ZA200005243B - Anthranilic acid derivatives as inhibitors of the CGMP-phosphodiesterase. - Google Patents

Anthranilic acid derivatives as inhibitors of the CGMP-phosphodiesterase. Download PDF

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Publication number
ZA200005243B
ZA200005243B ZA200005243A ZA200005243A ZA200005243B ZA 200005243 B ZA200005243 B ZA 200005243B ZA 200005243 A ZA200005243 A ZA 200005243A ZA 200005243 A ZA200005243 A ZA 200005243A ZA 200005243 B ZA200005243 B ZA 200005243B
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South Africa
Prior art keywords
group
nitrobenzamide
substituted
hydroxy
lower alkyl
Prior art date
Application number
ZA200005243A
Inventor
Teruo Oku
Akio Kuroda
Natsuko Kayakiri
Tsuyoshi Mizutani
Kozo Sawada
Takayuki Inoue
Yuki Sawada
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Fujisawa Pharmaceutical Co
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Publication of ZA200005243B publication Critical patent/ZA200005243B/en

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Description

[SEY ; ) ow
TL WO 99/54284 PCT/JP99/02028
DESCRIPTION
ANTHRANILIC ACID DERIVATIVES AS INHIBITORS OF THE CGMP-PHOSPHODIESTERASE
S Technical Field
This invention relates to novel anthranilic acid derivatives having pharmacological activity, to a process for their production, to a pharmaceutical composition containing the same, and to their use as a medicament.
Background Art
It is known that a cyclic guanosine-3',5'-monophosphate (hereinafter referred to as cGMP) derived from a guanosine-5'- triphosphate possesses a relaxant activity of smooth muscle and that a cyclic guanosine-3',5'-monophosphate phosphodiesterase (hereinafter refereed to as cGMP-PDE] acts to catalyze the degradation of cGMP to a guanosine-5'-monophosphate. The compounds having an inhibitory activity of cGMP-PDE are disclosed in European Patent Publication Nos. 579,496; 534,443; 526,004; 636,626; United States Patent Nos. 3,819,631; 5,294,612; 5,488,055; International Patent Publication Nos. 93/07,124;94/19,351; 95/18,097; 96/32,379; Japan Patent
Publication Nos. 05-222,000; 07-330,777; and so on.
Disdl 1 .
This invention relates to novel anthranilic acid derivatives, which have pharmaceutical activity such as inhibiting activity of cGMP-PDE, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.
Accordingly, one object of this invention is to provide the novel anthranilic acid derivatives, which have an inhibiting activity of cGMP-
PDE.
Another object of this invention is to provide a process for production of the anthranilic acid derivatives.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, an anthranilic acid
TTT Ta ; derivative.
Still further object of this invention is to provide a use of the anthranilic acid derivatives for treating or preventing various diseases.
S The new anthranilic acid derivatives of this invention can be represented by the following formula (J) : 0
SAL
YASH ® 2
R R4 wherein
R! is hydrogen atom or a halogen atom;
R2 is an electron withdrawing group;
R3 is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl;
A is a lower alkylene group;
R4 is a lower alkoxy group, a substituted or unsubstituted, saturated or unsaturated heterocyclic group, an amino group optionally substituted with halo(lower)alkyl or : lower alkyl, } 30 a group -CH2-RS wherein RS is a cycloalkyl group or an unsaturated : heterocyclic group, or a group -CRSR7Ré wherein
Ré and R7” are each independently carboxy group,
vos WO 99/54284 PCT/JP99/02028 a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or a lower alkyl group optionally substituted with one or > more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which : may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or :
R¢ and R7 together with the carbon atom to which Ré and R7 are attached may form a substituted or unsubstituted, saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and
Ré8 is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or lower alkoxy; provided that when R* is the group -CRSR7R8 wherein
R6 is a lower alkyl group optionally substituted with halogen,
R7 is a lower alkyl group optionally substituted with halogen, and R8 is hydrogen atom or a lower alkyl group, or when R# is the group -CH2-RS wherein RS is the same as the above,
R3 should be hydrogen atom, hydroxy group or a cycloalkyl group; and a pro-drug thereof, and a salt thereof.
The compounds of the formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers.
The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
It is further to be noted that isomerization or rearrangement of the compounds (I) may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
The compounds of the formula (I) and its salts can be in the form of a solvate, which is included within the scope of the present invention.
The solvate preferably include a hydrate and an ethanolate. ~ 15 Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
According to this invention, the object compounds (I) or its salts can be prepared by the following process.
Process 1
Oo . 0]
H.N—R .
EN NAR 2 (am EN nA Re
R'-¢ _ H _— Rw Pe H
SFE or its salt 7 NH
R? R? Le 0 O or its saft or its sat }
Process 2
Oo (0) ap? » Sy on HNTATR A! > 0a - —_— -
YP Lz by NH or its reactive i" NH
R* derivative at amino group, R* or its salt wv) 1) or its reactive derivative or its salt at carboxy group, or its salt 4
Co 1
I J
Process 3
O
0 J 0} 6 7 A x NARS R® RB’ (VD) ONE
R' H —_— R'- ” H {7 a
R R
A 7 =} R (VI) (I-1) or its salt or its salt
In the above formulae, R?, R?, R3, R4, RS, R7 and A are the same as those defined in the above. : Some of the starting materials are novel and can be prepared by the following processes.
Process A (0) 0 — A — 3 . of 50 HoN A—R (A) ot Se i -— _—> lv, pA F F or its reactive derivative A Z F
R? at amino group, R or its salt {vim {Im or its reactive derivative or its salt at carboxy group, or its salt ’
Process B 0) 1 lo) —_— ——— ee eee —_— g ¢ /~ NH, 7" NH
R? R? PN 8 7 x R R ( ) (IV-1) or its salt or its salt
S
Process C
Oo (o} _n4
YL A F or its reactive derivative NY. Z SNH
R? at amino group, R2 or its salt R*
X) mw or its salt
Process D 0 0] —-A-R? SAL
YF “No or its reactive derivative Lz NH
R2 H at amino group, R2 2 or its salt
X17 (\%] or its salt
In the above formulae, R!, R?, R3, R4, R6, R7and A are the same as those defined in the above, R is hydrogen atom or a lower alkyl group.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope are explained in detail in the following.
The term “lower” is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise indicated.
Suitably the lower alkyl groups and lower alkyl moieties in the _ 30 terms of the halo{lower)alkyl, lower alkanesulfonyl, lower oo alkanesulfonyloxy, lower alkoxy, lower alkylthio, hydroxy(lower)alkyl, ar(lower)alkyl, ar(lower)alkoxy and ar(lower)alkoxycarbonyl groups may include straight or branched ones having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
ad . WO 99/54284 PCT/IP99/02028 pentyl, isopentyl, hexyl or the like, more suitably the ones having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
Suitably the examples of the lower alkenyl groups include straight or branched ones having 2 to 6 carbon atoms, such as ethenyl,
S propenyl (i.e., allyl or 1-propenyl), butenyl, isobutenyl, pentenyl, hexenyl or the like.
Suitable lower alkylene groups and lower alkylene moieties in the lower alkylenedioxy group may include straight or branched ones having 1 to 6 carbon atoms, such as methylene, methylmethylene, ethylene, methylethylene, trimethylene, tetramethylene, 2- methyltrimethylene, pentamethylene, hexamethylene or the like, more suitably the ones having 1 to 3 carbon atoms.
Suitable examples of the acyl groups and acyl moieties in the term of the acyloxy group include aliphatic acyl groups such as lower alkanoyls (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl) and acyl groups containing an aromatic or heterocyclic ring such as aroyls (e.g., benzoyl, toluoyl, xyloyl or naphthoyl), ar(lower)alkanoyls (e.g., phenylacetyl or phenylpropionyl), ar(lowerjalkoxycarbonyls (e.g., benzyloxycarbonyl or phenethyloxycarbonyl), heterocyclic carbonyls (e.g., thenoyl or furoyl) and the like.
The cycloalkyl groups may include the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
Suitably the aryl groups and aryl moieties in the terms of the ar(lower)alkyl, ar(lower)alkoxy, aryloxy, aryloxycarbonyl and aroyloxy groups may be an aromatic group having 6 to 12 carbon atoms.
Specific examples thereof are phenyl, naphthyl, indenyl, azulenyl, biphenylenyl, fluorenyl and anthracenyl.
Suitable examples of the saturated carbocyclic groups may be the cycloalkyl groups as exemplified in the above.
Suitable examples of unsaturated carbocyclic groups may include cyclopentenyl, cyclohexenyl, cycloheptenyl, 2,3-dihydro-1H- indenyl, benzocyclohexyl and the like.
Suitable examples of the halogen atoms and halo moiety of the halo(lower)alkyl group may be fluorine, chlorine, bromine or iodine.
Suitable examples of the unsaturated heterocyclic group may include mono- or poly-cyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as
S (1) unsaturated 3 to 7-membered, preferably S or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl or 2H- 1,2,3-triazolyl], tetrazoly! [e.g., 1H-tetrazoly or 2H-tetrazolyl] or the like.; (2) unsaturated 3 to 7-membered, preferably 5S or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl or fury}; (3) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms, for example, thienyl or the like; 4) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazolyl] or the like; (5) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl] or the like; (6) unsaturated condensed heterocyclic groups containing 1 to 2 nitrogen atoms, for example, indolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzimidazolyl or the like; (7) unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms, for example, benzofuryl or the like; (8) unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms, for example, benzo[blthienyl or the like;
B 9) unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, : benzoxadiazolyl, phenoxazinyl or the like; (10) unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl,
ren A WO 99/54284 PCT/JP99/02028 benzoisothiazolyl, phenothiazinyl or the like.
Suitable examples of the saturated heterocyclic group and heterocyclic moiety in the saturated heterocyclic sulfonyl group include monocyclic groups containing at least one hetero atom selected from 5) nitrogen, sulfur and oxygen atoms, such as (1) saturated 3 to 7-membered, preferably S or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidyl or piperazinyl]; (2) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; (3) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl or thiomorpholinyl]; (4) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms [e.g., tetrahydrothiophenyl, tetrahydrothiopyranyl, 1- oxotetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, dioxacyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or dioxanyl]; or the like.
Suitably carboxy protective groups in the protected carboxy group may include lower alkyl groups (e.g., methyl, ethyl or tert-butyl), halo(lower)alkyl groups (e.g., 2-iodomethyl or 2,2,2-trichloroethyl), ar(lower)alkyl groups (e.g., benzyl, trityl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl or 4- : hydroxy-3,5-di-tert-butylbenzyl), aryl groups (e.g., phenyl, naphthyl, tolyl or xylyl), and the like, more suitably the lower alkyl groups such as methyl, ethyl or tert-butyl and ar(lower)alkyl groups such as benzyl.
Specific examples of the each group containing the above- mentioned moiety and having substituent(s) are as follows.
As the halo{lower) alkyl group, fluoromethyl, iodomethyl, chloromethyl, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 2,2,2-trichloroethyl or the like may be mentioned.
The lower alkanesulfonyl group is methanesulfonyl(mesyl), ethanesulfonyl, propanesulfonyl or the like.
The lower alkanesulfonyloxy group is methansulfonyloxy(mesyloxy), ethanesulfonyloxy, propanesulfonyloxy or the like,
The lower alkoxy group is methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy of the like.
The lower alkylthio group is methylthio, ethylthio, propylthio, butylthio, isobutylthio or the like.
The acyloxy group is formyloxy, acetyloxy, propionyloxy, benzoyloxy, toluoyloxy, naphthoyloxy, phenylacetyloxy, theonyloxys or the like.
The hydroxy(lower)alkyl group is hydroxymethyl, hydroxyethyl or the like. ‘15 The ar(lower)alkyl group is benzyl, 4-methoxybenzyl, 4- nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl, 3,4- dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl) or the like.
The ar(lower)alkoxy group is benzyloxy, 4-methoxybenzyloxy, 4- nitrobenzyloxy, phenethyloxy, trityloxy, bis(methoxyphenyl)methoxy, 3,4-dimethoxybenzyloxy, 4-hydroxy-3,5-di-tert-butylbenzyloxy or the like.
The lower alkylenedioxy group is methylenedioxy, ethylenedioxy and the like.
The aryloxy group is phenoxy, naphthoxy, tolyloxy, xylyloxy or the like,
The aroyloxy group is benzoyloxy, naphthoyloxy or the like.
The saturated heterocyclic sulfonyl group is piperazinesulfonyl, piperizinesulfonyl, morpholinesulfonyl, pyrazolidinesulfonyl or the like.
Preferred embodiments of the compounds (J) are those represented by the formula (I), wherein
R! is hydrogen atom or a halogen atom;
R? is an electron withdrawing group;
tan ® WO 99/54284 PCT/JP99/02028
R? is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl;
S A is a lower alkylene group;
R# is a lower alkoxy group, a substituted or unsubstituted, saturated or unsaturated heterocyclic group, an amino group optionally substituted with halo(lower)alkyl or lower alkyl, a group -CH2-RS wherein RS is a cycloalkyl group or an unsaturated heterocyclic group, or a group -CRSR7R8 wherein
R6 and R7 are each independently carboxy group, "a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or
RS and RY? together with the carbon atom to which R6 and R?
. co are attached may form a substituted or unsubstituted, saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and
S Re is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or a lower alkoxy; provided that when R¢* is the group ~-CRSR7R8 wherein
Ré¢ is a lower alkyl group optionally substituted with halogen,
R7 is a lower alkyl group optionally substituted with halogen, and R8 is hydrogen atom or a lower alkyl group, or when R? is the group -CH2-R5 wherein RS is the same as the above,
R3 should be hydrogen atom, hydroxy group or a cycloalkyl group, "15 the electron withdrawing group for R2 being selected from a group consisting of nitro group; cyano group; acyl group; halo(lower)alkyl group; sulfamoyl group; carbamoyl group optionally substituted with lower alkyl; halogen atom; lower alkenyl group optionally substituted with protected carboxy; lower alkanesulfonyl group; saturated heterocyclic sulfonyl group optionally substituted with protected carboxy; and unsaturated heterocyclic group, the substituent(s) on the aryl group for R3 being selected from a group consisting of lower alkyl group; halo(lower)alkyl group; lower alkylthio group; halogen atom; hydroxy group; lower alkylenedioxy group; cyano group; nitro group; carboxy group; protected carboxy group; sulfamoyl group; acyl group; aryl group; ar(lower)alkoxy group; aryloxy group; lower alkoxy group which may be substituted with lower alkoxy or cycloalkyl; amino group which may be substituted with acyl, protected carboxy or lower alkyl; and carbamoyl group which may be substituted with lower alkyl, the substituent(s) on the saturated or unsaturated heterocyclic group for
R4 being selected from a group consisting of oxo group; acyl group; protected carboxy group; lower alkanesulfonyl group; sulfamoyl group which may be substituted with protected carboxy; ar(lower)alkyl group; lower alkyl group which may be substituted with hydroxy or aryl; ureido
I WO 99/54284 PCT/JP99/02028 group which may be substituted with lower alkyl; guanidino group which may be substituted with protected carboxy; amidino group which may be substituted with protected carboxyl; and carbamoyl group which may be substituted with lower alkyl, and
S the substituent(s) on the saturated carbocyclic group formed by combination of Ré and R7 being selected from a group consisting of lower alkyl group; halogen atom; hydroxy group; lower alkoxy group; acyloxy group; carboxy group; protected carboxy group; oxo group; amidino group which may be substituted with protected carboxy; ureido group which may be substituted with lower alkyl or aryl; guanidino group which may be substituted with protected carboxy; amino group which may be substituted with acyl, lower alkanesulfonyl or protected carboxy; and carbamoyl group which may be substituted with lower alkyl or hydroxy(lower)alkyl; and a pro-drug thereof, and a salt thereof.
Another preferred embodiments are as follows: compounds of the formula (J), wherein
R! is hydrogen atom or a halogen atom;
R? is an electron withdrawing group;
R3 is a substituted or unsubstituted aryl group;
A is a lower alkylene group; and
R# is a group -CRSR7R8 wherein
R6 and R7 together with the carbon atom to which RS and R7 are attached may form a substituted or unsubstituted, saturated carbocyclic group, and
R8 is hydrogen atom; and compounds of the formula (I), wherein
R! is hydrogen atom or a halogen atom;
R? is an electron withdrawing group;
R3 is a substituted or unsubstituted aryl group;
A is a lower alkylene group; and
R¢4 is a group -CR6R7R8 wherein
Ré is a lower alkyl group substituted with hydroxy,
R7 is a lower alkyl which may be substituted with hydroxy, and
R8 is hydrogen atom or a lower alkyl group which may be substituted with hydroxy.
S Further preferred embodiments are as follows: compounds of the formula (I), wherein
R1is hydrogen atom or a halogen atom;
R? is nitro group, cyano group or a halo(lower)alkyl group;
R3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy;
A is a lower alkylene group; and
R% 1s a group -CR6R7R8 wherein
Ré and R7 together with the carbon atom to which Ré and R7 are attached may form a saturated carbocyclic group optionally substituted with hydroxy or amino which may be substituted with acyl; and
R8 is hydrogen atom; and compounds of the formula (I), wherein
R! is hydrogen atom or a halogen atom;
R? is nitro group, cyano group or a halo(lower)atkyl group;
R3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy;
A is a lower alkylene group; and
R# is a group -CRSR7R8 wherein
RS is a lower alkyl group substituted with hydroxy,
R7 is a lower alkyl group which may be substituted with hydroxy, and
R8 is hydrogen atom or a lower alkyl group which may be substituted with hydroxy. or In accordance with the invention, it includes salts of the compounds (I). The salts may be conventional non-toxic
Pharmaceutically acceptable salts, for example, a salt with an alkali metal (e.g., sodium or potassium) and an alkaline earth metal (e.g., calcium or magnesium), an ammonium, an organic base (e.g.,
-t WO 99/54284 PCT/JP99/02028 trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or dibenzylethylenediamine), an organic acid (e.g., acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, tartaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, formic
S acid, p-toluenesulfonic acid or trifluoroacetic acid), inorganic acid (e.g., hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid), an amino acid (e.g., arginine, aspartic acid or glutamic acid) or the like.
The processes for preparing the starting compounds and the object compounds (I) of the present invention are explained in detail in the following,
Process 1
A compound (I) or its salt can be prepared by reacting a compound (II) or its salt with a compound (Ill) or its salt.
This reaction is usually carried out in the presence of an inorganic or an organic base.
Suitable inorganic base may include an alkali metal le.g., sodium or potassium], an alkali metal hydroxide [e.g., sodium hydroxide or potassium hydroxide}, an alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate or potassium hydrogen carbonate}, an alkali metal carbonate [e.g., sodium carbonate], an alkali earth metal carbonate [e.g., calcium carbonate}, an alkali metal hydride fe.g., sodium hydride or potassium hydride] and the like.
Suitable organic base may include tri(lower)alkylamines [e.g., triethylamine or N,N-diisopropylethylamine}, alkyl lithiums [e.g., methyl lithium or butyl lithium], lithium diisopropylamide, lithium hexamethyldisilazido and the like.
The reaction is usually carried out in a conventional solvent such as water, alcohols [e.g., methanol, ethanol or isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform,
N,N-dimethylforrmamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
The reaction is preferably carried out at a temperature under cooling to warming. However, the reaction temperature is not limited.
Process 2
A compound (I) or its salt can be prepared by reacting a compound (IV) or its reactive derivative at the carboxy group, or its salt,
S with a compound (V) or its reactive derivative at the amino group, or its salt, according to a procedure known in the art.
Suitable reactive derivatives at the carboxy group of the compound (IV) may include the acid chloride, azide, acid anhydride, activated amide, activated ester and the like.
Suitably the acid anhydride may include anhydrides with an : acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid or ethanesulfonic acid), alkanoic acid (e.g., pivalic acid, pentanoic acid or isopentanoic acid), aromatic carboxylic acid (e.g., benzoic acid, chlorobenzoic acid, fluorobenzoic acid or nitrobenzoic acid),or the like.
Suitably the active amide may include the imidazoylylamide, 4- substituted imidazoylylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide or the like.
Suitably the active ester may include the dimethyliminomethyl [(CHj)2N*=CH-] ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8-quinolyl thioester, an ester with a N-hydroxy compound (e.g.,
N,N-dimethylhydroxylamine, 1-hydroxy-2H-pyridone, N- hydroxysuccinimide, N-hydroxybenzotriazole or N-hydroxyphthalimide) or the like.
Suitably the reactive derivative at amino group of the compound : oo (V) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (V) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (V) with a silylating reagent such as . 35 trimethylsilylchloride, N ,O-bis(trimethylsilyljacetamide, N-
Ct WO 99/54284 PCT/JP99/02028 trimethylsilylacetamide or the like.
Each reactive derivative of compounds (IV) and (V) can optionally be selected from the above according to the kinds of the compounds (IV) and (V) to be used, respectively.
S When the compound (IV) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a condensing agent.
Suitable condensing agent may include carbodiimides (e.g.,
N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4- diethylaminocyclohexyl)carbodiimide or N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide or its hydrochloride), diphenylphosphinic azide, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis(2-o0xo0-3-oxazolidinyl)phosphinic chloride,
N,N'-carbonyldiimidazole, 2-ethoxy- 1-ethoxycarbonyl-1,2- dihydroquinoline, cyanuric chloride or the like.
The reaction may be also carried out in the presence of an organic or inorganic base such as an alkali metal carbonate, trilower)alkylamine, pyridine, N- (lower) alkylmorphorine or the like.
The reaction is usually carried out in a conventional solvent such as water, acetone, alcohols [e.g., methanol, ethanol or isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N'-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
The reaction is preferably carried out at a temperature under cooling to warming. However, the reaction temperature is not limited.
Process 3
A compound (I-1) or its salt can be prepared by reacting a compound (VI) or its salt with a ketone compound (VI]) in the presence of an inorganic acid (e.g., sulfuric acid or hydrogen chloride) or an organic acid (e.g., acetic acid) and a reducing agent.
Suitable reducing agent may include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, borane-pyridine complex and the like.
The reaction is usually carried out in a conventional solvent

Claims (17)

N L . CLAIMS
1. A compound of the formula (I): S Q A gi N al K [ F (0 [7 R RB wherein R! is hydrogen atom or a halogen atom; R2 is an electron withdrawing group; R3 is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl; A is a lower alkylene group; R4 is a lower alkoxy group, a substituted or unsubstituted, saturated or unsaturated heterocyclic group, an amino group optionally substituted with halo(lower)alkyl or lower alkyl, a group -CHz-R5 wherein RS is a cycloalkyl group or an unsaturated heterocyclic group, or a group -CRSR7R8 wherein R6 and R7 are each independently carboxy group, a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or
! L . Ld a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; S protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or Ré and R7 together with the carbon atom to which R® and R” are attached may form a substituted or unsubstituted, saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and RS is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or a lower alkoxy; provided that when R* is the group -CR6R7R8 wherein RS is a lower alkyl group optionally substituted with halogen, R7 is a lower alkyl group optionally substituted with halogen, and R8 is hydrogen atom or a lower alkyl group, or : when R# is the group -CH;-RS wherein RS is the same as the above, R3 should be hydrogen atom, hydroxy group or a cycloalkyl group; and a pro-drug thereof, and a salt thereof.
2. A compound of claim 1, wherein the electron withdrawing group for R? is selected from a group consisting
¥ of nitro group; cyano group; acyl group; halo(lowerjalkyl group; sulfamoyl group; carbamoyl group optionally substituted with lower alkyl; halogen atom; lower alkenyl group optionally substituted with protected carboxy; lower alkanesulfonyl group; saturated heterocyclic ) sulfonyl group optionally substituted with protected carboxy; and unsaturated heterocyclic group, the substituent(s) on the aryl group for R3 is/are selected from a group consisting of lower alkyl group; halo(lower)alkyl group; lower alkylthio group; halogen atom; hydroxy group; lower alkylenedioxy group; cyano group; nitro group; carboxy group; protected carboxy group; sulfamoyl group; acyl group; aryl group; ar(lower)alkoxy group; aryloxy group;
lower alkoxy group which may be substituted with lower alkoxy or cycloalkyl; amino group which may be substituted with acyl, protected carboxy or lower alkyl; and carbamoyl group which may be substituted with lower alkyl, the substituent(s) on the saturated or unsaturated heterocyclic group for R+ is/are selected from a group consisting of oxo group; acyl group;
protected carboxy group; lower alkanesulfonyl group; sulfamoyl group which may be substituted with protected carboxy; ar(lower)alkyl group; lower alkyl group which may be substituted with hydroxy or aryl; ureido group which may be substituted with lower alkyl, guanidino group which may be substituted with protected carboxy; amidino group which may be substituted with protected carboxyl; and carbamoyl group which may be substituted with lower alkyl, and the substituent(s) on the saturated carbocyclic group formed by combination of R6 and R7 is/are selected from a group consisting of lower alkyl group; halogen atom; hydroxy group; lower alkoxy group; acyloxy group; carboxy group; protected carboxy group; oxo group; amidino group which may be substituted with protected carboxy; ureido group which may be substituted with lower alkyl or aryl; guanidino group which may be substituted with protected carboxy; amino group which may be substituted with acyl, lower alkanesulfonyl or protected carboxy; 177 _ ]
AJ and carbamoyl group which may be substituted with lower alkyl or hydroxy(lower)alkyl.
3. A compound of Claim 1, wherein R3 is a substituted or unsubstituted aryl group; R# is a group -CRéR’R8 wherein R6 and R7 together with the carbon atom to which R6 and R7 are attached may form a substituted or unsubstituted, saturated carbocyclic group, and : Ré8 is hydrogen atom.
4, A compound of Claim 3, wherein R2 is nitro group, cyano group or a halo(lower)alkyl group; R3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy; R# is a group -CRSR7R8 wherein R6 and R7 together with the carbon atom to which Ré and R7 are attached may form a saturated carbocyclic group optionally substituted with hydroxy or amino which may be substituted with acyl; and R2 is hydrogen atom. - 25
5. A compound of Claim 4 which is N-(2-chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide, N-(3-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide, N-{4-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide, 2-(cyclopentylamino)-N-(2,4- dichlorobenzyl)-5-nitrobenzamide, 2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-5-nitrobenzamide, 2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol- 5-ylmethyljbenzamide, 2-(cyclopentylamino)-N -(4-fluorobenzyl)-5-nitrobenzamide, 2-(cyclopentylamino)-N-(4-methoxybenzyl)-5-nitrobenzamide, N-(2-chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide, N-(4-bromobenzyl)-2-(cyclopentylamino)-5S-nitrobenzamide, ST 178 CL I" ~~
2-(cyclopentylamino)-5-nitro-N-phenethylbenzamide, 2-(cyclopentylamino)-5-nitro-N-(3-phenylpropyl)benzamide, N-benzyl-2-(cyclobutylamino)-5-nitrobenzamide, N-benzyl-2-cycloheptylamino-S-nitrobenzamide,
N-benzyl-2-(cyclohexylamino)-5-nitrobenzamide, N-benzyl-2-(trans<4-hydroxycyclohexylamino)-5-nitrobenzamide, 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-
ylmethyl)benzamide, 2-(cyclopentylamino)-N-(2,4-difluorobenzyl)-5-nitrobenzamide,
N-benzyl-2-(cyclopropylamino)-5-nitrobenzamide, N-benzyl-2-(2-hydroxycyclohexylamino)-5-nitrobenzamide, N-benzyl-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide, 2-(cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5-
ylmethyl)benzamide, :
2-(trans-2-hydroxycyclopentylamino)-5-nitro-N-(1,3-benzodioxol-5-
ylmethyl)benzamide, 2-[cis-4-(benzoyloxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-
nitrobenzamide, 2-(cis4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-
ylmethyl)benzamide,
N-(3,4-dimethoxybenzyl)-2-( trans-4-hydroxycyclohexylamino)-5- nitrobenzamide,
2-(cis4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5- ylmethyl)benzamide,
N-benzyl-2-(3-hydroxycyclopentylamino)-S-nitrobenzamide, 2-[3-(benzoyloxy)cyclopentylamino}-N-benzyl- 5-nitrobenzarmide, N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-
nitrobenzamide, 2-(trans-2-aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-
ylmethyl)benzamide, N-(3-chloro-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)- S5-
nitrobenzamide, 2-[cis4-(benzoyloxy) cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)-5- nitrobenzamide,
. Ce
N-(3-chloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5- nitrobenzamide, N-(3,4-dimethoxybenzyl)-2-(trans-2-hydroxycyclopentylamino)-5- nitrobenzamide, N-(3,5-dichloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)- 5-nitrobenzamide, N-(3,4-ethylenedioxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5- nitrobenzamide, 2-(cis4-hydroxycyclohexylamino)-5S-nitro-N-(3,4,5- trimethoxybenzyl)benzamide, 2-{cis-4-(acetoxy)cyclohexylamino}-N-(3,4-dimethoxybenzyl)-S- nitrobenzamaide, 2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5- nitrobenzamide, 2-(cis4-hydroxycyclohexylamino)-N-(1-naphthylmethyl)-5- nitrobenzamide, 2-(trans-4-acetamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5- nitrobenzamide, N-(3,4-dimethoxybenzyl)-2-[(trans4-formamidocyclohexyl)amino]-5- nitrobenzamide, N-(2-chloro-5-methoxybenzyl)-2-(cis4-hydroxycyclohexylamino)-5- nitrobenzamide, 2-(cis4-benzoyloxycyclohexylamino)- N-(3-fluoro-4-methoxybenzyl)-5- nitrobenzamide, N-(3-ethoxy-4-methoxybenzyl)-2-(cis4-hydroxycyclohexylamino)-5- nitrobenzamide, : N-(4-chloro-4-ethoxyb enzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitro- benzamide, N-(4-ethoxy-3 -methoxybenzyl)-2-(cis4-hydroxycyclohexylamino)-5- nitrobenzamide, 2-(trans-4-aminocyclohexylamino}-N- (4-ethoxy-3-methoxybenzyl)-5- nitrobenzamide, N-(4-ethoxy-3-methoxybenzyl) -2-(trans4-formamidocyclohexylamino}- 5-nitrobenzamide,
oT 5-cyano-2-(trans-<4-hydroxycyclohexylamino)-N-(1,3-benzodioxol-5- ylmethyl)benzamide, : 2-(cis4-formamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5- nitrobenzamide, S 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-{(1S)-1- phenylethyl]benzamide, 5-bromo-N-(3-chloro-4-methoxybenzyl)-2- {cyclopentylamino)benzamide, 5-chloro-2-(cyclopentylamino)-N-(1,3-benzodioxol-5- ylmethyl)benzamide, 4-chloro-N-(3,4-dimethoxybenzyl)-5S-fluoro-2-(trans-4- hydroxycyclohexylamino)benzamide, or 2-(cis4-aminocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5- nitrobenzamide, or a salt thereof.
6. A compound of Claim 1, wherein R3 is a substituted or unsubstituted aryl group; R4 is a group -CRSR’R8 wherein : RS is a lower alkyl group substituted with hydroxy, R7 is a lower alkyl which may be substituted with hydroxy, and R8 is hydrogen atom or a lower alkyl group which may be substituted with hydroxy.
7. A compound of Claim 6, wherein R2? is nitro group, cyano group or a halo(lower}alkyl group; and R3 is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy.
8. A compound of Claim 7 which is N-benzyl-2-[2-hydroxy- 1-(hydroxymethyljethylamino]-5- nitrobenzamide,
! '
‘ . : R)-2-( 1-ethyl-2-hydroxyethylamino)-5-nitro-N-(1 ,3-benzodioxol-5- ylmethyl)benzamide, (S)-2-[1 - (hydroxymethyl) propylamino]-5-nitro-N -(1,3-benzodioxol-5- ylmethyl)benzamide, 5) (R)-2-(2-hydroxy-1 -methylethylamino)-5-nitro-N-(1,3-benzodioxol-5- ylmethyl)benzamide, 2-[2-hydroxy-1,1 -bis(hydroxymethyl)ethylamino}-S-nitro-N-(1,3- benzodioxol-5-ylmethyl)benzamide, 2-(2-hydroxy-1,1 -dimethylethylamino)-S-nitro-N-(1 ,3-benzodioxol-5- ylmethyl)benzamide, 2-[2-hydroxy-1- (hydroxymethyl)ethylamino]- 5-nitro-N-(1,3-benzodioxol- 5-ylmethyl)benzamide, 2-[2-hydroxy-1-(hydroxymethyl)-1 -methylethylamino}-5-nitro-N-(1,3- benzodioxol-5-ylmethyl)benzamide, (S)-2-[1-(hydroxymethyl) -2-methylpropylamino}-5-nitro-N-(1,3- benzodioxol-5-ylmethyl)benzamide, 2-[(1R, 2R })-2-hydroxy- 1-(hydroxymethyl)propylamino]-5-nitro-N-(1 ,3- benzodioxol-5-ylmethyl)benzamide, N- (3-chloro-4-methoxybenzyl)-2-[2 -hydroxy-1-(hydroxy- methyl)ethylamino}-5-nitrobenzamide, 2-[1- {(hydroxyethyl)pentylamino}- 5-nitro-N-(1,3-benzodioxol-5- ylmethyl)benzamide, (R)-N-(3,4-dimethoxybenzyl) -2-(2-hydroxy-1 -methylethylamino)-5- nitrobenzamide, (S)-N-(3,4-dimethoxybenzyl)-2-[1- (hydroxymethyl)propylamino}-5- nitrobenzamide, N-(3,4-dimethoxybenzyl)-2- (2-hydroxy-1,1 -dimethylethylamino)-5- nitrobenzamide, N- (3-fluoro-4-methoxybenzyl) -2-[2-hydroxy-1- (hydroxymethyl) ethylamino]-5-nitrobenzamide, N-(4-chloro-3-methoxybenzyl)-2- [2-hydroxy-1- (hydroxymethyl) ethylamino]-5-nitrobenzamide, . 2-[2-hydroxy-1- (hydroxymethyljethylamino]-N-(2-naphthylmethyl)-5- nitrobenzamide, 2-[2-hydroxy-1- (hydroxymethyl)ethylamino}-N-[2-(2-
> : he } WO 99/54284 PCT/JP99/02028 methoxyphenyljethyl}-5-nitrobenzamide, N-(3-chloro-4-flucrobenzyl)-2-[2-hydroxy-1- (hydroxymethyl)ethylamino]-5-nitrobenzamide, (S)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy- 1-methylethylamino)-5- ) nitrobenzamide, (S)-N-(3,5-dimethoxybenzyl)-2-(2-hydroxy- 1-methylethyljamino-5- nitrobenzamide, N-(3-chloro-4-methoxybenzyl)-2-[2-hydroxy-1- (hydroxymethyl)ethylamino]-5- (trifluoromethyl)benzamide, (R )-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-{1,3-benzodioxol-5- ylmethyl)benzamide, (S )-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1- methylethylamino)benzamide, (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1- methylethylamino)benzamide, or (R)-N-(4-chloro-3-methoxybenzyl)-5-cyano-2-(hydroxy-1- methylethylamino)benzamide, or a salt thereof.
9. A compound of Claim 1 for use as a medicament.
10. A process for preparing a compound of the formula : O sali 0 7 NH R R* wherein R! is hydrogen atom or a halogen atom; : R2 is an electron withdrawing group; R3 is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower
N | ~ . x t ’
alkyl; A is a lower alkylene group; R4 is a lower alkoxy group, a substituted or unsubstituted, saturated or unsaturated heterocyclic group, an amino group optionally substituted with halo{lower)alkyl or lower alkyl, a group -CH2-R5 wherein RS is a cycloalkyl group or an unsaturated heterocyclic group, or a group -CRSR’R® wherein R6 and R7 are each independently carboxy group, a protected carboxy group, a carbamoyl group optionally substituted with lower alkyl, or a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or an aryloxycarbonyl, or R6 and R7 together with the carbon atom to which R® and R? are attached may form a substituted or unsubstituted,
\ PY . B
Cs WO 99/54284 PCT/JP99/02028 saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and R8 is hydrogen atom; a lower alkoxy group; or a lower alkyl S group optionally substituted with hydroxy or lower alkoxy; provided that when R¢4 is the group -CRSR7R8 wherein Ré is a lower alkyl group optionally substituted with halogen, R7 is a lower alkyl group optionally substituted with halogen, and R8 is hydrogen atom or a lower alkyl group, or when R# is the group -CHa2-RS wherein RS is the same as the above, R3 should be hydrogen atom, hydroxy group or a cycloalkyl group; and a salt thereof, which comprises (1) reacting a compound of the formula (II) : 0) SAL LOY ONTR? Reg JH (m /~F R2 or its salt, with a compound of (II) HN-R* (mm) or its salt, wherein R!, R2, R3, R* and A are as defined above, or (2) reacting a compound of the formula (IV): O XY oH RT, av) / NH R he
§ - PCT/JP99/02028 or its salt, with a compound of the formula (V]. H,N—A-R® (V) or its salt, S wherein R!, R?, R?3, R¢ and A are as defined above, or (3) subjecting a compound of the formula (VI): O ~ NTRS R'— H C2 (VI) /~ NH, R2 or its salt, to reductive alkylation with a compound of formula (VII): 0) J vi [J 7 R R or its salt, wherein R!, R?, R3, R6, R7 and A are as defined above.
11. A pharmaceutical composition which comprises, as an active ingredient, a compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising a compound of Claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
13. A substance or composition for use in a method of treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo- intestinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel potency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, erectile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence Or Storage of urine 186 AMENDED SHEET
". . PCT/JP99/02028 disorder, said substance or composition comprising a compound of Claim 1, and said method comprising administering said substance or composition.
14. A composition of Claim 11 for use in a method of treatment of erectile dysfunction or impotence.
15. A use of the compound of Claim 1 for the manufacture of a medicament for inhibiting cGMP-PDE.
16. A use of the compound of Claim 1 for the manufacture of a medicament for treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel potency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, erectile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder.
17. A method for the prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, erectile 187 AMENDED SHEET
ZA200005243A 1998-04-20 2000-09-28 Anthranilic acid derivatives as inhibitors of the CGMP-phosphodiesterase. ZA200005243B (en)

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