WO1999021831A1

WO1999021831A1 - Tricyclic compounds as cgmp-pde inhibitors

Info

Publication number: WO1999021831A1
Application number: PCT/JP1998/004429
Authority: WO
Inventors: Teruo Oku; Kozo Sawada; Akio Kuroda; Kazuhiko Ohne
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1997-10-27
Filing date: 1998-10-01
Publication date: 1999-05-06
Also published as: JP2002509553A

Abstract

This invention relates to new tricyclic compounds of formula (I), wherein X is halogen, Y is lower alkoxy, hydroxy or amino, R1 is hydrogen or lower alkyl optionally substituted with a heterocyclic group or aryl, and n is 1 or 2, and its salt, which is useful as a medicament; and to new use of cyclic nucleotide-PDE inhibitors.

Description

D E S C R I P T I O N

TRICYCLIC COMPOUNDS AS CGMP-PDE INHIBITORS

Technical Field

This invention relates to novel tricyclic compounds 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

The compounds, which have an inhibitory activity of cyclic guanosine 3 ' , 5 ' -monophosphate phosphodiesterase (hereinafter described as cGMP-PDE) , were described in the European Patent Publication Nos. 579,496, 534,443, 526,004, 636,626; United State Patent Nos. 3,819,631, 5,294,612, 5,488,055; International Patent Publication Nos. 93/07,124, 94/19,351, 96/32,379; Japan Patent Publication No. 05- 222,000, 07-330,777; and so on.

Disclosure of Invention

This invention relates to novel tricyclic compounds, 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 tricyclic compounds, which have an inhibiting activity of cGMP-PDE. Another object of this invention is to provide a process for production of the tricyclic compounds.

A further object of this invention is to provide a pharmaceutical composition containing, as active ingredients, the tricyclic compounds. Still further object of this invention is to provide a use of the tricyclic compounds for treating or preventing various diseases.

The new tricyclic compounds of this invention can be represented by the following general formula :

wherein X is halogen

Y is lower alkoxy, hydroxy or a ino,

R¹ is hydrogen or lower alkyl optionally substituted with a heterocyclic group or aryl, and n is 1 or 2, and its salt.

The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers .

The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers . The compound of the formula (I) and its salt 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.

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 compound (I) or its salt can be prepared from the compound (II), which are prepared in a similar manner to that of the Preparations and the Examples described in WO 96/32379, by the following process .

Process 1

or its reactive derivative at carboxy group, or its salt wherein R¹, X, Y and n are each as defined above.

In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention 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 provided.

Suitable "lower alkyl" and lower alkyl moiety in the term "lower alkoxy" may be a straight or branched C*-_-Cg alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like, in which preferable one is C*_]_-C^ lower alkyl such as methyl, ethyl, propyl, butyl, or isobutyl.

Suitable "lower alkoxy" may be ethoxy, ethoxy, or the like.

Suitable "aryl" may include phenyl, naphthyl, tolyl, mesityl, xylyl, or the like.

Suitable "halogen" may be fluoro, chloro, bro o or iodo . Suitable "heterocyclic group" may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and preferable one is unsaturated monocyclic heterocyclic group such as

(1) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group 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, 2H-1, 2, 3-triazolyl, etc.], tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.;

(2) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.;

(3) unsaturated, 3 to 7-membered, preferably 5 or 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc.;

(4) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group 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, 1, 2, 5-oxadiazolyl, etc.], etc.;

(5) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; (6) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group 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, 1, 2, 5-thiadiazolyl, etc.]; or the like.

Suitable salts of the compounds (I), (II) and (III) may include pharmaceutically acceptable ones and include a metal salts an alkali metal salt (e.g., sodium salt, pottassiu salt, etc.), an alkali earth salts (e.g., calcim salt, magnecium salt, etc.), an organic base salt (e.g., trietylamine salt, dicyclohexyl salt, etc.), acid addition salts (e.g., hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, p- toluenesulfonate, etc.), or the like.

The processe for preparing the object compound (I) is explained in detail in the following.

Process 1

The compound (I) or its salt can be prepared by reacting a compound (II) or its reactive derivative at the carboxy group, or its salt, with a compound (III) or its reactive derivative at the amino group, or its salt, according to any well known procedure.

Suitable reactive derivative at the amino group of the compound (III) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silylating reagent such as trimethylsilyl chloride, N, O-bis (tri ethylsilyl) acetamide, N-trimethylsilylacetamide, or the like. Suitable reactive derivative of the compound (II) may include an acid chloride, acid azide, an acid anhydride, an activated amide, an activated ester, or the like.

The suitable acid anhydride may include a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkanoic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, etc.), aromatic carboxylic acid (e.g., benzoic acid, chlorobenzoic acid, fluorobenzoic acid, nitrobenzoic acid, etc.), or the like.

Suitable activated amide may be imidazoylamide, 4-substituted imidazoylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide, or the like.

Suitable activated ester may be dimethyliminomethyl + [ (CH3) 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-dirαethylhydroxylamine, l-hydroxy-2H- pyridone, N-hydroxysuccinimido, N-hydroxybenzotriazole, N-hydroxyphthalimide, etc.), or the like.

These reactive derivatives can optionally be selected from them according to the kind of compound (II) to be used. When the compound (II) is used -in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of condensing agent.

Suitable condensing agent may include a carbodiimide (e.g., N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N' - (4- diethylaminocyclohexyl) carbodiimide, N-ethyl-N'- (3- dimethylaminopropyl) carbodiimide or its hydrochloride, etc.) diphenylphosphinic azido, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis (2-oxo-3-oxazolidinyl) - phosphinic chloride, N,N' -carbonyldiimidazole, 2-ethoxy-l- ethoxycarbonyl-1, 2-dihydroquinoline, cyanuric chloride, or the like.

The reaction may be also carried out in the presence of organic or inorganic base such as alkali metal carbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorphorine, or the like. The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol [e.g., methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform,

N,N' -dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The compounds (I) and pharmaceutically acceptable salts thereof of the present invention possess inhibitory activity of cGMP-PDE (especially PDE-V) , relaxant activity of smooth muscle, bronchodilator activity, vasodilative activity, inhibitory activity of smooth muscle cells proliferation, inhibitory activity of allergy, and so on. The compounds (I) and pharmaceutically acceptable salts thereof, therefore, have utility in the treatment and prevention of various diseases, such as angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases (e.g. diabetic glomerulosclerosis, etc.), renal tubulo-intestitinal diseases (e.g. nephropathy induced by FK506, cyclosporins, or the like) , renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g., post-percutaneous transluminal coronary angioplasty) , peripheral vascular disease, stroke, chronic reversible obstructive lung diseases (e.g. bronchitis, asthma (chronic asthma, allergic asthma) ) , allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility (e.g., irritable bowel syndrome), impotence (e.g. organic impotence, psychic impotence, etc.), or diabetic complications (e.g. diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.).

Further, the compounds (I) and pharmaceutically acceptable salts thereof are also useful for the treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder (such as the ones ascribed to nerve regressive affection, inflammation, injury, neoplasm, diabetes ellitus, cerebral vascular accident, surgery, prostatomegaly, urethra relaxation incompetence, dysuria, or the like) .

The invention also includes a new method for the treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder by administering the cGMP-PDE inhibitor or a pharmaceutically acceptable salts thereof, and new use of the cGMP-PDE inhibitor or a pharmaceutically acceptable salts thereof for treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder. And further, it is considered that the compounds, which have a cyclic nucleotide-PDE inhibitory activity, described in the European Patent Publication Nos. 579,496, 534,443, 526,004, 636,626; United State Patent Nos. 3,819,631, 5,294,612, 5,488,055; International Patent Application Nos . 93/07,124, 94/19,351, 96/32379; Japan Patent Publication No. 07-330,777; and so on, are useful for the treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder.

The compound (I) and its salt of the present invention has much advantage, such as stronger activity, more suitable half-life, decreased adverse effect, or the like, compared to the known indole compounds having an infibitory activity of cGMP-PDE, which are shown in the prior arts (e.g., WO 96/32379) .

The compound (I) and its salt can be administered in a pure or impure form and in a single compound or a mixture thereof, preferably, in a pharmaceutical vehicle or carrier. The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the compound (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, intravenous, intramuscular, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solutions (saline, for example) , emulsion, suspensions (olive oil, for example) , and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.

Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans.

For applying this composition to a human, it is preferable to apply it by external (topical) , oral, parenteral, enteral, intravenous, or intramuscular administration. While the dosage of therapeutically effective amount of the compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in case of the systemic administration, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5- 100 mg of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg-* and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.3 mg/body to 1,000 mg/body.

In order to exhibit the usefulness of the present invention, the activity of compound (I) is shown in the following.

Test 1

cGMP-Phosphodiesterase (PDE) assay cGMP-PDE was separated from other isozymes in human platelets by a modification of the method of Thompson et. al . (Cyclic Nucleotide Phosphodiesterase (PDE) , in Methods of Enzymatic analysis, Vol 4, pl27-234, 1984) . In enzyme inhibition assays, the test compounds were dissolved in 30 mM MgCl -6H₂0 DMSO and then diluted with assay buffer (50 mM Tris-HCl, 0.154 mg/ml dithiothreitol and 10 u/ml snake venom, pH 8.0), at final concentrations ranging from 10^-10 to 10^-δM. Assays were performed at 0.1 μM substrate ([^JH]-cGMP) concentration, at 30°C for 10 minutes using enzyme dilutions which gave 10-20% hydrolysis of substrate. Each assay was initiated by addition of substrate and terminated by addition of anion exchange resin (Dowex® 1-X8, 25 μg/mg) followed by centrifugation for 10 minutes (3000 rpm, at 4°C) . R Raaddiiooaaccttiivviittyy ooff ssuuppeerrrnatant (³H-GMP) was assayed by liquid scintillation counting.

The compounds prepared in the present Examples 2 and 4(1) -4 (4), which were selected as the representative compounds of the present invention, had IC₅₀ values below 100 nM. The patents, patent applications and publications cited herein are incorporated by referance.

The following preparations and examples are given for the purpose of illustrating the present invention.

ito be continued on the next page)

Preparation 1

To a solution of N-tert-butoxycarbonyl-3-chloro-4- methylaniline (11.2 g) in tetrahydrofuran (50 ml) was added di-tert-butyl dicarbonate (14.2 g) and 4-dimethylamino- pyridine (452 mg) , and the mixture was heating under reflux for 4 hours. The solvent was evaporated in vacuo and the residue was diluted with ether and washed successively diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from hexane to give N,N-bis (tert-butoxycarbonyl) -3-chloro-4- methylaniline (9.05 g) as crystals.

NMR (CDCla, δ) : 1.43 (18H, s), 2.37 (3H, s), 6.95 (1H, dd, J=2, 8Hz), 7.14 (1H, d, J=2Hz) , 7.19 (1H, d, J=8Hz)

Preparation 2

To a solution of N,N-bis (tert-butoxycarbonyl) -3-chloro- 4-methylaniline (5.0 g) in dichloromethane (50 ml) were added N-bromosuccinimide (2.86 g) and 2, 2 ' -azobis (4-methoxy-2, 4- dimethylvaleronitrile) (180 mg) , and the mixture was heated under reflux for 20 minutes. After evaporation of solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (9:1) to give N,N-bis (tert-butoxycarbonyl) -4-bromomethyl-3-chloroaniline (4.9 g) as crystals.

NMR (CDCI3, δ) : 1.42 (18H, s), 4.57 (2H, s) , 7.04 (1H, dd, J=2.8Hz), 7.22 (1H, d, J=2Hz) , 7.43 (1H, d, J=8Hz )

Preparation 3

A mixture of methyl 3-oxo-l, 2, 3, 4-tetrahydrocyclopent- [b] indole-6-carboxylate (12 g) , N,N-bis (tert-butoxycarbonyl) 4-bromomethyl-3-chloroaniline (24.3 g) and potassium carbonate (21.7 g) in N,N-dimethylformamide (120 ml) was heated under stirring at 40°C for 1 hour. After cooling to 20°C, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and hexane (1:1) to give methyl 4- [4-bis (tert-butoxycarbonyl) amino-2- chlorobenzyl] -3-oxo-l, 2,3, 4-tetrahydrocyclopent [b] indole-6- carboxylate (25 g) as pale yellow crystals. NMR (DMSO-de, δ) : 1.36 (18H, s), 2.98 (2H, m) , 3.11

(2H, m) , 3.82 (3H, s), 5.74 (2H, s),6.51 (1H, d, J=8Hz), 7.03 (1H, d, J=8Hz) , 7.48 (1H, s), 7.78 (1H, d, J=8Hz), 7.94 (1H, d, J=8Hz) , 8.10 (1H, s )

Preparation 4

The following compounds described in (1) to (2) were prepared in a similar manner to that of Preparation 3.

(1) Methyl 4- (2-chloro-4-methoxybenzyl) -3-oxo-l, 2, 3, 4- tetrahydrocyclopent [b] indole-6-carboxylate

NMR (CDCI3, δ) : 3.04 (2H, m) , 3.15 (2H, m) , 3.74 (3H, s), 3.92 (3H, s), 5.62 (2H, s) , 6.58-6.65 (2H, m) , 6.93 (1H, d, J=2Hz), 7.76 (1H, d, J=8Hz) , 7.84 (1H, d, J=8Hz), 8.12 (1H, s)

(2) Mέthyl 9- (2-chloro-4-methoxybenzyl) -8-0x0-5, 6,7, 8- tetrahydrocarbazole-2-carboxylate

NMR (CDCI3, δ) : 2.28 (2H, m) , 2.67 (2H, m) , 3.08 (2H, m) , 3.72 (3H, s) , 3.92 (3H, s) , 5.88 (2H, s) , 6.24 (1H, d, J=8Hz), 6.53 (1H, dd, J=2.8Hz) , 6.97

(1H, d, J=2Hz), 7.72 (1H, d, J=8Hz) , 7.82 (1H, d, J*=8Hz), 8.01 (1H, s)

Preparation 5 To a solution of methyl 9- (2-chloro-4-methoxybenzyl) -8- oxo-5, 6, 7, 8-tetrahydrocarbazole-2-carboxylate (100 mg) in dichloromethane (4 ml) was added a 1M solution of boron tribromide in dichloromethane (1.0 ml) and the resulting mixture was stirred at 0°C for 1 hour. After evaporation of solvent, the residue was diluted with a mixture of chloroform and methanol. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with ether to give methyl 9-(2-chloro- 4-hydroxybenzyl) -8-oxo-5, 6, 7, 8-tetrahydrocarbazole-2- carboxylate (91 mg) as a solid.

NMR (DMSO-de, δ) : 2.19 (2H, m) , 2.63 (2H, ) , 3.07 (2H, m) , 4.84 (3H, s) , 5.82 (2H, s), 6.09 (1H, d, J=8Hz), 6.52 (1H, dd, J=2, 8Hz) , 6.89 (1H, d, J=2Hz), 7.69 (1H, d, J=8Hz) , 7.90 (1H, d, J=8Hz) , 8.01 (1H, s)

Preparation 6

To a suspension of methyl 4- [4-bis (tert-butoxycarbonyl) amino-2-chlorobenzyl] -3-oxα-l, 2, 3, 4-tetrahydrocyclo- pent [b] indole-6-carboxylate (25.1 g) in ethanol (850 ml) was added IN sodium hydroxide (133 ml) , and the mixture was heated at 65°C for 90 minutes. After evaporation of solvent, the residue was diluted with IN hydrochloric acid (135 ml) and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of solvent, the residue was triturated with ether to give 4- (4-tert-butoxycarbonylamino-2-chlorobenzyl) -3-oxo-l , 2, 3, 4-tetrahydrocyclopent [b] indole-6-carboxylic acid (20.7 g) as crystals. NMR (DMSO-dβ, δ) : 1.44 (9H, s), 2.98 (2H, m) , 3.10 (2H, m) , 5.62 (2H, s),6.60 (1H, d, J=8Hz) , 7.18 (1H, d, J=8Hz), 7.68 (1H,. s) , 7.73 (1H, d, J=8Hz) , 7.87 (1H, d, J=8Hz), 8.03 (1H, s) , 9.54 (1H, s ) Preparation 7

The following compounds described in (1) to (3) were prepared in a similar manner to that of Preparation 6.

(1) 4- (2-Chloro-4-methoxybenzyl) -3-oxo-l,2, 3, 4-tetrahydro- cyclopent [b] indole-6-carboxylic acid

NMR (CDCI3, δ) : 3.06 (2H, m) , 3.17 (2H, m) , 3.73 (3H, s), 5.62 (2H, s), 6.60-6.66 (2H, m) , 6.94 (1H, d, J=2Hz), 7.77 (1H, d, J=8Hz) , 7.86 (1H, d, J=8Hz) , 8.12 (1H, s)

(2) 9- (2-Chloro-4-methoxybenzyl) -8-oxo-5, 6, 7, 8-tetrahydro- carbazole-2-carboxylic acid

NMR (DMS0-d₆, δ) : 2.20 (2H, m) , 2.63 (2H, ) , 3.08 (2H, m) , 3.71 (3H, s) , 5.86 (2H, s) , 6.17 (1H, d,

J=8Hz), 6.70 (1H, dd, J=2, 8Hz) , 7.10 (1H, d, J=2Hz), 7.72 (1H, d, J=8Hz) , 7.87 (1H, d, J=8Hz), 7.97 (1H, s)

(3) 9- (2-Chloro-4-hydroxybenzyl) -8-0x0-5, 6,7, 8-tetrahydro- carbazole-2-carboxylic acid

NMR (DMSO-de, δ) : 2.19 (2H, m) , 2.62 (2H, m) , 3.06 (2H, ) , 5.82 (2H, s), 6.10 (1H, d, J=8Hz) , 6.51 (1H, dd, J=2,8Hz), 6.89 (1H, d, J=2Hz) , 7.72 (1H, d, J=8Hz), 7.87 (1H, d, J=8Hz) , 7.96 (1H, s)

Example 1

To a stirring solution of 4- (4-tert-butoxycarbonyl- amino-2-chlorobenzyl) -3-oxo-l, 2, 3, 4-tetrahydrocyclopent [b] - indole-6-carboxylic acid (20.7 g) in N,N-dimethylformamide (140 ml) were added 1-hydroxybenzotriazole (85 mg) , 28% ammonia (5 ml) and 1- (3-dimethylaminopropyl) -3-ethyl- carbodiimide hydrochloride (14 g) at 0°C. After stirring at 25°C o,ver night, the reaction mixture was diluted with water and IN hydrochloric acid (50 ml) . The precipitates were collected by filtration, washed with water and triturated with methanol to give 4- (4-tert-butoxycarbonylamino-2- chlorobenzyl) -3-oxo-l, 2, 3, 4-tetrahydrocyclopent [b] indole-6- caboxamide (18.8 g) as colorless crystals.

NMR (DMSO-d₆, δ) : 1.44 (9H, s) , 2.97 (2H, m) , 3.09 (2H, m) , 5.57 (2H, s),6.43 (1H, d, J=8Hz) , 7.14 (1H, d, J=8Hz) , 7.39 (1H, br.s), 7.68 (1H, s), 7.70 (1H, d, J=8Hz), 7.84 (1H, d, J=8Hz) , 7.99 (1H, br.s), 8.02 (1H, s), 9.53 (1H, s)

Example 2

To a suspension of 4- (4-tert-butoxycarbonylamino-2- chlorobenzyl) -3-oxo-l, 2, 3, 4-tetrahydrocyclopent [b] indole-6- caboxamide (18.8 g) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) , and the mixture was heated at 35°C for 150 minutes. After evaporation of solvent, the residue was diluted with IN sodium hydroxide (200 ml) , and the resulting solid was filtered and washed succesively with water and methanol. Recrystallization from a mixture of N,N' -dimethylformamide and ethanol gave 4- (4-amino-2- chlorobenzyl) -3-oxo-l, 2, 3, 4-tetrahydrocyclopent [b] indole-6- caboxamide (14.3 g) as crystals, mp : 293 - 295°C

NMR (DMSO-ds, δ) : 2.96 (2H, m) , 3.06 (2H, m) , 5.35 (2H, s), 5.46 (2H, s) , 6.33 (2H, s ), 6.62 (1H, s) ,

7.38 (1H, br.s), 7.68 (1H, d, J=8Hz ), 7.81 (1H, d, J=8Hz), 7.99 (1H, br.s), 8.02 (1H, s)

Example 3 To a suspension of 4- (4-amino-2-chlorobenzyl) -3-oxo-

1,2, 3, 4-tetrahydrocyclopent [b] indole-6-carboxamide (46 mg) in methanol was added concentrated hydrochloric acid (0.05 ml), and the mixture was evaporated in vacuo. The residue was triturated with methanol to give 4- (4-amino-2-chlorobenzyl) - 3-oxo-l, 2,3, 4-tetrahydrocyclopent [b] indole-6-caboxamide hydrochloride (39 mg) as a solid, mp : 256°C (dec.)

NMR (DMSO-ds, δ) : 2.97 (2H, m) , 3.08 (2H, m) , 5.52 (2H, s), 6.38 (1H, d, J=8Hz), 6.59 (1H, dd, J=2, 8Hz) , 6.92 (1H, d, J=2Hz), 7.39 (1H, br.s), 7.70 (1H, d,

J=8Hz), 7.84 (1H, d, J=8Hz) , 8.01 (1H, br.s), 8.03 (1H, s)

Example 4 The following compounds described in (1) to (4) were prepared in a similar manner to that of Example 1.

(1) 4- (2-Chloro-4-methoxybenzyl) -3-oxo-N- (2-thienylmethyl) - 1,2,3, 4-tetrahydrocyclopent [b] indole-6-carboxamide mp : 184-186°C

NMR (DMSO-ds, δ) : 2.98 (2H, m) , 3.12 (2H, m) , 3.71 (3H, s), 4.62 (1H, d, J=7Hz), 5.60 (2H, s) , 6.47 (1H, d, J=8Hz), 6.76 (1H, dd, J=2, 8Hz) , 6.94 (1H, m) , 7.00 (1H, m) , 7.10 (1H, d, J=2Hz) , 7.37 (1H, m) , 7.70 (1H, d, J=8Hz), 7.86 (1H, d, J=8Hz) , 8.03

(1H, s) , 9.07 (1H, m)

(2) 4- (2-Chloro-4-methoxybenzyl) -3-oxo-N-propyl-l, 2, 3, 4- tetrahydrocyclopent [b] indole-6-carboxamide mp : 187-189°C

NMR (DMSO-ds, δ) : 0.89 (1H, t, J=7Hz) , 1.52 (2H, m) , 2.96 (2H, ) , 3.10 (2H, m) , 3.23 (2H, q, J=7Hz) , 3.72 (3H, s), 5.59 (2H, s), 6.47 (1H, d, J=8Hz) , 6.78 (1H, dd, J=2,8Hz), 7.09 (1H, d, J=2Hz) , 7.18 (1H, d, J=8Hz), 7.35 (1H, d, J=8Hz), 7.98 (1H, s),

8.49 (1H, m)

(3) 9- (2-Chloro-4-hydroxybenzyl) -8-oxo-N- (3-pyridylmethyl) - 5,6,7, 8-tetrahydrocarbazole-2-carboxamide mp : 244-246°C NMR (DMSO-ds, δ) : 2.19 (2H, m) , 2.59 (2H, m) , 3.06 (2H, m) , 4.49 (1H, d, J=7Hz) , 5.78 (2H, s), 5.98 (1H, d, J=8Hz), 6.50 (1H, dd, J=2, 8Hz) , 6.88 (1H, d, J=2Hz) , 7.36 (1H, m) , 7.68-7.72 (2H, m) , 7.87 (1H, d, J=8Hz), 7.98 (1H, s) , 8.45 (1H, m) , 8.53 (1H, m) , 9.12 (1H, m)

(4) 9- (2-Chloro-4-methoxybenzyl) -N- (2-furfuryl) -8-oxo- 5,6,7, 8-tetrahydrocarbazole-2-carboxamide mp : 185-18β°C

NMR (DMSO-ds, δ) : 2.29 (2H, quintet, J=7Hz), 2.67 (2H, t, J=7Hz), 3.09 (2H, t, J=7Hz), 3.74 (3H, s), 4.65 (2H, d, J=7Hz), 5.89 (2H, s), 6.26-6.37 (3H, ) , 6.45 (1H, t, J=7Hz), 6.54 (1H, dd, J=7,4Hz), 6.94 (1H, d, J=4Hz), 7.39 (1H, s), 7.62 (2H, AB,

J=8Hz), 7.80 (1H, s) Mass : 463 (M+H)⁺, 85 (bp)

Example 5 To a suspension of 4- (4-amino-2-chlorobenzyl) -3-oxo-

1, 2, 3, 4-tetrahydrocyclopenta [b] indole-β-carboxamide (10.5 g) in ethanol (250 ml) was added methanesulfonic acid (3.14 g) , and the mixture was refluxed for 30 minutes. The resulting mixture was filterd and washed with ethanol to give 4- (4-amino-2-chlorobenzyl) -3-oxo-l, 2, 3, 4-tetrahydrocyclo- penta [b] indole-6-caboxamide methanesulfonate (13.0 g) as a solid. mp : 240°C(dec.)

NMR (DMSO-ds, δ) : 2.36 (3H, s), 2.97 (2H, m) , 3.08 (2H, m) , 5.52 (2H, s) , 6.39 (1H, d, J=8Hz) , 6.71 (1H, dd, J=2, 8Hz), 7.03 (1H, d, J=2Hz), 7.39 (1H, br.s), 7.70 (1H, d, J=8Hz) , 7.85 (1H, d, J=8Hz) , 8.01 (1H, br.s), 8.03 (1H, s)

Example 6 To a suspension of 4- (4-amino-2-chlorobenzyl) -3-oxo- 1, 2, 3, 4-tetrahydrocyclopenta [b] indole-6-carboxamide (10.0 g) in ethanol (350 ml) was added IM sulfuric acid (22.6 ml), and the mixture was refluxed for 15 minutes. The resulting mixture was filterd and washed with ethanol to give bis [4- (4-amino-2-chlorobenzyl) -3-oxo-l, 2,3, -tetrahydrocyclop enta [b] indole-6-carboxamide] sulfate (10.8 g) as a solid, mp : 240°C(dec.)

NMR (DMSO-ds, δ) : 2.97 (2H, m) , 3.04 (2H, m) , 5.55 (2H, s), 6.39 (1H, d, J=8Hz), 6.65(1H, d, J=8Hz) , 6.98 (1H, s), 7.40 (1H, br.s), 7.70 (1H, d, J=8Hz) ,

7.85 (1H, d, J=8Hz), 8.01 (1H, br.s), 8.03 (1H, s)

Claims

C L A I M S

A compound of the formula

wherein X is halogen

Y is lower alkoxy, hydroxy or amino,

A compound according to claim 1, wherein R¹ is hydrogen.

A compound avvording to claim 2, wherein X is chloro.

A compound avvording to claim 2, wherein n is 1.

A process for preparing the compound of the formula

wherein X is halogen

Y is lower alkoxy, hydroxy or amino, RI is hydrogen or lower alkyl optionally substituted with a heterocyclic group or aryl, and n is 1 or 2, or its salt, by reacting a compound of the formula :

[wherein X, Y and n are each as defined above] , or its reactive derivative at carboxy group, or its salt, with a compound of the formula :

R¹-NH2

[wherein R¹ is as defined above] , or its reactive derivative at the amino group, or its salt .

6. A pharmaceutical composition comprising the compound of the claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non- toxic carrier or excipient.

7. A compound of claim 1 for use as a medicament.

8. A use of the compound of claim 1 for the manufacture of a medicament for inhibiting cGMP-PDE.

9. A use of the compound of the claim 1 for the manufacture of a medicament for treatment and prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal 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, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder.

10. A method for the treatment and prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal 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, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder, by administering the compound of claim 1.

11. A use of a cGMP-PDE inhibitor, or its pharmaceutical acceptable salt, for the manufacture of a medicament for the treatment and prevention of micturition disorder, or incontinence or storage of urine disorder.

12. A method for the treatment and prevention of micturition disorder, or incontinence or storage of urine disorder, by administering the cGMP-PDE inhibitor.