03 (3H, s),
4.31-4.40 (2H, m), 6.37 (1H, d, J=8.8Hz), 8.57 (1H, d, J=8.8Hz),
10.65 (1H, brs) 438
[0199] TABLE-US-00008 TABLE 8 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 29 ##STR35## colorless solid 253.5-255.5 (EtOH) CDCl.sub.3
1.24-1.50 (5H, m), 1.69-1.88 (5H, m), 1.94-2.11 (4H, m), 1.98 (3H,
s), 3.01-3.15 (3H, m), 3.92 (3H, s), 4.01-4.14 (1H, m), 4.08 (3H,
s), 4.33-4.42 (2H, m), 5.30-5.39 (1H, m), 6.37 (1H, d, J=8.8Hz),
8.58 (1H, d, J=8.8Hz), 10.63 (1H, brs) 480 30 ##STR36## pale yellow
solid 230-232 CDCl.sub.3 1.21-1.36 (1H, m), 1.41-1.56 (2H, m),
1.65-1.80 (5H, m), 1.84-2.06 (6H, m), 2.51 (3H, s), 3.75-3.80 (4H,
m), 4.00 (4H, s), 4.08 (3H, s), 4.94-5.04 (1H, m), 6.38 (1H, d,
J=8.8Hz), 8.57 (1H, d, J=8.8Hz), 10.81 (1H, brs) 481 31 ##STR37##
colorless solid 277-278 (AcOEt/EtOH) CDCl.sub.3 1.22-1.36 (1H, m),
1.42-1.56 (2H, m), 1.69-1.77 (1H, m), 1.85-2.10 (6H, m), 2.52 (3H,
s), 2.55-2.61 (4H, m), 3.97-4.03 (4H, m), 4.12 (3H, s), 4.94-5.04
(1H, m), 6.45 (1H, d, J=8.7Hz), 8.66 (1H, d, J=8.7Hz), 10.77 (1H,
brs) 437 32 ##STR38## colorless solid 185-189 (AcOEt/ diisopropyl
ether) CDCl.sub.3 1.20-1.42 (5H, m), 1.66-1.74 (1H, m), 1.83-2.06
(8H, m), 2.47 (3H, s), 2.51 (3H, s), 2.60-2.69 (1H, m), 3.00-3.09
(2H, m), 4.08 (3H, s), 4.28-4.36 (2H, m), 4.94-5.04 (1H, m), 6.36
(1H, d, J=8.8Hz), 8.56 (1H, d, J=8.8Hz), 10.82 (1H, brs) 452
[0200] TABLE-US-00009 TABLE 9 Properties Example m.p. (.degree. C.)
MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 33 ##STR39## colorless solid 230-231 (EtOH/AcOEt)
CDCl.sub.3 1.22-1.36 (1H, m), 1.42-1.58 (4H, m), 1.66-1.75 (1H, m),
1.83-2.08 (8H, m), 2.30 (6H, s), 2.36-2.46 (1H, m), 2.51 (3H, s),
2.89-2.99 (2H, m), 4.08 (3H, s), 4.39-4.48 (2H, m), 4.95-5.05 (1H,
m), 6.36 (1H, d, J=8.8Hz), 8.56 (1H, d, J=8.8Hz), 10.82 (1H, brs)
466 34 ##STR40## colorless solid 184 (dec.) CDCl.sub.3 1.28-1.51
(3H, m), 1.69-1.91 (5H, m), 1.98-2.09 (2H, m), 3.03-3.17 (1H, m),
3.96 (3H, s), 4.15 (1H, s), 4.17 (3H, s), 7.02 (1H, d, J=8.1Hz),
8.65 (1H, d, J=8.1Hz), 10.62 (1H, brs) 372 35 ##STR41## pale yellow
solid 229-232 CDCl.sub.3 1.28-1.52 (3H, m), 1.68-1.90 (5H, m),
1.98-2.06 (2H, m), 3.04-3.15 (1H, m), 3.99 (3H, s), 4.33 (3H, s),
7.87 (1H, d, J=7.8Hz), 9.12 (1H, d, J=7.8Hz), 10.54 (1H, brs) 438
36 ##STR42## pale yellow solid 153.5-155.5 (AcOEt/hexane)
CDCl.sub.3 1.22-1.51 (3H, m), 1.60-2.04 (9H, m), 2.37 (3H, s),
2.61-2.72 (4H, m), 3.02-3.15 (1H, m), 3.53-3.67 (4H, m), 3.98 (3H,
s), 4.22 (3H, s), 7.74 (1H, d, J=7.8Hz), 9.00 (1H, d, J=7.8Hz),
10.56 (1H, brs) 516
[0201] TABLE-US-00010 TABLE 10 Properties Example m.p. (.degree.
C.) MS (FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR
(M + 1).sup.+ 37 ##STR43## colorless solid 217-220 CDCl.sub.3
1.20-1.35 (1H, m), 1.42-1.64 (4H, m), 1.68-1.75 (1H, m), 1.83-2.08
(8H, m), 2.51 (3H, s), 3.27-3.35 (2H, m), 3.94-4.02 (1H, m), 4.09
(3H, s), 4.08-4.17 (2H, m), 4.94-5.04 (1H, m), 6.38 (1H, d,
J=8.8Hz), 8.57 (1H, d, J=8.8Hz), 10.81 (1H, brs) 439 38 ##STR44##
colorless solid 231-233 (2-butanone) CDCl.sub.3 1.21-1.34 (1H, m),
1.41-1.57 (2H, m), 1.69-1.76 (1H, m), 1.85-2.06 (6H, m), 2.37 (3H,
s), 2.52 (3H, s), 4.11 (3H, s), 4.95-5.06 (1H, m), 7.27 (2H, d,
J=8.1Hz), 7.67 (2H, d, J=8.1Hz), 7.84 (1H, d, J=8.0Hz), 8.96 (1H,
d, J=8.0Hz), 10.59 (1H, brs) 478 39 ##STR45## pale yellow oil
CDCl.sub.3 1.30 (3H, t, J=7.1Hz), 1.32 (3H, t, J=7.1Hz), 2.39 (3H,
s), 4.29 (2H, q, J=7.1Hz), 4.32 (2H, q, J=7.1Hz), 6.42 (1H, d,
J=8.1Hz), 7.19-7.29 (2H, m), 7.43-7.52 (2H, m), 7.91 (1H, d,
J=8.1Hz) 318 40 ##STR46## colorless solid 136.5-140 CDCl.sub.3 1.38
(3H, t, J=7.1Hz), 2.41 (3H, s), 4.49 (2H, q, J=7.1Hz), 6.58 (1H, d,
J=8.1Hz), 7.22-7.30 (2H, m), 7.43-7.50 (2H, m), 8.14 (1H, d,
J=8.1Hz) 290
[0202] TABLE-US-00011 TABLE 11 Properties Example m.p. (.degree.
C.) MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR
(M+1).sup.+ 41 ##STR47## colorless solid 190-191 (EtOH) CDCl.sub.3
1.20-1.35(1H, m), 1.39-1.52(2H, m), 1.42(3H, t, J=7.1Hz),
1.66-1.76(1H, m), 1.83-2.09(6H, m), 2.41(3H, s), 2.49(3H, s),
4.64(2H, q, J=7.1Hz), 4.92-5.02(1H, m), 6.63(1H, d, J=8.2Hz),
7.20-7.28(2H, m), 7.46-7.51(2H, m), 8.57(1H, d, J=8.2Hz), 10.93(1H,
brs) 476 42 ##STR48## pale yellow solid 229-230 (EtOH) CDCl.sub.3
121-1.36(1H, m), 1.40-1.52(2H, m), 1.46(3H, t, J=7.1Hz),
1.69-1.75(1H, m), 1.86-2.08(6H, m). 2.43(3H, s), 2.53(3H, s),
4.57(2H, q, J=7.1Hz), 4.94-5.03(1H, m), 7.31-7.38(2H, m),
7.9-7.99(3H, m), 9.00 (1H, d, J=8.1Hz), 10.78(1H, brs) 508 43
##STR49## colorless solid 162.5-163.5 (EtOH) CDCl.sub.3
1.21-1.35(1H, m), 1.40-1.57(2H, m), 1.53(3H, t, J=7.1Hz),
1.67-1.75(1H, m), 1.83-2.09(6H, m), 2.34(3H, s), 2.45-2.57 (4H, m),
2.51(3H, s), 3.60-3.71(4H, m), 4.56(2H, q, J=7.1Hz), 4.93-5.05(1H,
m), 6.34(1H, d, J=8.8Hz), 8.59(1H, d, J=8.8Hz), 11.02(1H, brs) 452
44 ##STR50## colorless solid 151-152 (AcOEt/hexane) CDCl.sub.3
1.21-1.36(1H, m), 1.40-1.58(2H, m), 1.52(3H, t, J=7.1Hz),
1.61-1.781H, m), 1.82-2.09(8H, m), 2.38(3H, s), 2.51(3H, s),
2.54-2.51(2H, s), 2.69-2.77(2H, m), 3.62-3.73(2H, m), 3.80-3.91(2H,
m), 4.54(2H, q, J=7.1Hz), 4.92-5.06(1H, m), 6.22(1H, d, J=8.9Hz),
8.56(1H, d, J=8.9Hz), 11.02(1H, brs) 466
[0203] TABLE-US-00012 TABLE 12 Properties Example m.p. (.degree.
C.) MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR
(M+1).sup.+ 45 ##STR51## colorless solid 166-167 CDCl.sub.3
1.22-1.38(1H, m), 1.41-1.56(2H, m), 1.52(3H, t, J=7.1Hz),
1.68-1.79(5H, m), 1.84-2.09(6H, m), 2.51(3H, s), 3.71-3.81 (4H, m),
4.00(4H, s), 4.55(2H, q, J=7.1Hz), 4.92-5.04(1H, m), 6.38(1H, d,
J=8.8Hz), 8.57(1H, d, J=8.8Hz), 11.01(1H, brs) 495 46 ##STR52##
colorless solid 220-221 (AcOEt) CDCl.sub.3 1.21-1.36(1H, m)
1.40-1.59(2H, m), 1.55(3H, t, J=7.1Hz), 1.67-1.79(1H, m),
1.84-2.10(6H, m), 2.52(3H, s), 2.53-2.61 (4H, m), 3.94-4.04(4H, m),
4.58(2H, q, J=7.1Hz), 4.91-5.03(1H, m), 6.45(1H, d, J=8.7Hz),
8.66(1H, d, J=8.7Hz), 10.97(1H, brs) 451 47 ##STR53## colorless
solid 186-186.5 (EtOH) CDCl.sub.3 1.22-1.39(1H, m) 1.41-1.59(4H,
m), 1.54(3H, t, J=7.1Hz), 1.68-1.77(1H, m), 1.85-2.10(8H, m),
2.31(6H, s), 2.35-2.49 (1H, m), 2.53(3H, s), 2.89-3.00(2H, m),
4.38-4.49(2H, m), 4.57(2H, q, J=7.1Hz), 4.97-5.08(1H, m), 6.37(1H,
d, J=8.8Hz), 8.58(1H, d, J=8.8Hz), 11.03(1H, brs) 480 48 ##STR54##
colorless solid 155-156.5 (AcOEt/hexane) CDCl.sub.3 1.22-1.62(5H,
m), 1.54(3H, t, J=7.1Hz), 1.69-1.78(1H, m), 1.86-2.10(8H, m),
2.48(3H, s), 2.53(3H, s), 2.61-2.70(1H, m), 3.00-3.10(2H, m),
4.27-4.38(2H, m), 4.57(2H, q, J=7.1Hz), 4.96-5.08(1H, m), 6.37(1H,
d, J=8.8Hz), 8.58(1H, d, J=8.8Hz), 11.04(1H, brs) 466
[0204] TABLE-US-00013 TABLE 13 Properties Example m.p. (.degree.
C.) MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR
(M+1).sup.+ 49 ##STR55## colorless solid 198-199 (EtOH) CDCl.sub.3
1.22-1.37(1H, m), 1.41-1.65(4H, m), 1.54(3H, t, J=7.1Hz),
1.68-1.78(1H, m), 1.86-2.10(8H, m), 2.53(3H, s), 3.26-3.37(2H, m),
3.94-4.03(1H, m), 4.07-4.16(2H, m), 4.57(2H, q, J=7.1 Hz),
4.94-5.05(1H, m), 6.38(1H, d, J=8.8Hz), 8.59(1H, d, J=8.8Hz),
11.03(1H, brs) 453
INDUSTRIAL APPLICABILITY
[0205] The compounds of the present invention inhibit PDE 7
selectively, and therefore, enhance cellular CAMP level.
Consequently, the compounds of the present invention are useful for
treating various kinds of disease such as allergic disease,
inflammatory disease or immunologic disease.
[0206] That is, the compounds of the present invention are useful
for treating or preventing the diseases such as bronchial asthma,
chronic bronchitis, chronic obstructive pulmonary disease, allergic
rhinitis, psoriasis, atopic dermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, septicemia, Crohn's disease,
rejection for organ transplantation, GVH disease, and restenosis
after angioplasty.
* * * * *