CZ20002137A3 - Substances opening potassium passages - Google Patents

Abstract

Compounds of formula I assist in the opening of potassium channels effective in preventing disease or pro improving the disease. Also included are formulations opening potassium channels and ways of opening potassium channels in mammals.

Description

SUBSTANCES OPENING POTASSIUM CHANNELS

Technical field

The novel dihydropyridine compounds and their derivatives can open potassium channels and are thus effective in the treatment of various diseases.

BACKGROUND OF THE INVENTION

Potassium channels play an important role in regulating the irritability of cell membranes. When potassium channels are opened, changes in the electrical potential across the cell membrane result in a more polarized state. Many diseases or conditions can be treated with therapeutic agents that are capable of opening these potassium channels. See K. Lawon, Pharmacol. Ther., V. 70, 39-63; (1996) D. R. Gehlert et al., Prog. Neuro-Psychopharmacol & Biol. Psychiat., V. 18, 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28, 95-127 (1993); J.E. Freedman et al., The Neuroscientist, v. 145-152 (1996). Such conditions or diseases include asthma, epilepsy, hypertension, impotence, migraine, pain, urinary incontinence, stroke, Raynaud's syndrome, eating disorders, intestinal functional disorders and neurodegeneration.

Potassium channel openers also act as smooth muscle relaxants. Since urinary incontinence can arise from spontaneous uncontrolled bladder smooth muscle contractions, it provides the ability of potassium channel opener to hyperpolarize bladder cells and relax bladder smooth muscle, a method for improving or preventing urinary incontinence.

Patent applications WO 9408966 and EP 0539154 A1 disclose a family of acridinedione and quinolone compounds which are patented, effective in the treatment of urinary incontinence. These compounds belong to the chemical group of dihydropyridines. The compounds of the present invention are chemically different from those disclosed in patent applications WO 94/08966 and EP 0539154 A1 because they have at least one sulfonyl group attached at the 3-position of the dihydropyridine ring.

Dihydropyridines of different chemical structures may be biologically active in different ways. For example, U.S. Patent No. 4,879,384 discloses a group of thiacycloalkeno [3,2-b] pyridines which belong to the group of dihydropyridines and belong to

• · * - * · ¹¹ · »·, -s. · <- «* <. Calcium channel antagonists. The compounds of the present invention are chemically different from those disclosed in patent application 4,879,384 because they do not have carboxylic acid derivatives attached at the 3-position of the dihydropyridine ring.

Therefore, the compounds of the present invention are chemically different from the prior art by hyperpolarizing cell membranes, opening potassium channels, relaxing smooth muscle cells, inhibiting bladder contractions, and are effective in treating diseases that can be improved by opening potassium channels.

SUMMARY OF THE INVENTION

The present invention relates to a compound having formula (I)

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein R ¹ is alkyl;

R ² is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; index n is 0-2;

A is selected from the group consisting of hydrogen, alkyl and -X-R;

R ³ is alkyl or haloalkyl;

X is -C (O) - or -S (O) _P -, wherein the index p is 1-2;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl or haloalkyl; or ^R! and R ⁵ together with the ring to which they are attached form a 5-membered, 6-membered or 7-membered ring that contains a sulfur atom, with 1-2 double bonds and 0-2 oxo substituents; or the substituents A and R ⁴ taken together form with the ring to which they are attached a ring selected from the group consisting of a 5-membered, 6-membered or 7-membered carbocyclic ring of 1 - 2 double bonds and 0-1 oxo substituents and a 5-membered, 6-membered or 7-membered ring containing a sulfur atom with 1 - 2 double bonds and 0-2 oxo substituents, provided that at least one of the substituents R ¹ and R ⁵ or A and R ⁴ form a ring.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds having formula (I)

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein R ¹ is alkyl;

R ² is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; index n is 0-2;

A is selected from the group consisting of hydrogen, alkyl and -X-R;

R ³ is alkyl or haloalkyl;

X is -C (O) - or -S (O) p - wherein the index p is 1-2;

R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl or haloalkyl; or R ¹ and R ⁵ together with the ring to which they are attached form a 5-membered, 6-membered or 7-membered ring containing a sulfur atom with 1-2 double bonds and 0-2 oxo substituents; or the substituents A and R ⁴ taken together form to the ring to which they are attached a ring selected from the group consisting of a 5-membered, 6-membered or 7-membered carbocyclic ring with 1-2 double bonds and 0-1 oxo substituents az A 5-membered, 6-membered or 7-membered ring containing a sulfur atom with 1 - 2 double bonds and O - 2 oxo substituents, provided that at least one of the substituents R ¹ and R ⁵ or A and R ⁴ form a ring.

In another embodiment, the present invention provides compounds of formula (II)

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, R is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; n is 1 or 2;

X is selected from the group consisting of -CH 2 -, -C (O) -, -S (O) - or -S (O) ₂ -; and n and n are independently 1-3.

In another embodiment, the present invention provides pharmaceutical compositions comprising compounds having formulas (I) and (II).

In another embodiment, the present invention provides methods of treatment comprising administering an effective amount of compounds having formulas (I) and (II).

Explanation of technical terms

The term "alkanoyl" as used herein refers to an alkyl group attached to the parent molecular moiety through a carbonyl (-C (O) -) group. Examples of alkanoyl include acetyl, propionyl, and the like.

The term "alkanoyloxy" as used herein refers to an alkanoyl group attached to the parent molecule via an oxygen atom.

• · »

The term "lower alkyl" or "alkyl" as used herein refers to branched or unbranched chains of alkyl radicals having 1 to 10 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.

The term "alkenyl" as used herein refers to a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by removal of a single hydrogen atom. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl, and the like.

The term "alkylene" denotes a divalent group obtained from a straight or indirect saturated hydrocarbon chain by removal of two hydrogen atoms. Examples of the alkylene group include, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.

The term "alkenylene" refers to a divalent group obtained from a straight or indirect hydrocarbon chain containing at least one carbon-carbon double bond. Examples of alkenylene include -CIT CH-, -CH ₂ CH = CH-, -C (CH ₃ ) = CH-, -CH ₂ CH = CHCH ₂ -, and the like.

The term "alkylsulfinyl" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl (-S (O)) group. Examples of alkylsulfinyl include methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, and the like.

The term "alkylsulfonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group (-S (O) ₂ ). Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, and the like.

The term "alkynylene" as used herein refers to a divalent group obtained by the removal of two hydrogen atoms from a branched or unbranched chain of a carbon-carbon-containing acyclic hydrocarbon triple bond. Examples of alkynylene include -GC-, -C =C-CH ₂ -, -QC-CH (CH 3) -, and the like.

The term "alkoxy" as used herein refers to R ⁴¹ O-, wherein R ⁴¹ is a lower alkyl group as defined above. Examples of the alkoxy group include, but are not limited to, ethoxy, tert-butoxy, and the like.

The term "alkoxyalkoxy" as used herein refers to an alkoxy group attached to the parent molecular moiety through an alkoxy group. Examples of the alkoxyalkoxy group include an ethoxymethoxy group, a propoxymethoxy group, and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined above. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

The term "alkoxycarbonyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and the like.

The term "alkynyl" as used herein refers to a monovalent branched or unbranched group of two or more carbon atoms obtained from at least one alkyne.

The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or more aromatic rings. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl, and the like. The aryl groups of the present invention may be optionally substituted with 15 substituents independently selected from alkanoyl, alkenyl, alkoxy, alkoxyalkoxy, alkyl, alkylsulfinyl , alkylsulfonyl, alkoxycarbonyl, alkynyl, aryl, azido groups, carboxy groups, cyano groups, halogen, haloalkyl, haloalkoxy groups, heteroaryl, hydroxy groups, nitro groups, thioalkoxy groups, -C (O) NR ⁶ R ⁷ (wherein R ⁶ substituents and R ⁷ are independently hydrogen, alkyl or aryl), thioureido, ureido, and S (O) p NR ⁶ R ⁷ In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl

The term "arylalkyl" as used herein refers to an aryl group, as defined herein, appended to a lower alkyl radical, e.g., benzyl, and the like.

The term "azido," as used herein, refers to -N 3.

The term "carboxy," as used herein, refers to -CO 2 H.

The term "cyano" as used herein refers to -CN.

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3-10 carbon atoms and 1-3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbomyl, adamantyl, and the like. Cycloalkyl groups may include: be unsubstituted or substituted by one, two or three substituents independently selected from the group consisting of lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide.

The term "cycloalkylalkyl," as used herein, refers to a cycloalkyl group attached to a lower alkyl radical, including, but not limited to, cyclohexylmethyl.

The term "halogen" or "halo" as used herein refers to I, Br, Cl or F.

• · · t t t t t t t t * * * * * * · ·

The term "haloalkyl" as used herein refers to a lower alkyl radical as defined above bearing at least one halogen substituent, e.g., chloromethyl, fluoroethyl, 1-chloro-2-fluoropropyl, 2,3-dichloropropyl or trifluoroethyl, and the like.

The term "haloalkoxy" as used herein refers to a lower alkoxy radical as defined above bearing at least one halogen substituent, e.g., chloromethoxy, fluoroethoxy, 1-chloro-2-fluoropropoxy, 2,3-dichloropropoxy or trifluoroethoxy, and the like.

The term "heteroaryl" as used herein refers to a 5-membered, 6-membered or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 5-membered ring has two double bonds and the 6-membered and 7-membered ring has three double bonds. The term "heteroaryl" also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heteroaryl rings is fused to one or two rings independently selected from the group consisting of aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring and other monocyclic rings. heterocyclic rings such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofiiryl, benzothienyl, and the like. The heteroaryl groups of the present invention may be optionally substituted with 1-4 substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkyl, alkylsulfinyl , alkylsulfonyl, alkoxycarbonyl, alkynyl, aryl, azido groups, carboxy groups, cyano groups, halogen, haloalkyl, haloalkoxy groups, heteroaryl, hydroxy groups, hydroxyalkyl, nitro groups, thioalkoxy groups, -C (O) NR ⁶ R ⁷ (wherein substituents R ⁶ and R ⁷ are independently hydrogen, alkyl or aryl), thioureido, ureido, and -S (O) _P NR ⁶ R ⁷ . Examples of heteroaryl include, but are not limited to, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, benzothiyl, thiazolyl, benzoxazolyl, furryl, thienyl, benzoxadiazole and benzothiadiazole.

The terms "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein refer to any 3-membered or 4-membered ring containing a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur; or a 5-membered, 6-membered or 7-membered ring containing one, two or three nitrogen atoms; one nitrogen atom and one sulfur atom; or one nitrogen atom and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6-membered and 7-membered ring has 0-3 double bonds. "Heteroaryl" as defined above falls under "heterocycle". The nitrogen heteroatoms may optionally be quaternized. Term •• F · * v, · *, *, '*, ··' ***,

"Heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a cyclohexane ring or other heterocyclic ring and the like. Heterocycles include: azetidinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl, isoquinolinyl.

Heterocycles may be unsubstituted or monosubstituted, disubstituted or trisubstituted with substituents independently selected from the group consisting of hydroxy, halogen, oxo (= O), alkylimino (R * N = wherein R * is lower alkyl), amino groups, alkylamino groups, dialkylamino groups, alkoxy groups, alkoxyalkoxy groups, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO 3 H and lower alkyl. In addition, the nitrogen-containing heterocycles may be N-protected.

The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkyl" as used herein refers to a lower alkyl radical as defined above bearing at least one hydroxy substituent, eg, hydroxymethyl, hydroxyethyl, 1-hydroxy-2-hydroxypropyl, 2,3-dihydroxypropyl, and the like.

The term "nitro" as used herein refers to -NO2.

The term "thioalkoxy," as used herein, refers to R 70 S- wherein R is lower alkyl.

Examples of the thioalkoxy group include, but are not limited to, a methylthio group, an ethylthio group, and the like.

The term "thioureido" as used herein refers to -NH-SC-NH 2.

The term "ureido" as used herein refers to -NH-CO-NH 2.

The term "pharmaceutically acceptable prodrugs", as used herein, refers to those prodrugs of the compounds of the present invention which, to the extent of reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without causing toxicity, irritation, allergic reactions , etc., proportional to the reasonable benefit / risk ratio and effective for their intended use, as well as the zwitterion forms of the compounds of the present invention, where possible. The prodrugs of the medicaments of the present invention can be rapidly transformed in vivo to the parent compound of the above formula, e.g. Complete information can be found in T.Higuchi and V. Stella, Pro-drugs and Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference.

• *

The compounds of the present invention may exist as sterioisomers where asymmetric or chiral centers are present. These compounds are designated "R" and "S" according to their configuration of substituents on the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. The individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparing a racemic mixture followed by resolution into enantiomers, a technique well known to the skilled artisan. Such methods of resolution into enantiomers are such as: (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary group, or (2) directly separating the mixture of optical enantiomers on chiral chromatography columns.

Representative compounds of the present invention include, but are not limited to:

3,4,6,7,8,10-hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-Fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-chlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3,4-difluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- [3-Fluoro-5- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ;

10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ;

3,4,6,7,8,10-Hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

9- (3-cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

3,4,5,6,7,9-hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

«<1

9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone;

4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4 (3-nitrophenyl) -5 (1H) -quinolinone;

4.6.7.8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone;

4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4.6.7.8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3 (methylsulfonyl) -5 (1H) -quinolinone;

4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone;

4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

9- (3-cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide,

9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (4-methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide;

8- (3-bromo-4-fluorophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide;

1- [8- (3,4-dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone;

[8- (4-chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone;

10- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bis-thiopyrano [3,2-b: 2 ', 3'-e] 1,1,9,9-tetraoxide ] pyridine;

3,4,6,7,8,10-Hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-chlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3,4-difluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- [3-Fluoro-5- (trifluoromethyl) phenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ;

10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ;

3,4,6,7,8,10-Hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (3-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

10- (4-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide;

9- (3-cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrothieno [3,2b] quinolin-8 (2H) -one, 1,1-dioxide;

3,4,5,6,7,9-hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3,4-Difluorophenyl) -3,4,5,6,7,9-hexahydrothieno 1,1-dioxide

[3,2-b] quinolin-8 (2H) -one;

9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide;

4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4.6.7.8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- (3-nitrophenyl) -5 (1H) quinolinone;

4.6.7.8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone;

4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4.6.7.8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3- (methylsulfonyl) -5 (1H) -quinolinone;

4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone;

9- (3-cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one;

9- (4-methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide;

8- (3-Bromo-4-fluorophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide;

1- [8- (3,4-Dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone;

1- [8- (4-Chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl) ethanone ;

10- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bisthiopyrano [3,2-b: 2 ', 3'-pyridine] 1,1,9,9-tetraoxide ;

9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

8- (4-chloro-3-nitrophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine, 1,1,7,7-tetraoxide;

8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-pyridine] 1,1,7,7-tetraoxide;

10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H, 5H-dithiopyrano [3,2-b: 2H, 3H- e] pyridine;

3,4,5,6,7,9-hexahydro-9- (3-nitrophenyl) cyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide;

8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

2,3,4,5,6,8-hexahydro-8- (3-nitrophenyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

3,4,6,7,8,10-hexahydro-10- (3-nitrophenyl) -2H, 5H16-dithiopyrano [3,2b: 2H, 3e-e] pyridine 1,1,9,9-tetraoxide;

8- (3,4-dichlorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide;

8- (2-Cyano-4-pyridinyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (3-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2b; 1,1,7,7-tetraoxide] 1,1,7,7-tetraoxide 2 ', 3'-e] pyridine;

8- (4-bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide;

8- (5-bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide ;

2,3,4,5,6,8-Hexahydro-8- (5-nitro-3-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide ;

2,3,4,5,6,8-hexahydro-8- (5-nitro-2-furyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-76-one 1,1-dioxide,

8- (3,4-Dibromophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

2,3,4,5,6,8-Hexahydro-8- (3-nitrophenyl) dithieno [3,2-b; 2 ', 3'-e] pyridine

8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine, 1,1,7,7-tetraoxide;

8- (3,4-Chloro-phenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-pyridine] 1,1,7,7-tetraoxide;

8- (4-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (3,4-Difluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide;

8- (4-chloro-3-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-a] pyridin-7-one 1,1-dioxide;

9- (3-chloro-4-fluorophenyl) -2,3,5,6,7,9-hexahydro-thieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide;

8- (3-Cyano-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine, 1,1,7,7-tetraoxide;

(+) (9R) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) 1,1-dioxide -one;

(-) (9S) -9- (3-Bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) 1,1-dioxide -one;

8- (2,1,3-Benzoxadiazol-5-yl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-1,1-dioxide -one;

(-) (8S) -8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] 1,1-dioxide pyridin-7-one;

(+) (8R) -8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one ;

9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide;

9- (4-fluoro-3-iodophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide;

8- (4-fluoro-3-iodophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide;

(+) 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3- e] pyridin-8 (2H) -one;

(-) 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one;

(+) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) 1,1-dioxide -one;

(-) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) 1,1-dioxide -one;

(+) (9R) -9- (3,4-Dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ;

1,1-Dioxide (-) (9S) -9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one;

(+) (9R) -9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,91,1-hexahydrothieno [3,2-b] dioxide quinolin-8 (4H) -one;

(-) (9S) -9- (2,1,3-benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) - onu;

(+) (9R) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one 1,1-dioxide ;

(-) (9S) -9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) - onu;

11- (3-bromo-4-fluorophenyl) -2,3,4,5,7,8,9,11-octahydrothiepino [3,2-b] quinolin-10 (6H) -one, 1,1-dioxide; and

10- (3-bromo-4-fluorophenyl) -2,3,4,5,6,7,8,10-octahydro-9H-cyclopenta [b] thiepino [2,3-e] pyridin-9-one or their pharmaceutically acceptable salts, esters, amides or prodrugs.

Preparation of the compounds of the present invention

The compounds and processes of the present invention will be better understood in connection with the following synthesis schemes and methods which illustrate the means by which the compounds of the present invention can be prepared.

The compounds of the present invention can be prepared by a variety of synthetic methods. Representative procedures are shown in Schemes 1-2.

Scheme 1

(Q) n 2 R , _f ^A -. ^rVS yt ^a * r ⁵ ^ o CHO (and) (ii) (iii) AND

As shown in Scheme 1, dihydropyridines of formula (I) are prepared by heating ketone (i) with aldehyde (ii) and enamine (iii) in a protic solvent such as ethyl alcohol.

• 9 • 9

In the case where R ¹ and R ⁵ form a 5-membered ring, an additional step in which the mixture is heated may be required to obtain the product.

As shown in Scheme 2, for those examples where X is S (O) _P , wherein p is 2, R ^{1 = x} R ³ and R ⁴ = R ⁵ , dihydropyridines of formula (I) are prepared by heating 2 equivalents of ketone (i) with 1 equivalent of aldehyde (ii) and concentrated ammonium hydroxide in a protic solvent such as ethyl alcohol.

The following methods are intended to be illustrative and are not intended to limit the scope of the invention, which is fully defined in the appended claims. Furthermore, all citations are added as a reference.

Scheme 3

The compounds in the examples of the present invention having a chiral center and thus in racemic form were separated into the individual enantiomers by the methods outlined in Scheme 3. Racemic compounds of formula (I) were reacted with potassium tert-butoxide (1 equivalent) ) in tetrahydrofuran and then with chloroformate

8-phenylmenthylcarbamates to obtain a mixture of diastereomeric 8-phenylmenthylcarbamates (i) and (ii). The diastereomers (i) and (ii) are separated on a silica gel column, and the 8-phenylmenthol portion is removed by treatment with sodium methoxide in methanol to give said simple enantiomers.

In addition to using the method illustrated in Scheme 3, the individual enantiomers of the compounds of the present invention were also separated by chiral chromatography.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 1,1-dioxide Prepare a solution of 3- nitrobenzaldehyde (151 mg, 1.00 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (148 mg, 1.00 mmol) according to the method described in J. Heterocycl. Chem. (1990), 27, 1453 and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol (7 mL) was heated at reflux for 24 hours and cooled. The solid that precipitates is washed with ethanol, dried and triturated with hot methanol to give the desired compound. MS (APCI) m / e 375 (M + H) ^{+, 3} H NMR (DMSO- _d d), 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H) 2.55 (m, 4H), 3.22 (m, 2H), 5.15 (s, 1H), 7.55 (t, 1H), 7.65 (d, 1H), 8.00 ( m, 1H), 9.48 (br s, 1H), Calcd for C, 57.74; H, 4.85; N, 7.48. Found: C, 57.41; H, 4.75; N, 7.39.

Example 2

10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide

3,4-Dichlorobenzaldehyde (175 mg, 1.00 mmol) was treated according to the procedure in Example 1 to give the title compound. MS (APCI) m / e 398 (M + H) ^&lt; ^{+ &gt};, 400 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.06 (dd, 1H), 7.32 (d, 1H), 7.50 (d, 1H), 9.40 (br s, 1H); Anal Calcd for C ₈ H ₁₇ C1 ₂ NO ₃ S: C, 54.28; H, 4.30; N, 3.52. Found: C, 54.13; H, 4.18; N, 3.46.

Example 3

10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (159 mg, 1.00 mmol)) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 382 (M + H) ^&lt; ^{+ &gt};, 384 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.15 (ddd, 1H), 7.26 (m, 3H), 9.38 (br s, 1H); Anal Calcd for C ₈ H ₁₇ C1FNO ₃ S: C, 56.62; H, 4.49; N, 3.67. Found: C, 56.64; H, 4.43; N, 3.57.

Example 4

10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide

3-Bromo-4-fluorobenzaldehyde (203 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the title compound. MS (APCI) m / e 426 (M + H) ^&lt; ^{+ &gt};, 428 (M + H) ^&lt; ^{+ &gt};; ^! 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H) 1.01 (s, 1H), 7.20 (m, 2H), 7.40 (dd, 1H), 9.35 (br s, 1H); Anal Calcd for C ₈ Hi ₇ BrFNO ₃ S: C, 50.71; H, 4.02; N, 3.29. Found: C, 50.69; H, 3.99; N, 3.16.

Example 5

10- (3-Cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 1,1-dioxide

3-Cyanobenzaldehyde (131 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 355 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.07 (s, 1H), 7.45 (t, 1H),

7.52 (s, 1H), 7.54 (dt, 1H), 7.60 (dt, 1H), 9.40 (br s, 1H); Anal Calcd for C ₉ H ₁₈ N ₂ O ₃ S: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.18; H, 5.15; N, 7.83.

Example 6

3,4,6,7,8,10-Hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9- (5H) -one 1,1-dioxide • · < <I <»,

3-Trifluoromethylbenzaldehyde (134 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 398 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSOd 6) 1.74 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.18 (m, 2H) , 5.11 (s, 1H), 7.48 (br s, 4H), 9.40 (br s, 1H); Calcd for C19H18F3NO3S: C, 57.42; H, 4.57; N, 3.52. Found: C, 57.12; H, 4.67; N, 3.39.

Example 7

10- (3,4-Difluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 1,1-dioxide

3,4-Difluorobenzaldehyde (110L, 1.00 mmol) was treated according to the procedure in Example 1 to give the title compound. MS (APCI) m / e 366 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 1H), 2H), 5.02 (s, 1H), 7.02 (m, 1H), 7.10 (m, 1H), 7.26 (dt, 1H), 9.37 (br s, 1H); Calcd for C18H17F2NO3S: C, 59.17; H, 4.69; N, 3.83. Found: C, 58.91; H, 4.70; N, 3.69.

Example 8

10- (3-Bromo-phenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 3-Bromobenzaldehyde (117 mL, 1.00 mmol) was treated according to the procedure of Example 1 to obtain the desired compound. MS (APCI) m / e 408 (M + H) ^{& lt} ; ^{+ &gt};, 410 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 1H), 2H), 5.01 (s, 1H), 7.20 (m, 2H), 7.30 (m, 2H), 9.40 (br s, 1H); Calcd for C 18 H 18 BrNO 5 S: C, 52.95; H, 4.44; N, 3.43. Found: C, 52.91; H, 4.53; N, 3.37.

Example 9

3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin9 (5H) -one 1,1-dioxide

3,4,5-Trifluorobenzaldehyde (160 mg, 1.00 mmol) was treated according to the procedure in Example 1 to give the title compound. MS (APCI) m / e 384 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 1H) 2H), 5.02 (s, 1H), 7.00 (m, 2H), 9.41 (br s, 1H); Calcd for C18H16F3NO3S: C, 56.39; H, 4.21; N, 3.65. Found: C, 56.26; H, 4.27; N, 3.55.

• ·

Example 10

10- [3-Fluoro-5- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2b] quinolin-9 (5H) -one, 1,1-dioxide

3-Fluoro-5-trifluoromethylbenzaldehyde (192 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the title compound. MS (APCI) m / e 416 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m 2H, 5.14 (s, 1H), 7.23 (d, 1H), 7.36 (s, 1H), 7.44 (d, 1H), 9.45 (br s, 1H); Calcd for C19H17F4NO3S: C, 54.94; H, 4.12; N, 3.37. Found: C, 54.84; H, 4.20; N, 3.26.

Example IX

10- (3-Fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide 3-Fluorobenzaldehyde (106) ml, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 348 (M + H) ^&lt; ^{+ &gt};; ^! 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H) ), 5.05 (s, 1H), 6.93 (m, 2H), 7.04 (d, 1H), 7.25 (dt, 1H), 9.35 (br s, 1H); Anal Calcd For C 16 H 18 FNCl 3 S: C, 62.23; H, 5.22; N, 4.03. Found: C, 61.95; H, 5.03; N, 3.89.

Example 12

3,4,6,7,8,10-Hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 1,1-dioxide

Benzaldehyde (102 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the title compound. MS (APCI) m / e 330 (M + H) ^&lt; ^{+ &gt};; 1 HNMR (DMSO-d 6) 1.73 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.18 (m, 2H) 1.03, 5.03 (s, 1H), 7.10 (m, 1H), 7.20 (m, 4H), 9.28 (br s, 1H); Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25. Found: C, 65.57; H, 5.99; N, 4.12.

Example 13

10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2b] quinolin-9 (5H) -one, 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (194 mg, 1.01 mmol) was treated according to the procedure of Example 1 to give the title compound. MS (APCI) m / e 416 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 4H), 2.52 (m, 4H), 3.20 (m, 1H), 2H), 5.09 (s, 1H), 7.38 (dd, 1H), 7.50 (m, 2H), 9.42 (br s, 1H); Calcd for C19H17F4NO3S: C, 54.93; H, 4.12; N, 3.37. Found: C, 54.77; H, 4.16; N, 3.26.

Example 14

3,4,6,7,8,10-Hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 1,1-dioxide

4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 389 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSOd 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.22 (m, 4H), 2.45 (s, 3H), 2.55 (m, 4H) 3.20 (m, 2H); 5.09 (s, 1H); 7.35 (d, 1H); 7.43 (dd, 1H); 7.72 (d, 1H); 9.42 (d, 1H); br s, 1H); Anal Calcd for C ₉ H2oN20 ₅ S * 0.25H ₂ 0: C, 58.07; H, 5.25; N, 7.12. Found: C, 58.21; H, 5.36; N, 6.95.

Example 15

10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide

4-Chloro-3-fluorobenzaldehyde (159 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the title compound. MS (APCI) m / e 382 (M + H) ^&lt; ^{+ &gt};, 384 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 1H), 2H), 5.03 (s, 1H), 7.07 (m, 2H), 7.42 (t, 1H), 9.37 (br s, 1H); Calcd

C ₈ Hi ₇ C1FNO ₃ S: C, 56.62; H, 4.49; N, 3.67. Found: C, 56.36; H, 4.53; N; 3.59.

Example 16

10- (3-Chloro-phenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one

3-Chlorobenzaldehyde (113 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 364 (M + H) ^&lt; ^{+ &gt};, 366 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.18 (m, 2H), 5.02 (s, ιι) I ιι AU 11. »χιιWBWBWMBBWIWr

Δ), 7.15 (m, 3H), 7.25 (m, 1H), 9.35 (br s, 1H); Calcd for C18H18ClNCl2S: C, 59.42; H, 4.99; N, 3.85. Found: C, 59.16; H, 5.13; N, 3.71.

Example 17

3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethylphenyl) -2H-thiopyrano [3,2-b] quinolin9 (5H) -one 1,1-dioxide

4-Trifluoroethylbenzaldehyde (137 mL, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 398 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSOd 6) 1.75 (m, 1H), 1.89 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.19 (m, 2H) 5.10 (s, 1H); 7.38 (d, 2H); 7.58 (d, 2H); 9.37 (br s, 1H); Anal Calcd for Ci9Hi ₈ F3NO ₃ S: C, 57.42; H, 4.56; N, 3.52. Found: C, 57.28; H, 4.58; N, 3.32.

Example 18

10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one 1,1-dioxide

4-Bromobenzaldehyde (185 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the title compound. MS (APCI) m / e 408 (M + H) ^{& lt} ; ^{+ &gt};, 410 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.00 (s, 1H), 7.12 (d, 2H), 7.40 (d, 2H), 9.32 (br s, 1H); Anal Calcd For C 18 H 18 BrNO 3 S: C, 52.95; H, 4.44; N, 3.43. Found: C, 52.76; H, 4.34; N, 3.40.

Example 19

10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin9 (5H) -one, 1,1-dioxide

4-Chloro-3-nitrobenzaldehyde (185 mg, 1.00 mmol) was treated according to the procedure of Example 1 to give the desired compound. MS (APCI) m / e 409 (M + H) ^&lt; ^{+ &gt};, 411 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.21 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.10 (s, 1H), 7.50 (dd, 1H), 7.63 (d, 1H), 7.75 (d, 1H), 9.45 (br s, 1H); Anal Calcd for C ₈ H, 7C1N ₂ O ₅ S: C, 52.88; H, 4.19; N, 6.85. Found: C, 52.59; H, 4.11; N, 6.72.

Example 20

4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone

A solution of methanesulfonylacetone (135 mg, 1.00 mmol), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol ( 7 ml) was heated at reflux for 24 hours and cooled. The precipitated solid was combined, washed with ethanol, dried and triturated with methanol to give the desired compound. MS (APCI) m / e 386 (M + H) ^&lt; ^{+ &gt};, 388 (M + H) ^&lt; ^{+ &gt};; ¹ H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.21 (m, 2H), 2.32 (s, 3H), 2.50 (m 2H, 2.73 (s, 3H), 4.94 (s, 1H), 7.18 (dd, 1H), 7.34 (d, 1H), 7.53 (d, 1H),

9.48 (brs, 1H); Calcd for C17H17Cl2NO3S: C, 52.86; H, 4.44; N, 3.63. Found: C, 52.91; H, 4.31; N, 3.55.

Example 21

4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone

3-Cyanobenzaldehyde (131 mg, 1.00 mmol) was treated according to the procedure of Example to give the desired compound. MS (APCI) m / e 343 (M + H) ^&lt; ^{+ &gt};; ¹ H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.32 (s, 3H), 2.50 (m, 2H), 2.68 (s, 3H), 4.99 (s, 1H), 7.50 (m, 3H), 7.63 (dt, 1H), 9.48 (br s, 1H); Calcd for C18H18N2O3S: C, 63.14; H, 5.30; N, 8.18. Found: C, 63.15; H, 5.35; N, 8.11.

Example 22

4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone

3,4,5-Trifluoromethylbenzaldehyde (160 mg, 1.00 mmol) was treated according to the procedure of Example 20 to give the title compound. MS (APCI) m / e 370 (M-H) -, 406 (M + Cl) -; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.76 (s, 3H), 4.97 (s, 1H), 7.00 (m, 2H), 9.51 (br s, 1H); Calcd for C17H16F3NO3S: C, 54.98; H, 4.34; N, 3.77. Found: C, 55.14; H, 4.16; N, 3.76.

Example 23

4,6,7,8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3- (methylsulfonyl) -5 (1H) quinolinone * *

4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure of Example 20 to give the title compound. MS (APCI) m / e 377 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.73 (m, 1H), 1.90 (m, 1H), 2.20 (m, 2H), 2.32 (s, 3H), 2.45 (s, 3H), 2.50 (m, 2H), 2.70 (s, 3H), 5.00 (s, 1H), 7.39 (d, 1H), 7.43 (dd, 1H), 7, 75 (d, 1H), 9.48 (brs, 1H); Calcd for C18H20N2O5S: C, 57.43; H, 5.36; N, 7.44. Found: C, 57.41; H, 5.28; N, 7.48.

Example 24

4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone 4-Chloro-3-nitrobenzaldehyde (185 mg, 1 (00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m / e 397 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.33 (s, 3H), 2.50 (m, 2H), 2.78 (s, 3H), 5.02 (s, 1H), 7.50 (dd, IH), 7.67 (d, IH), 7.76 (d, IH), 9, 51 (br s, 1H); Calcd for C17H17ClN2O5S: C, 51.45; H, 4.32; N, 7.06. Found: C, 51.50; H, 4.26; N, 7.10.

Example 25

4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone 3-Bromo-4-fluorobenzaldehyde (203 mg, 1 (00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m / e 414 (M + H) ^&lt; ^{+ &gt};; ^! 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.31 (s, 3H), 2.50 (m, 2H) 1.70 (s, 3H), 4.94 (s, 1H), 7.25 (m, 2H), 7.40 (dd, 1H), 9.47 (br s, 1H); Calcd for C ₁₇ H ₁₇ BrFNO ₃ S: C, 49.29; H, 4.14; N, 3.38. Found: C, 49.57; H, 3.93; N, 3.39.

Example 26

4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- (3-nitrophenyl) -5 (1H) -quinolinone

3-Nitrobenzaldehyde (151 mg, 1.00 mmol) was treated according to the procedure of Example 20 to give the title compound. MS (APCI) m / e 363 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.70 (m, 1H), 1.90 (m, 1H), 2.32 (s, 3H), 2.50 (m, 2H), 2.70 (s, 3H), 5.07 (s, 1H), 7.57 (t, 1H), 7.65 (dt, 1H), 8.00 (m, 2H), 9.50 (br s, 1H); Calcd for C17H18N2O5S: C, 56.34; H,

5.01; N, 7.73. Found: C, 56.39; H, 4:92; N, 7.75.

 • · fc · ·

Example 27

4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone 4-Chloro-3-fluorobenzaldehyde (159 mg, 1 (00 mmol) was treated according to the procedure of Example 20 to give the desired compound. MS (APCI) m / e 370 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d ₆ ) 1.73 (m, 1H), 1.90 (m, 1H), 2.21 (m, 2H), 2.31 (s, 3H), 2.50 (m 2H, 2.70 (s, 3H), 4.96 (s, 1H), 7.10 (m, 2H), 7.46 (t, 1H), 9.46 (br s, 1H); Calcd for C17H17ClFNO3S: C, 55.21; H, 4.63; N, 3.79. Found: C, 55.07; H, 4.50; N, 3.67.

Example 28

4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone 4-Trifluoromethylbenzaldehyde (137 mL, 1.00 mmol) was processed according to the procedure of Example 20 to obtain the desired compound. MS (APCI) m / e 386 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.72 (m, 1H), 1.90 (m, 1H), 2.21 (m, 1H), 2.31 (s, 3H), 2.50 (m, 1H), 3H), 2.63 (s, 3H), 5.02 (s, 1H), 7.41 (d, 2H), 7.61 (d, 2H), 9.65 (br s, 1H); Anal. Calcd for C ₁₈ H ₁₈ F ₃ NO ₃ S: C, 56.10; H, 4.71; N, 3.63. Found: C, 56.13; H, 4.61; N, 3.56.

Example 29

9- (3,4-Dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (144 mg, 1.07 mmol), prepared according to the method of J. Heterocycl. Chem., N. 27, 1453 (1990), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclohexen-1-one (111 mg, 1.00 mmol) in ethanol ( 7 ml) was heated at reflux for 24 hours and cooled. The precipitate was isolated and heated at reflux in toluene (5 mL) for 24 hours and cooled. The precipitated solid was combined, cooled, washed with toluene and ethanol and triturated to give the desired compound. MS (APCI) m / e 384 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d ₆ ) 1.75-2.0 (m, 2H), 2.23 (m, 2H), 2.57 (m, 2H), 2.85 (dt, 1H), 3 Δ3 (dt, 1H), 3.38 (m, 2H), 4.84 (s, 1H), 7.17 (dd, 1H), 7.35 (d, 1H), 7.50 (d, 1H), 9.85 (brs, 1H); Calcd for C17H15Cl2NO3S: C, 53.14; H, 3.93; N, 3.64. Found: C, 52.97; H, 3.90; N, 3.56.

Example 30

9- (3-Cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

3-Cyanobenzaldehyde (136 mg, 1.04 mmol) was treated according to the procedure of Example to give the title compound. MS (APCI) m / e 341 (M + H) ^&lt; ^{+ &gt};; ¹ H NMR (DMSO-d 6) 1.88 (m, 2H), 2.22 (m, 2H), 2.56 (m, 2H), 2.85 (dtd, 1H), 3.03 (dt, 1H), 3.36 (m, 2H), 4.90 (s, 1H),

7.45 (td, 1H), 7.54 (dd, 1H), 7.56 (d, 1H), 7.61 (dd, 1H), 9.81 (br s, 1H); Calcd for C18H16N2O3S: C, 63.51; H, 4.73; N, 8.22. Found: C, 63.31; H, 4.61; N, 8.19.

Example 31

9- [4-fluoro-3- (trifluoromethyl) phenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (130 mL) was treated according to the procedure in Example 29 to give the desired compound. MS (APCI) m / e 402 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.88 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.85 (dtd, 1H), 3.03 (dt, 1H), 3.35 (m, 2H), 4.95 (s, 1H), 7.40 (dd, 1H), 7.52 (m, 2H), 9.60 (br s, 1H); Calcd

Ci8H ₁₅ F ₄ NO3S * 0.25H2 O: C, 53.27; H, 3.85; N, 3.49. Found: C, 53.29; H, 3.74; N, 3.55.

Example 32

3,4,5,6,7,9-Hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 4-methyl-, 1,1-dioxide 3-Nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure in Example 29 to give the title compound. MS (APCI) m / e 375 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.88 (m, 2H), 2.23 (m, 2H), 2.45 (s, 3H), 2.56 (m, 2H), 2.85 (dtd, 1 H), 3.03 (dt, 1 H), 3.35 (m, 2H), 4.93 (s, 1 H), 7.36 (d, 1 H), 7.45 (dd, 1 H), 7, 72 (d, 1H), 9.83 (br s, 1H); Calcd for C18H18N2O5S * 0.25H2O: C, 57.06; H, 4.92; N, 7.39. Found: C, 57.24; H, 4.77; N, 7.23.

Example 33

9- (3,4-Difluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one 1,1-dioxide

3,4-Difluorobenzaldehyde (100 mL, 1.00 mmol) was treated according to the procedure of Example to give the title compound. MS (APCI) m / e 352 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.90

(m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.82 (dt, 1H), 3.02 (dt, 1H), 3.35 (m, 2H) 4.86 (s, 1H), 7.02 (m, 1H), 7.15 (ddd, 1H), 7.29 (dt, 1H), 9.79 (br s, 1H); Calcd for C17H15F2NO3S: C, 58.11; H, 4.30; N, 3.99. Found: C, 57.90; H, 3.96; N, 3.88.

Example 34

9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 4-Chloro-3, 1,1-dioxide -nitrobenzaldehyde (185 mg, 1.00 mmol) was treated according to the procedure in Example 29 to give the desired compound. MS (APCI) m / e 393 (MH) -, 395 (MH) -; ¹ H NMR (DMSO-d ₆ ) 1.90 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.85 (dtd, 1H), 3.01 (dt) 1 H, 3.35 (m, 2H), 4.95 (s, 1H), 7.51 (dd, 1H), 7.64 (d, 1H), 7.79 (d, 1H), 9 88 (br s, 1H); Calcd for C, 51.71; H, 3.38; N, 7.09. Found: C, 51.46; H, 3.86; N, 6.95.

Example 35

- [8- (3,4-dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone

A solution of tetrahydrothiopyran-3-one-1,1-dioxide (255 mg, 1.72 mmol), 3,4-dichlorobenzaldehyde (250 mg, 1.43 mmol) and 4-amino-3-penten-2-one (140 mg, 1.41 mmol) in ethanol (5 mL) was heated at reflux for 24 hours and cooled. The precipitated solid was combined, washed with ethanol and dried to give the desired compound. MS (APCI) m / e 386 (M + H) ^&lt; ^{+ &gt};, 388 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d ₆ ) 2.19 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.50 (m, 2H), 3.20 (m 2H, 5.07 (s, 1H), 7.15 (dd, 1H), 7.34 (d, 1H), 7.51 (d, 1H), 9.15 (br s, 1H); Calcd for C17H17Cl2NO3S: C, 52.86; H, 4.44; N, 3.63. Found: C, 52.74; H, 4.39; N, 3.64.

Example 36

- [8- (4-chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2b] puridin-7-yl] ethanone

4-Chloro-3-nitrobenzaldehyde (220 mg, 1.19 mmol) was treated according to the procedure of Example 35 to give the title compound. MS (APCI) m / e 397 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 2.19 (m, 2H), 2.23 (s, 3H), 2.31 (s, 3H), 2.4-2.6 (m, 2H), 3, 1-3.3 (m, 2H), 5.15 (s, · · Λ f f f f f f f f f f f) · ·· · · «« »# 31

Δ), 7.49 (dd, 1H), 7.64 (d, 1H), 7.76 (d, 1H), 9.19 (br s, 1H); Calcd for C17H17ClN2O5S: C, 51.45; H, 4.32; N, 7.06. Found: C, 51.18; H, 4.12; N, 7.03.

Example 37

9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide

A solution of tetrahydrothiopyran-3-on-1,1-dioxide (175 mg, 1.20 mmol), 3,4-dichlorobenzaldehyde (175 mg, 1.00 mmol) and 3-amino-2-cyclopenten-1-one (101 mg, 1.05 mmol), prepared as described in Synthesis, p. 176 (1990), in ethanol (5 mL) was heated at reflux for 24 hours and cooled. The precipitated solid was combined, washed with ethanol and dried to give the desired compound. MS (APCI) m / e 384 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 2.25 (m, 4H), 2.60 (m, 4H), 3.20 (m, 2H), 4.82 (s, 1H), 7.20 (dd, 1H), 7.36 (d, 1H), 7.52 (d, 1H), 9.98 (br s, 1H); Calcd for C17H15Cl2NO3S * 0.25H2O: C, 52.52; H, 4.02; N, 3.60. Found: C, 52.36; H, 3.69; N, 3.63.

Example 38

9- (4-chloro-3-nitrophenyl) -3,4,5 6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3e] pyridin-8 (2H) -one 1,1-dioxide

4-Chloro-3-nitrobenzaldehyde (187 mg, 1.01 mmol) was treated according to the method described in Example 37 to give the desired compound. MS (APCI) m / e 395 (M + H) ^&lt; ^{+ &gt};; NMR (DMSO-d 6) 2.25 (m, 4H), 2.60 (m, 4H), 3.24 (m, 2H), 4.93 (s, 1H), 7.55 (dd, 1H) 7.67 (d, 1H), 7.80 (d, 1H), 10.03 (br s, 1H); Calcd for C17H15ClN2O5S * 0.2H2O: C, 51.13; H, 3.91; N, 7.01. Found: C, 50.96; H, 4.02; N, 6.79.

Example 39

9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3e] pyridin-8 (2H) -one 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (158 mg, 1.00 mmol) was treated according to the procedure of Example 37 and recrystallized from methanol / ethanol acetate to give the desired compound. MS (APCI) m / e 368 (M + H) ^&lt; ^{+ &gt};, 370 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6): 2.25 (m, 4H), 2.62 (m, 4H), ¹ H NMR (DMSO-d 6)? * · • · 4 9 9 « _t 9 9 9 9 9 9 9 9 9

3.20 (m, 2H), 4.93 (s, 1H), 7.20 (ddd, 1H), 7.30 (m, 2H), 9.96 (br s, 1H); Calcd for C17H15ClFNO3S: C, 55.51; H, 4.11; N, 3.81. Found: C, 55.24; H, 3.85; N, 3.67.

Example 40

9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3 e] pyridin-8 (2H) -one 1,1-dioxide

3-Bromo-4-fluorobenzaldehyde (212 mg, 1.04 mmol) was treated according to the procedure of Example 37 to give the title compound. MS (APCI) m / e 412 (M + H) ^&lt; ^{+ &gt};, 414 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d ₆ ) 2.25 (m, 4H), 2.60 (m, 4H), 3.20 (m, 2H), 4.83 (s, 1H), 7.25 (m 2H), 7.41 (dd, 1H), 9.96 (br s, 1H); Anal Calcd for Ci7Hi BrFNO3S ₅ * 0.25H2 O: C, 48.99; H, 3.75; N, 3.36. Found: C, 48.98; H, 3.63; N, 3.28.

Example 41

9- (3-Nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one 1,1-dioxide

3-Nitrobenzaldehyde (153 mg, 1.01 mmol) was treated according to the procedure in Example 29 to give the desired compound. MS (APCI) m / e 359 (MH) &lt; + &gt;; 1 H NMR (DMSO-d 6) 1.83 (m, 1H), 1.92 (m, 1H), 2.24 (m, 2H), 2.57 (m, 2H), 2.85 (dtd, 1 H), 3.05 (dt, 1 H), 3.35 (m, 2H), 4.99 (s, 1 H), 7.55 (t, 1 H), 7.67 (dt, 1 H), 7, 98 (t, 1H), 8.03 (ddd, 1H), 9.91 (s, 1H); Calcd for C ₁₇ H ₁₆ N ₂ O ₅ S: C, 56.65; H, 4.47; N, 7.77. Found: C, 56.67; H, 4.35; N, 7.59.

Example 42

9- (3-Cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide

3-Cyanobenzaldehyde (131 mg, 1.0 mmol) was treated according to the procedure of Example 37 to give the desired compound. MS (APCI) m / e 339 (MH) &lt; + &gt;; ^! 1 H NMR (DMSO-d 6) 2.25 (m, 4H), 2.60 (m, 4H), 3.21 (m, 2H), 4.89 (s, 1H), 7.47 (t, 1H), 7.57 (dd, 1H), 7.59 (d, 1H), 7.64 (dt, 1H), 9.98 (br s, 1H); Anal Calcd For C 18 H 16 N 2 O 3 S * 0.25H 2 O: C, 62.68; H,

4.82; N, 8.12. Found: C, 62.53; H, 4.53; N, 8.08.

• fc 9 * * - - I *

Afc fcfc

Example 43

9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide 3-Bromo-4-dioxide -fluorobenzaldehyde (201 mg, 0.99 mmol) was treated according to the procedure of Example 29 and recrystallized from methanol / chloroform to give the desired compound. MS (APCI); m / e 410 (MH) -, 412 (MH) -; 1 H NMR (DMSO-d ₆ ) 1.88 (m, 2H), 2.23 (m, 2H), 2.56 (m, 2H), 2.83 (dtd, 1H), 3.03 (dt, 1H), 3.33 (t, 2H), 4.85 (s, 1H), 7.22 (m, 2H), 7.40 (dd, 1H), 9.78 (br s, 1H); Anal Calcd For C 11 H 18 BrFNO 3 S: C, 49.52; H, 3.66; N, 3.39. Found: C, 49.19; H, 3.59; N, 3.24.

Example 44

8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide

A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (171 mg, 1.28 mmol), 4-chloro-3-nitrobenzaldehyde (210 mg, 1.13 mmol) and 3-amino-2-cyclopenten-1-one (110 mg (1.13 mmol) in ethanol (3 mL) was heated at reflux for 24 h and cooled. The precipitate was combined, washed with ethanol, dried and recrystallized from methanol / chloroform to give the desired compound. MS (APCI); m / e 379 (MH) -; 1 H NMR (DMSO-d 6) 2.30 (t, 2H), 2.65 (m, 2H), 2.89 (dt, 1H), 3.05 (dt, 1H), 3.40 (t, 2H), 4.87 (s, 1H), 7.58 (dd, 1H), 7.68 (d, 1H), 7.88 (d, 1H), 10.4 (s, 1H); Anal Calcd for Ci6Hi3ClN2O5S 0,25CH * ₃ OH: C, 50.19; H, 3.62; N, 7.20. Found: C, 49.87; H, 3.26; N, 7.07.

Example 45

10- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bisthiopyrano [3,2b] -pyridine 1,1,9,9-tetraoxide

A solution of tetrahydrothiopyran-3-one-1,1-dioxide (150 mg, 1.01 mmol), 4-chloro-3-nitrobenzaldehyde (95 mg, 0.51 mmol) and concentrated ammonium hydroxide (0.5 mL) was heated at 78 ° C. ° C in ethanol (1 mL) for 24 hours in a sealed vessel and cooled. The precipitated solid was washed with ethanol, dried and triturated with hot acetone to give the desired compound. MS (APCI); m / e 443 (M-H) -; 1 H NMR (DMSO-d 6) 2.18 (m, 4H), 2.50 (m, 4H), 3.20 (m, 4H), 5.18 (s, 1H), 7.51 (dd, 1H) ), 7.69 (d, 1H), 7.76 (d, 1H), 9.24 (s, 1H); Anal Calcd for C 11 H 11 ClN 2 Cl 2 N 2 O 4 • OH: C, 45.36; H, 3.99; N, 6.72. Found: C, 45.71; H, 3.85; N, 7.02.

Example 46

10- (3-Pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide

3-Pyridinecarboxaldehyde (94 mL, 1.0 mmol) was treated according to the procedure of Example 1 with recrystallization from methanol to give the desired compound. MS (APCI); m / e 331 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.53 (m, 4H), 3.20 (m, 1H), 2H), 5.03 (s, 1H), 7.25 (dd, IH), 7.52 (dt, IH), 8.31 (dd, IH), 8.38 (dd, IH), 9, 40 (br s, 1H); Calcd for C11H18N3O5S: C, 58.60; H, 5.79; N, 8.04. Found: C, 58.79;

H, 5.81; N, 7.63.

Example 47

10- (4-Pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide

4-Pyridinecarboxaldehyde (95 mL, 1.0 mmol) was treated according to the procedure of Example 1 and recrystallized from methanol to give the desired compound. MS (APCI); m / e 331 (M + H) ^&lt; ^{+ &gt};; 1 H NMR (DMSO-d ₆ ) 1.75 (m, 1H), 1.90 (m, 1H), 2.20 (m, 4H), 2.53 (m, 4H), 3.20 (m 2H, 5.03 (s, 1H), 7.20 (d, 2H), 8.41 (d, 2H), 9.44 (br s, 1H); Anal Calcd for C ₇ H 8 N ₂ O3S: C, 61.80; H, 5.49; N, 8.48. Found: C, 61.71; H, 5.40; N, 8.42.

Example 48

9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3e] pyridin-8 (2H) -one, 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (130 mL) was treated according to the procedure in Example 37 to give the title compound. MS (APCI); m / e 400 (M-H) -; 1 H NMR (DMSO-d 6) 2.25 (m, 4H), 2.58 (m, 4H), 3.20 (m, 2H), 4.92 (s, 1H), 7.40 (dd) 1 H), 7.54 (m, 2H), 9.96 (br s, 1H); Calcd for C18H15F4NO3S: C, 53.86; H, 3.77; N, 3.49. Found: C, 53.60; H, 3.82; N, 3.38.

• ·

Example 49

9- (4-Methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide

4-Methyl-3-nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according to the procedure in Example 37 to give the title compound. MS (APCI); m / e 373 (M-H) -; 1 H NMR (DMSO-d 6) 2.24 (m, 4H), 2.45 (s, 3H), 2.60 (m, 4H), 3.20 (m, 2H), 4.90 (s, 1H), 7.38 (d, 1H),

7.46 (dd, 1H), 7.73 (d, 1H), 9.97 (br s, 1H); Anal Calcd for C ₈ Hi ₈ N ₂ O ₅ S: C,

57.74; H, 4.85; N, 7.48. Found: C, 57.43; H, 4.72; N, 7.34.

Example 50

9- (3,4-Difluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin8 (2H) -one, 1,1-dioxide

3,4-Difluorobenzaldehyde (110 mL) was treated according to the procedure in Example 37 to give the title compound as a white solid. 1 H NMR (DMSO-d 6) 2.25 (m, 4H), 2.60 (m, 4H), 3.20 (m, 2H), 4.83 (s, 1H), 7.05 (m, 1H), 7.16 (ddd, 1H), 7.30 (dt, 1H), 9.95 (br s, 1H); MS (APCI-) m / z 350 (M-H) &apos;; Calcd for C17H15F2NO3S: C, 58.11; H, 4.30; N, 3.98. Found: C, 58.10; H, 4.32; N, 3.94.

Example 51

8- (4-Chloro-3-nitrophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2,1-a] pyridine 1,1,7,7-tetraoxide

4-Chloro-3-nitrobenzaldehyde (215 mg, 1.16 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (310 mg, 2.32 mmol) and 2.0 Μ NH 3 in ethanol (0.75 mL) (1.5 mmol) was heated in ethanol (4 mL) for 3 days at 80 ° C in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol. Then the solid is heated at reflux in toluene with a catalytic amount of para-toluenesulfonic acid, cooled, the solid is combined, washed with toluene, ethanol, methanol and dried. Trituration with hot methanol / chloroform (1: 1) gave 184 mg of an off-white solid.

1 H NMR (DMSO-d 6) 2.85 (m, 2H), 3.00 (dt, 2H), 3.40 (m, 4H), 5.12 (s, 1H), 7.63 (dd, 1H), 7.72 (d, 1H), 7.97 (d, 1H), 10.11 (br s, 1H); MS (APCI &lt; - &gt;) m / z 415 (M-H) &lt; - &gt;; Anal Calcd for C 18 H 16 ClN 2 O 6 Si 4 -toluene: C, 44.26; H, 3.26; N, 6.57. Found: C, 44.63; H, 3.06; N, 6.53.

Example 52

8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

3-Cyanobenzaldehyde (206 mg, 1.57 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (212 mg, 1.58 mmol) and 3-amino-2-cyclopenten-1-one (150 mg, 1 , 55 mmol) were heated in ethanol (4 mL) at 80 ° C for 3 days in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol. Then, the solid was heated at reflux in ethanol (10 mL) with 1N HCl in ether (0.5 mL) for 2 hours, cooled and the solvent was evaporated. The crude oil was triturated with ethyl acetate and the resulting solid was combined, washed with ethyl acetate and dried to give 252 mg of tanning solid.

Melting point: 156-176 ° C;

¹ H NMR (DMSO-d 6) 2.30 (t, 2H), 2.63 (m, 2H), 2.88 (dt, 1H), 3.07 (dt, 1H), 3.40 (t, 2H),

4.70 (s, 1H), 7.49 (t, 1H), 7.60 (d, 1H), 7.64 (s, 1H), 7.66 (dd, 1H), 10.38 (s , 1H);

MS (APCI &lt; - &gt;) m / z 325 (M-H) &lt; - &gt;;

Calcd for C17H14N2O3S * 0.33EtOAc * 0.75 H2O: C, 59.64; H, 4.95; N, 7.59. Found: C, 59.32; H, 4.77; N, 7.41.

Example 53

8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine 1,1,7,7-tetraoxide

3-Bromo-4-fluorobenzaldehyde (305 mg, 1.5 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (402 mg, 3.00 mmol) and 2.0 M NH ₃ in ethanol (1.1 mL, 2.2 mmol) in ethanol (3 mL) was heated at 80 ° C for 3 days in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol. The solid was heated at reflux overnight in ethanol with 1.0 M HCl in ether (1 mL), cooled, the solid was combined, washed with ethanol and dried to give 185 mg of the desired compound as an off-white solid.

1 H NMR (DMSO-d 6) 2.80 (m, 2H), 3.01 (dt, 2H), 3.35 (m, 4H), 4.97 (s, 1H), 7.30 (m, 2H),

7.53 (dd, 1H), 9.19 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 432 (MH) &lt; - &gt;; Calcd for C ₁₅ H ₃ BrFNO ₄ S ₂ : C, 41.48; H, 3.01;

N, 3.22. Found: C, 41.61; H, 2.76; N, 3.14.

Example 54

10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H, 5H-dithiopyrano [3,2b: 2H, 3i-e] 1,1,9,9-tetraoxide ] pyridine

3-Bromo-4-fluorobenzaldehyde (202 mg, 1.0 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (305 mg, 2.06 mmol) and 2.0 M NH ₃ in ethanol (0.70 mL, 1.4 mmol) was heated in ethanol (3 mL) at 80 ° C for 5 days in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol. The solid in toluene (10 mL) was heated at reflux overnight, cooled, combined, washed with ethanol and dried to give 129 mg of the desired compound as a white solid.

1 H NMR (DMSO-d 6) 2.17 (m, 4H), 2.50 (m, 4H), 3.18 (m, 4H), 5.09 (s, 1H), 7.2a (m, 2H),

7.38 (dd, 1H), 9.11 (s, 1H);

MS (APCI-) m / z 460 (M-H) &apos;;

Calcd for C 11 H 11 BrFNO 4: C, 44.16; H, 3.70; N, 3.02. Found: C, 43.97;

H, 3.80; N, 2.95.

Example 55

3,4,5,6,7,9-hexahydro-9- (3-nitrophenyl) cyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide

3-Nitrobenzaldehyde (153 mg, 1.0 mmol), tetrahydrothiopyran-3-one-1,1-dioxide (148 mg, 1.00 mmol) and 3-amino-2-cyclopenten-1-one (97 mg, 1 (00 mmol) were heated at 80 ° C for 5 days in a sealed vessel, cooled, the precipitated solid was collected and washed with ethanol and dried to give 145 mg of the desired compound as tanning solid.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.25 (m, 4H), 2.60 (m, 4H), 3.23 (m, 2H), 4.98 (s, 1H), 7.57 (t, 1H) )

7.69 (d, 1H), 8.00 (s, 1H), 8.04 (d, 1H), 10.03 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 359 (M-H) &lt; - &gt;;

Calcd for C17H16N2O5S: C, 56.65; H, 4.47; N, 7.77. Found: C, 56.34; H,

4.44; N, 7.50.

Example 56

8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3e] pyridin-7-one 1,1-dioxide

3-Bromo-4-fluorobenzaldehyde (250 mg, 1.23 mmol) was treated according to the procedure of Example 44 except that it was heated for 3 days and no recrystallization was necessary to obtain 241 mg of the title compound as an off-white solid.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.30 (t, 2H), 2.63 (m, 2H), 2.85 (dt, 1H), 3.06 (dt, 1H), 3.40 (t, 2H),

4.72 (s, 1H), 7.27 (m, 2H), 7.47 (d, 1H), 10.33 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 396 (M-H) &lt; - &gt;;

Anal Calcd for C 16 H 11 BrFNO 3 S: C, 48.25; H, 3.29; N, 3.52. Found: C, 48.26; H, 3.17; N, 3.34.

Example 57

8- (4-Fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

4-Fluoro-3-trifluoromethylbenzaldehyde (0.20 mL), tetrahydrothiophene-3-oxo-1,1-dioxide (136 mg, 1.01 mmol) and 3-amino-2-cyclopenten-1-one (97 mg) , 1.00 mmol) were heated in ethanol (4 mL) at 80 ° C in a sealed vessel for 3 days, cooled and the solvent was evaporated. Flash chromatography on silica gel (10% methanol / chloroform) followed by trituration of the product with ethyl acetate gave the title compound as a white solid.

Melting point: 254 ° C;

1 H NMR (DMSO- d 6) 2.30 (t, 2H), 2.65 (m, 2H), 2.88 (dt, 1H), 3.06 (dt, 1H), 3.40 (t, 2H),

4.85 (s, 1H), 7.41 (dd, 1H), 7.58 (m, 2H), 10.38 (s, 1H),

MS (APCI-) m / z 386 (M-H) &apos;;

Anal Calcd for Ci7Hi3F4NO3S * 0.25H ₂ O: C, 52.10; H, 3.47; N, 3.57. Found: C, 52.13; H, 3.31; N, 3.47.

A A UWAJ-WW A.AA9

R * r 'Μ ^ ΑΛ A ^ Α ^'. Α, * y?

Example 58

2,3,4,5,6,8-Hexahydro-8- (3-nitrophenyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

3-Nitrobenzaldehyde (225 mg, 1.49 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (202 mg, 1.51 mmol) and 3-amino-2-cyclopenten-1-one (144 mg, 1 (48 mmol) were heated in ethanol (5 mL) at 80 ° C in a sealed vessel for 3 days, cooled and the precipitated solid was filtered off. The filtrate was treated with 1.0 M HCl in ether (0.1 mL), heated at reflux for 1.5 hours, cooled and the solvent was evaporated. Recrystallization from ethanol gave 130 mg of the desired compound as a pale yellow solid.

^! 1 H NMR (DMSO-d 6) 2.31 (t, 2H), 2.65 (m, 2H), 2.90 (dt, 1H), 3.08 (dt, 1H), 3.40 (t, 2H) )

4.90 (s, 1H), 7.58 (t, 1H), 7.73 (dt, 1H), 8.05 (m, 2H), 10.41 (s, 1H);

MS (APCI &lt; - &gt;) m / z 345 (M-H) &lt; - &gt;;

Calcd for C16H14N2O5S: C, 55.48; H, 4.07; N, 8.08. Found: C, 55.37; H, 4.02; N, 7.88.

Example 59

3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H, 5H-dithiopyrano [3,2-b: 2H], 3'-pyridine 1,1,9,9-tetraoxide

3-Nitrobenzaldehyde (153 mg, 1.0 mmol) was treated according to the procedure of Example 54 to give 188 mg of the desired compound as a white solid.

M.p. > 260 DEG C. @ 1 H NMR (DMSO-d6) 2.19 (m, 4H), 2.52 (m, 4H), 3.20 (m, 4H), 5.23 (s, 1H) 7.60 (t, 1 H),

7.68 (d, 1H), 7.98 (s, 1H), 8.08 (d, 1H), 9.23 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 409 (M-H) &lt; - &gt;;

Calcd for C17H18N2O6S2: C, 49.75; H, 4.42; N, 6.82. Found: C, 49.58; H, 4.34; N, 6.79.

Example 60

8- (3,4-dichlorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

3,4-Dichlorobenzaldehyde (175 mg, 1.0 mmol) was treated according to the procedure of Example 52 to give 204 mg of the title compound as a white solid.

Mp > 260 ° C;

1 H NMR (DMSO-d ₆ ) 2.30 (t, 2H), 2.63 (m, 2H), 2.87 (dt, 1H), 3.05 (dt, 1H), 3.40 (t , 2H),

4.72 (s, 1H), 7.22 (dd, 1H), 7.41 (d, 1H), 7.52 (d, 1H), 10.36 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 368 (M-H) &lt; - &gt;; Calcd for C16H13Cl2NO3S: C, 51.90; H, 3.54; N, 3.78. Found: C, 51.93; H, 3.59; N, 3.53.

Example 61

8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3e] pyridin-7-one 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (0.16 mL) was treated according to the procedure of Example 56 to give 107 mg of the desired compound as a white solid.

1 H NMR (DMSO-d 6) 2.30 (t, 2H), 2.64 (m, 2H), 2.85 (dt, 1H), 3.05 (dt, 1H), 3.39 (t, 2H),

4.72 (s, 1H), 7.23 (m, 1H), 7.28 (m, 1H), 7.37 (d, 1H), 10.31 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 352 (M-H) &lt; - &gt;;

Calcd for C16H13ClFNO3S: C, 54.32; H, 3.70; N, 3.96. Found: C, 54.34; H, 3.68; N, 3.85.

Example 62

8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide

3-Cyanobenzaldehyde (132 mg, 1.01 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (272 mg, 2.03 mmol) and 2.0 Μ NH 3 in ethanol (0.75 mL, 1.5 mmol) were heated at 80 ° C in ethanol (4 mL) in a sealed vessel for 3 days, cooled, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 1 hour, Cool and evaporate the solvent. The crude product was flash chromatographed on a silica gel column (15% methanol / chloroform) and the product was triturated with ethyl acetate to give 87 mg of the title compound as an off-white solid, mp 248 ° C;

1 H NMR (DMSO-d 6) 2.83 (dt, 2H), 3.02 (dt, 2H), 3.40 (m, 4H), 5.03 (s, 1H), 7.50 (t, 1H) )

7.61 (d, 1H); 7.70 (d, 1H), 7.73 (s, 1H), 10.07 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 361 (M-H) &lt; - &gt;;

Calcd for C16H14N2O4S2 * 0.33EtOAc * 0.6H2O: C, 51.71; H, 4.47; N, 6.96.

Found: C, 51.84; H, 4.21; N, 6.61.

Example 63

8- (2-Cyano-4-pyridinyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3e] pyridin-7-one 1,1-dioxide

2-Cyanopyridine-4-carboxaldehyde (0.20 g, 1.52 mmol), prepared according to the method of Ashimori (Chem Farm Bull 1990, 38, 2446), tetrahydrothiophene-3-oxo-1,1-dioxide (241 mg) , 1.8 mmol) and 3-amino-2-cyclopenten-1-one (0.146 g, 1.5 mmol) were heated at 40-50 ° C in isopropanol for 3 days, cooled, the solvent was evaporated and flash chromatography (10% methanol / methylene chloride) was performed. The product was dissolved in isopropanol, treated with 1.0 M HCl in ether (1.5 mL), heated at 50 ° C for 10 minutes, cooled and the solvent was evaporated. The residue was triturated with ether, combined, washed with ether and dried to give 63.5 mg of the desired compound as a pale yellow powder.

¹ H NMR (DMSO-d 6) 2.30 (t, 2H), 2.65 (m, 2H), 3.02 (m, 2H), 3.45 (t, 2H), 4.85 (s, 1H), 7.64 (d, 1H), 7.94 (s, 1H), 8.65 (d, 1H), 10.48 (s, 1H);

MS (APCI &lt; - &gt;) m / z 326 (M-H) &lt; - &gt;;

Calcd for C16H11N3O3S * 0.42C2H6O * 0.25H2O * 0.15HCl: C, 57.31; H, 4.48;

Example 64

8- (3-Bromophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

3-Bromobenzaldehyde (0.12 mL, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (137 mg, 1.02 mmol) and 3-amino-2-cyclopenten-1-one (98 mg , 1.0 mmol) were heated in ethanol (4 mL) at 80 ° C in a sealed flask for 3 days and then treated with 1.0 M HCl in ether (1.5 mL), heated at reflux for 1 h. After 3 hours, cool and evaporate the solvent. The crude product was flash chromatographed on a silica gel column (10% methanol / chloroform) and triturated with ethyl acetate to give 147 mg of the desired compound as an off-white solid.

Mp: 246 ° C;

«·

1 H NMR (DMSO-d 6) 2.32 (t, 2H), 2.65 (m, 2H), 2.85 (dt, 1H), 3.07 (dt, 1H), 3.40 (t, 2H) )

4.69 (s, 1H), 7.22 (m, 2H), 7.36 (m, 2H), 10.33 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 378 (M-H) &lt; - &gt;;

Calcd for C 16 H 14 BrNO 3 S: C, 50.54; H, 3.71; N, 3.68. Found: C, 50.62; H,

3.63; N, 3.54.

Example 65

8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H], 3'-pyridine 1,1,7,7-tetraoxide

4-Fluoro-3-trifluoromethylbenzaldehyde (0.19 mL) was treated according to the procedure in Example 62 to give 35 mg of the desired compound as a white solid.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.83 (dtd, 2H), 3.02 (dt, 2H), 3.39 (m, 4H), 5.11 (s, 1H), 7.45 (dd, 1H), 7.62 (d, 1H), 7.67 (m, 1H), 10.07 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 422 (M-H) &lt; - &gt;;

Calcd for C16H13F4NO4S2: C, 45.39; H, 3.09; N, 3.31. Found: C, 45.23; H, 2.87; N, 3.12.

Example 66

- [8- (3-Bromo-4-fluorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2b] pyridin-7-yl)] ethane- 1 -on

3-Bromo-4-fluorobenzaldehyde (246 mg, 1.21 mmol) was treated according to the procedure of Example 35 to give 325 mg of the desired compound as a white solid.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.17 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.50 (m, 2H), 3.20 (m, 2H), 5.06 (s, 1H), 7.20 (m, 2H), 7.40 (dd, 1H), 9.11 (s, 1H);

MS (APCI &lt; - &gt;) m / z 412 (M-H) &lt; - &gt;;

Calcd for C 11 H 11 BrFNO 5 S: C, 49.28; H, 4.13; N, 3.38. Found: C, 49.06; H, 4.10; N, 3.28.

W »II» w). _g o «» her

Example 67

8- (4-Bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

4-Bromothiophene-2-carboxaldehyde (500 mg, 2.6 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (295 mg, 2.2 mmol) and 3-amino-2-cyclopenten-1-one (215 mg , 2.2 mmol) were heated in ethanol (5 mL) at 80 ° C in a sealed vessel for 2 days, cooled, the precipitated solid was collected, washed with ethanol, dissolved in methanol / methyl chloride 1: 3 solution, filtered over cotton, concentrated on a steam bath and crystallized to give 0.34 g of the desired compound as a white-brown solid.

Mp 254-255 ° C;

1 H NMR (DMSO-d 6) 2.35 (t, 2H), 2.53-2.75 (m, 2H), 2.78-2.91 (m, 1H), 2.97-3.10 ( m, 1H),

3.42 (t, 2H), 4.95 (s, 1H), 6.88 (d, 1H), 7.46 (d, 1H), 10.43 (bs, 1H);

MS (APCI +) m / z 386 (M + H), 403 (M + NH ₄ +), MS (APCI-) m / z 384 (MH) +;

Anal Calcd For C 1 H 11 NCl 2 SiBr: C, 43.53; H, 3.13; N, 3.63. Found: C, 43.39; H, 2.84; N, 3.41.

Example 68

8- (5-Bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

5-Bromothiophene-2-carboxaldehyde (500 mg, 2.6 mmol) was treated according to the procedure of Example 67 to give 0.297 g of the desired compound as a brown solid.

Melting point: 246-247 ° C;

¹ H NMR (DMSO-d 6) 2.35 (t, 2H), 2.52-2.73 (m, 2H), 2.78-2.90 (m, 1H), 2.95-3.08 (m, 1H), 3.41 (t, 2H), 4.92 (s, 1H), 6.73 (d, 1H), 6.97 (d, 1H), 10.39 (s, 1H) ;

MS (APCI &lt; - &gt;) m / z 384 (M-H) &lt; - &gt;;

Calcd for C14H12NO3S2Br: C, 43.53; H, 3.13; N, 3.63. Found: C, 43.19; H, 3.16; N, 3.31.

Example 69

2,3,4,5,6,8-Hexahydro-8- (5-nitro-3-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

2-Nitrothiophene-4-carboxaldehyde (0.41 g, 2.6 mmol) was treated according to the procedure of Example 67 to give 0.423 g of the desired compound as a brown powder.

^! 1 H NMR (DMSO-d ₆ ) 2.34 (t, 2H), 2.52-2.74 (m, 2H), 2.80-2.92 (m, 1H), 2.98-3.11 (m, 1H)

3.43 (t, 2H), 4.84 (s, 1H), 7.78 (d, 1H), 7.94 (d, 1H), 10.39 (s, 1H);

MS (APCI &lt; + &gt;) m / z 353 (M + H) ^&lt; ^{+ &gt};, 370 ([delta] + -4 &lt; + &gt;), MS (APCI &lt; + &gt;) m / z 351 (MH) &lt; + &gt;

Calcd for C14H12N2O5S2: C, 47.72; H, 3.43; N, 7.95. Found: C, 47.43; H, 3.22; N, 7.65.

Example 70

2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

5-Nitrothiophene-2-carboxaldehyde (205 mg, 1.30 mmol) was treated according to the procedure of Example 67 to give 238 mg of the desired compound as a brown solid.

M.p. 251-254 ° C;

1 H NMR (DMSO-d 6) 2.37 (t, 2H), 2.56-2.78 (m, 2H), 2.83-2.96 (m, 1H), 3.01-3.14 (m, 1H), 3.46 (t, 2H), 5.07 (s, 1H), 7.10 (d, 1H), 7.97 (d, 1H), 10.59 (s, 1H) ;

MS (APCI ⁺ ) m / z 353 (M + H) ^&lt; ^{+ &gt};, 370 (M + NH4), (APCI-) m / z 351 (MH) &lt; - &gt;;

Calcd for C14H12N2O5S2: C, 47.72; H, 3.43; N, 7.95. Found: C, 47.39; H, 3.39; N, 7.67.

Example 71

2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-furyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

5-Nitro-2-furaldehyde (185 mg, 1.30 mmol) was treated according to the procedure of Example 67 to give 117 mg of the desired compound as a brown solid.

1 H NMR (DMSO-d 6) 2.38 (t, 2H), 2.57-2.79 (m, 2H), 2.83-2.96 (m, 1H), 2.96-3.09 ( m, 1H),

3.43 (t, 2H), 4.96 (s, 1H), 6.71 (d, 1H), 7.65 (d, 1H), 10.52 (s, 1H);

MS (APCI +) m / z 337 (M + H) ^&lt; ^{+ &gt};, 354 (M + H) &lt; ⁺ &gt;, MS (APCI &lt; ⁺ &gt;) m / z 335 (MH) &lt; + &gt;

Calcd for C14H12N2O6S: C, 50.00; H, 3.60; N, 8.33. Found: C, 49.80; H, 3.42; N, 8.14.

Example 72

8- (3,4-Dibromophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

3,4-Dibromobenzaldehyde (293 mg, 1.11 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (146 mg, 1.09 mmol) and 3-amino-2-cyclopenten-1-one (107 mg , 1.10 mmol) were heated in ethanol (4 mL) at 80 ° C in a sealed flask for 3 days, cooled, the precipitated solid was collected, washed with ethanol and dried to give 211 mg of the desired compound. The filtrate was treated with 1.0 M HCl in ether (1 mL), heated at reflux for 2 hours, cooled and the solvent was evaporated. The residue was treated with ethanol, heated, and the resulting solid was combined, washed with ethanol and dried to give an additional 29 mg of the title compound. The two combined portions were triturated with hot ethyl acetate, washed with ethyl acetate, and dried to give 197 mg of the desired compound as tanning solid.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.30 (t, 2H), 2.55-2.75 (m, 4H), 2.85 (dt, 1H), 3.05 (dt, 1H), 3, 40 (t, 2H), 4.71 (s, 1H), 7.17 (dd, 1H), 7.54 (d, 1H), 7.65 (d, 1H), 10.36 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 458 (M-H) &lt; - &gt;;

Calcd for C 16 H 11 BrNO 5 S: C, 41.85; H, 2.85; N, 3.05. Found: C, 41.79; H, 2.75; N, 2.78.

Example 73

2,3,4,5,6,8-Hexahydro-8- (3-nitrophenyl) dithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide

3-Nitrobenzaldehyde (155 mg, 1.03 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (273 mg, 2.04 mmol) and 2.0 Μ NH 3 in ethanol (0.7 mL, 1.4 mmol) were heated at 80 ° C in ethanol (4 mL) for 3 days in a sealed vessel, cooled, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 15 minutes The mixture was cooled, the precipitated solid was collected, washed with ethanol and dried. The solid was triturated with hot ethyl acetate, combined, washed with ethyl acetate and dried to give 174 mg of the desired compound as an orange-yellow solid.

M.p .: 248-252 ° C;

1 H NMR (DMSO-d 6) 2.85 (m, 2H), 3.05 (m, 2H), 3.40 (m, 4H), 5.15 (s, 1H), 7.61 (t, 1H),

7.77 (dt, 1H), 8.10 (m, 2H), 10.09 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 381 (M-H) &lt; - &gt;;

• ·

Calcd for C15H14N2O6S2: C, 47.11; H, 3.68; N, 7.32. Found: C, 47.47; H,

3.68; N, 7.29.

Example 74

8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2,1-a] pyridine 1,1,7,7-tetraoxide

3-Chloro-4-fluorobenzaldehyde (160 mg, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (273 mg, 2.04 mmol) and 2.0 Μ NH 3 in ethanol (0.7 mL) , 1.4 mmol) were heated at 80 ° C in ethanol (4 mL) for 3 days in a sealed vessel, cooled, the precipitated solid was collected, washed with ethanol and dried to give 146 mg of the desired compound as a pale solid. yellow solid.

Mp > 260 ° C;

1 H NMR (DMSO-d ₆ ) 2.82 (dt, 2H), 3.02 (dt, 2H), 3.38 (m, 4H), 4.97 (s, 1H), 7.24-7 38 (m, 2H), 7.43 (dd, 1H), 9.35 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 388 (M-H) &lt; - &gt;;

Calcd for C15H13ClFNO4S2: C, 46.09; H, 3.61; N, 3.58. Found: C, 45.91; H, 3.40; N, 3.63.

Example 75

4- (3,4-dichlorophenyl) -1,4,6,7-tetrahydro-2-methyl-3- (methylsulfonyl) -5H-cyclopenta [b] pyridin-5-one

3,4-Dichlorobenzaldehyde (175 mg, 1.0 mmol), methanesulfonylacetone (137 mg, 1.01 mmol) and 3-aminocyclopentenone (95 mg, 0.98 mmol) were heated at 80 ° C in ethanol (4 mL) ) in a sealed vessel for 3 days, cooled and the solvent evaporated. The crude material was flash chromatographed on a silica gel column (5% methanol / chloroform) to give 80 mg of the desired compound as a tan solid.

Melting point: 218-220 ° C;

1 H NMR (CDCl 3) 2.48-2.50 (br s, 5H), 2.59 (s, 3H), 2.63 (m, 2H), 5.01 (s, 1H), 6.53 (br s,

1H), 7.25 (m, 1H), 7.48 (m, 2H);

MS (APCI &lt; - &gt;) m / z 370 (M-H) &lt; - &gt;;

Calcd for C16H15Cl2NO3S: C, 51.62; H, 4.06; N, 3.76. Found: C, 51.36; H,

3.99; N, 3.83.

Example 76

4- (4-chloro-3-nitrophenyl) -1,4,6,7-tetrahydro-2-methyl-3- (methylsulfonyl) -5H-cyclopenta [b] pyridin-5-one

4-Chloro-3-nitrobenzaldehyde (186 mg, 1.0 mmol) was treated according to the procedure of Example 75 to give 105 mg of the desired compound as an off-white solid.

Mp 232 ° C;

1 H NMR (DMSO-d 6) 2.27 (m, 2H), 2.36 (s, 3H), 2.58 (m, 2H), 2.83 (s, 3H), 4.87 (s, 1H), 7.53 (dd, 1H), 7.70 (d, 1H), 7.80 (d, 1H), 10.10 (s, 1H);

MS (APCI &lt; - &gt;) m / z 381 (M-H) &lt; - &gt;;

Calcd for C16H15ClN2O5S: C, 51.62; H, 4.06; N, 3.76. Found: C, 51.36; H, 3.99; N, 3.83.

Example 77

8- (3,4-Chloro-phenyl-2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine) 1,1,7,7-tetraoxide

3,4-Dichlorobenzaldehyde (196 mg) was treated according to the procedure in Example 74 to give 165 mg of the desired compound as a pale yellow solid.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.82 (m, 2H), 3.00 (dt, 2H), 3.39 (m, 4H), 4.97 (s, 1H), 7.26 (dd, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 9.53 (br s, 1H);

MS (APCI-) m / z 404 (M-H) &apos;;

Calcd for C15H13Cl2NO4S2: C, 44.34; H, 3.22; N, 3.44. Found: C, 43.99; H, 3.11; N, 3.68.

Example 78

8- (4-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide. * * «•«:::::::.. ®

4-Bromobenzaldehyde (377 mg, 2.00 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (230 mg, 1.7 mmol) and 3-amino-2-cyclopenten-1-one (165 mg, 1 (7 mmol) was heated at 80 ° C in a sealed vessel for 2 days, cooled, the precipitated solid was collected and washed with ethanol. The filtrate was treated with 1.0 M HCl / diethyl ether (4 mL), heated at reflux for 15 minutes, cooled, concentrated, combined with a precipitated solid, and purified by flash column chromatography on silica gel (5% methanol / methylene chloride). ). The product was crystallized from ethanol to give 218 mg of the desired compound.

Mp 253-256 ° C;

1 H NMR (DMSO-d ₆ ) 2.30 (t, 2H), 2.51-2.72 (m, 2H), 2.79-2.91 (m, 1H), 2.97-3, 09 (m, 1H),

3.34-3.42 (m, 2H), 4.66 (s, 1H), 7.17 (d, 2H), 7.43 (d, 2H), 10.27 (s, 1H);

MS (APCI +) m / z 380 (M + H) &lt; ⁺ &gt;, MS (APCI-) m / z 378 (MH) &lt; - &gt;;

Anal Calcd For C 16 H 16 NO 2 S: C, 50.54; H, 3.71; N, 3.68. Found: C, 50.50; H, 3.74; N, 3.52.

Example 79

8- (3,4-Difluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide

3,4-Difluorobenzaldehyde (162 mg) was treated according to the procedure of Example 56 to give 169 mg of the desired compound as a white powder.

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.30 (t, 2H), 2.5-2.75 (m, 2H), 2.86 (dt, 1H), 3.07 (dt, 1H), 3, 40 (t, 2 H),

4.72 (s, 1H), 7.08 (m, 1H), 7.18-7.36 (m, 2H), 10.32 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 336 (M-H) &lt; - &gt;;

Calcd for C16H13F2NO3S: C, 56.96; H, 3.88; N, 4.15. Found: C, 57.01; H, 3.78; N, 4.08.

Example 80

8- (4-Chloro-3-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3e] pyridin-7-one 1,1-dioxide

4-Chloro-3-fluorobenzaldehyde (180 mg, 1.13 mmol) was treated according to the procedure of Example 56 to give 135 mg of the desired compound as tanning solid.

.Λ.ΙΛΑΑ U. «X ·« «« · · »

Mp > 260 ° C;

1 H NMR (DMSO-d 6) 2.30 (t, 2H), 2.50-2.75 (m, 2H), 2.87 (dt, 1H), 3.05 (dt, 1H), 3.40 (t, 2H), 4.73 (s, 1H), 7.10 (dd, 1H), 7.21 (dd, 1H), 7.45 (t, 1H), 10.32 (br s, 1H) );

MS (APCI &lt; - &gt;) m / z 352 (M-H) &lt; - &gt;;

Calcd for C16H13ClFNO3S: C, 54.31; H, 3.70; N, 3.95. Found: C, 54.08; H, 3.65; N, 3.88.

Example 81

9- (3-chloro-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide

3-Chloro-4-fluorobenzaldehyde (264 mg, 1.66 mmol) was treated according to the procedure of Example 43 to give 317 mg of the desired compound as a pale yellow solid. Mp> 260 ° C 1 H NMR (DMSO-d 6) 1.73-1.96 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.82 (dt) 1 H, 3.02 (dt, 1 H), 3.46 (m, 2 H), 4.85 (s, 1 H), 7.17 (m, 1 H), 7.28 (m, 2 H), 9 75 (br s, 1H);

MS (APCI-) m / z 366 (M-H) &lt; - &gt;;

Calcd for C17H15ClFNO3S: C, 55.51; H, 4.11; N, 3.80. Found: C, 55.24; H, 3.97; N, 3.85.

Example 82

8- (3-Cyano-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine 1,1,7,7-tetraoxide

Example 82A

-cyano-4-fluorobenzyl bromide

A solution of 3-cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and a catalytic amount of 2,2'-azobisisobutyronitrile (AIBN) in benzene was heated at reflux for 16 hours, evaporated to dryness and flash chromatographed on silica gel (10% ethyl acetate / hexane) to give 1.0 g of 3-cyano-, 4-fluorobenzyl bromide.

1 H NMR (CDCl 3) d 4.45 (s, 2H), 7.21 (t, 1H), 7.65 (m, 2H).

Example 82B

3-Cyano-4-fluorobenzyl alcohol

A solution of 85% formic acid (0.63 mL) and triethylamine (2.32 mL, 16.7 mmol) in acetonitrile at 0 ° C was treated with the product of Example 82A (13 g, 5.6 mmol). , stirred at room temperature for 3 hours, the reaction mixture was evaporated to dryness, partitioned between ethyl acetate / water, the organic layer was dried over sodium sulfate, filtered and the solvent was evaporated to give the crude formate ester. This residue was dissolved in methanol: water (5: 1), treated with a catalytic amount of concentrated hydrochloric acid, stirred at room temperature overnight, evaporated to dryness and flash chromatographed on a silica gel column (ethyl acetate: hexane 1: 1) to give 0, 40 g of 3-cyano-4-fluorobenzyl alcohol.

1 H NMR (CDCl 3) d 1.81 (t, 1H), 4.72 (d, 2H), 7.21 (t, 1H), 7.62 (m, 2H).

Example 82C

-cyano-4-fluorobenzaldehyde

A solution of the product of Example 82B (0.40 g, 2.6 mmol) in chloroform (50 mL) was treated with manganese dioxide (0.55 g, 7.8 mmol), stirred at room temperature overnight, filtered, solvent It was evaporated and the residue was flash chromatographed on silica gel (ethyl acetate: hexane 1: 1) to give 0.21 g of 3-cyano-4-fluorobenzaldehyde.

1 H NMR (CDCl 3) d 7.43 (t, 1H), 8.17 (m, 2H), 9.99 (s, 1H).

Example 82D

3-Cyano-4-fluorobenzaldehyde (0.21 g, 1.4 mmol) was treated according to the procedure of Example 62 to give 0.20 g of the desired compound as tanning solid.

Melting point: 275-280 ° C (decomposition);

1 H NMR (DMSO-d 6) 2.82 (m, 2H), 3.0 (m, 2H), 3.4 (m, 4H), 5.06 (s, 1H), 7.48 (t, 1 H), 7.7 (m, 1 H), 7.86 (dd, 1 H) 10.1 (s, 1 H);

MS (ESI -) m / z 398 (M + NH ₄ ) ⁺ , MS (ESI -) m / z 379 (MH) -;

Calcd for C16H13FN2O4S2: C, 50.52; H, 3.44; N, 7.36. Found: C, 50.47; H,

3.52; N, 7.26.

- «W

Example 83

(+) (9R) -9- (3-Bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide .

The product of Example 43 (0.50 g) is chromatographed on a 5x25 cm Regis WhelkO 2 chiral column with 280 g of mobile phase packing (hexane: methanol: methylene chloride 77.5 / 15 / 7.5) at a flow rate of 117 ml / min to give 220 mg of the desired compound as the more polar enantiomers.

[Α] ²³ D + 50.24 ° (CH ₃ CN);

1 H NMR (DMSO-d ₆ ) 1.72-1.98 (m, 2H), 2.22 (m, 2H), 2.55 (m, 2H), 2.8 (m, 1H), 3 , 1 (m,

1H), 3.32 (m, 2H), 4.82 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 9.8 (s, 1H);

MS (APCI +) m / z 414 (M + H) ^&lt; ^{+ &gt};;

Anal Calcd for Ci7Hi5BrFNO ₃ S: C, 49.52; H, 3.66; N, 3.39. Found: C, 49.56; H, 3.86; N, 3.33.

Example 84

(-) (9S) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -oxide onu

From the above chiral chromatography in Example 83, 210 mg of the desired compound is obtained as the less polar enantiomers.

[] ²³ D-48.8 (CH ₃ CN);

1 H NMR (DMSO-d 6) 1.72-1.98 (m, 2H), 2.22 (m, 2H), 2.52 (m, 2H), 2.8 (m, 1H), 3, 1 (m,

1H), 3.31 (m, 2H), 4.82 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 9.8 (s, 1H);

MS (APCI +) m / z 414 (M + H) ^&lt; ^{+ &gt};;

Anal Calcd for Ci7Hi5BrFNO ₃ S: C, 49.52; H, 3.66; N, 3.39. Found: C, 49.54; H,

3.76; N, 3.41.

·· * ·

Example 85

8- (2,1,3-Benzoxadiazol-5-yl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3e] pyridin-7-1,1-dioxide -he

2,1,3-Benzoxadiazole-5-carboxaldehyde (0.296 g, 2.00 mmol), prepared according to Gasco (Eur. J. Med. Chem. 1996, 31, 3), tetrahydrothiophene-3-oxo-1, 1-Dioxide (0.27 g, 2.0 mmol) and 3-amino-2-cyclopenten-1-one (0.194 g, 2.00 mmol) were heated in ethanol (4 mL) at 80 ° C for 2 days in a sealed vessel, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 3 hours, cooled, precipitated solid was combined, washed with ethanol and dried to give 0.27 g of the desired Compound ¹ H NMR (DMSO-d 6) 2.31 (t, 2H), 2.65 (m, 2H), 2.9 (m, 1H), 3.05 (m, 1H), 3.42 (m 2H, 4.92 (s, 1H), 7.55 (d, 1H), 7.82 (s, 1H), 7.96 (d, 1H), 10.42 (s, 1H);

MS (CI / NH 3) m / z 361 (M + NR 3) ⁺ ;

Calcd for C10H13N3O4S: C, 55.96; H, 3.81; N, 12.23. Found: C, 55.80, H, 3.73; N, 12.18.

Example 86

(-) (8S) -8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] 1,1-dioxide pyridin-7-one

The product of Example 56 (0.80 g) is chromatographed on a 5x25 cm Regis WhelkO 2 chiral column with 280 g of mobile phase packing (hexane: methanol: methylene chloride 77/15/15) at a flow rate of 117 ml / min to give 250 mg of the desired compound. in the form of the less polar enantiomer.

[Α] ²³ d -4.5 ° (CH ₃ CN) 1 H NMR (DMSO-d 6) 2.3 (t, 2H), 2.63 (m, 2H), 2.85 (m, 1H), 3 06 (m, 1H); 3.4 (m, 2H); 4.71 (s, 1H); 7.25 (d, 2H); 7.47 (d, 1H) 10.35 (s, 1H) );

MS (ESI &^lt; ^{+ &gt};) m / z 400 (M + H) ^&lt; ^{+ &gt};;

Calcd for C16H11BrFNO5S: C, 48.25; H, 3.29; N, 3.52. Found: C, 48.14; H,

3.42; N, 3.42.

• · 1 1 1 1 1 1 1 1 1 1... .. .. .. .. .. .. ... . «

Example 87

(+) (8R) -8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] 1,1-dioxide pyridin-7-one

8 (4H) -one

From the above chiral chromatography in Example 86, 264 mg of the desired compound is obtained as the more polar enantiomer.

[Α] ²³ D + 4.8 ° (CH ₃ CN);

¹ H NMR (DMSO-d 6) 2.3 (m, 2H), 2.62 (m, 2H), 2.85 (m, 1H), 3.05 (m, 1H), 3.4 (m, 2H),

4.72 (s, 1H), 7.25 (m, 2H), 7.48 (d, 1H), 10.35 (s, 1H);

MS (ESI &^lt; ^{+ &gt};) m / z 400 (M + H) ^&lt; ^{+ &gt};;

Calcd for C ₁₆ H ₁₃ BrFNO ₃ S: C, 48.25; H, 3.29; N, 3.52. Found: C, 48.14; H, 3.52; N, 3.42.

Example 88

9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide

2,1,3-Benzoxadiazole-5-carboxaldehyde (0.296 g, 2.00 mmol) was treated according to the method of Example 89 to give 0.42 g of the title compound.

¹ H NMR (DMSO-d 6) 1.9 (m, 2H), 2.25 (m, 2H), 2.55 (m, 2H), 2.88 (m, 1H), 3.05 (m, 2H) IH),

3.4 (m, 2H), 5.0 (s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d, 1H), 9.96 (s) , 1H);

MS (ESI &^lt; ^{+ &gt};) m / z 358 (M + H) ^&lt; ^{+ &gt};;

Calcd for C11H18N3S: C, 57.13; H, 4.23; 11, 11.75. Found: C, 57.05; H, 4.31; N, 11.73.

Example 89

9- (4-fluoro-3-iodophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one 1,1-dioxide

Example 89A

amino-4-fluorobenzyl alcohol. · »· <· ·· ·· ·, <« «* · _(. ,,« "» * » '* ♦

4 «· ·»

.. <· * · * · '”

............

3-Amino-4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0 ° C was treated with 1.0 M BH 3 * THF (50 mL), stirred overnight at room temperature, treated with another 130 mL 1.0 M BH 3 * THF, stirred for 10 hours, quenched by addition of methanol, stirred for 3 hours at room temperature, evaporated the solvent, partitioned between aqueous sodium bicarbonate / methylene chloride, dried the organic layer (sodium sulfate), filtered and solvent evaporate. The product was purified by flash column chromatography on silica gel (ethyl acetate / hexane 1: 1) to give 7.0 g of the desired compound.

1 H NMR (CDCl 3) 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

Example 89B

4-fluoro-3-i-benzyl alcohol

The product of Example 89A (7.0 g, 50 mmol) in water (100 mL) at 0 ° C was carefully treated with concentrated sulfuric acid (30 mL) to maintain the temperature below 10 ° C, then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated at 60 ° C for 2 hours, cooled, extracted with methylene chloride, and the organic layers were washed with 10% sodium hydroxide, 1 M sodium thiosulfate, 10% hydrochloric acid, aqueous sodium bicarbonate, dried (sodium sulfate), filtered and the solvent was evaporated. The material is purified by flash chromatography on silica gel (ethyl acetate / hexane 7: 3) to give 6.4 g of the desired compound.

¹ H NMR (CDCl 3) 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (ζ 1H), 7.60 (d, 1H), 7.78 (dd, 1H).

Example 89C

4-fluoro-3-iodobenzaldehyde

The product of Example 89B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol), stirred overnight, treated with another portion of manganese dioxide (2.25). g), stirred overnight, filtered and the solvent was evaporated. The material is purified by flash chromatography on silica gel (ethyl acetate / hexane 1: 4) to give 1.9 g of the desired compound.

1 HNMR (CDCl 3) 7.23 (t, 1H), 7.89 (m, 1H), 832 (dd, 1H), 9.91 (s, 1H).

Example 89D

9- (4-fluoro-3-iodophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one 1,1-dioxide

4-Fluoro-3-iodobenzaldehyde (0.25 g, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (0.13 g, 1.0 mmol), 3-amino-2-cyclohexene- 1-one (0.11 g, 1.0 mmol) and triethylamine (0.07 mL) were heated in ethanol (2 mL) at 80 ° C in a sealed vessel for 96 hours, cooled, the solvent was evaporated, accelerated Chromatograph on a silica gel column (10% ethanol / methylene chloride), dissolve the product in ethanol, treat with 1.0 M HCl in ether (1 mL), heat at reflux for 2 hours, cool, precipitate the solid, wash, wash ethanol and dried to give 0.20 g of the title compound.

Mp > 250 ° C;

1 H NMR (DMSO-d 6) 1.88 (m, 2H), 2.22 (m, 2H), 2.62 (m, 2H), 2.7 (m, 1H), 3.02 (m, 1H), 3.45 (m, 2H), 4.81 (s, IH), 7.12 (m, IH), 7.18 (m, IH), 7.55 (dd, IH), 9, 81 (s, 1H); MS (ESI +) m / z 460 (M + H) ^&lt; ^{+ &gt};;

Calcd for C17H15FINO3S: C, 44.45; H, 3.29; N; 3.04. Found: C, 44.51; H, 3.31; N, 2.97.

Example 90

8- (4-Fluoro-3-iodophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3e] pyridin-7-one 1,1-dioxide

4-Fluoro-3-iodobenzaldehyde (0.25 g, 1.0 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (0.13 g, 1.0 mmol) and 3-amino-2-cyclopentene- 1-one (97 mg, 1.0 mmol) was heated in ethanol (2 mL) at 80 ° C in a sealed vessel for 96 hours, cooled, the solvent was evaporated, flash chromatographed on a silica gel column (10% ethanol / methylene chloride) ), the product is dissolved in ethanol, treated with 1.0 M HCl in ether (1 mL), heated at reflux for 2 hours, cooled, the precipitated solid is combined, washed with ethanol and dried to give 0.10 g of the desired product. compounds.

Mp > 250 ° C;

1 H NMR (DMSO-d 6) 2.3 (t, 2H), 2.62 (m, 2H), 2.85 (m, 1H), 3.08 (m, 1H), 3.4 (m 2H), 4.68 (s, 1H), 7.13 (t, 1H), 7.24 (m, 1H), 7.6 (dd, 1H), 10.33 (s, 1H);

MS (ESI +) m / z 446 (M + H) ^&lt; ^{+ &gt};;

Calcd for C16H13FINO3S: C, 43.16; H, 2.94; N, 3.14. Found: C, 42.91; H,

2.94; N; 3.00.

Example 91

(+) 9- (3-Bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3e] pyridin-8 (2H) -one, 1,1-dioxide

The product of Example 40 (1.476 g, 3.58 mmol) as a slurry in THF (20 mL) under nitrogen at 5 ° C was treated dropwise with a solution of 1.0 M potassium tert-butoxide in THF (3 mL). 9 ml), allowed to warm to room temperature over 20 minutes, then treated with a solution of (-) - 8-phenylmenthylchloroformate (1.17 g, 3.97 mmol) in THF (5 ml), stirred at room temperature The mixture was extracted with diethyl ether (2x), the organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to give a mixture of diastereomeric carbamates. This mixture was flash chromatographed on a 6x36 cm silica gel column (ether: hexane 85/15) to give 746 mg of less polar diastereomer. This material in the form of a slurry in methanol (10 ml) under nitrogen was treated with a catalytic amount of sodium methoxide, stirred at room temperature for 24 hours, treated with glacial acetic acid (3 drops), the solid precipitate was combined, washed with ethyl alcohol. and dried to give 227 mg of the desired compound as a white solid.

[] ²³ d +63.9 (MeCN);

¹ H NMR (DMSO-d 6) 2.15-2.35 (m, 4H), 2.46-2.70 (m, 4H), 3.23 (m, 2H), 4.83 (s, 1H ), 7.25 (m, 2H), 7.42 (dd, 1H), 9.96 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 410 (M-H) &lt; - &gt;;

Calcd for C11H18BrFNO3S: C, 49.53; H, 3.67; N, 3.40. Found: C, 49.47; H, 3.53; N, 3.37.

Example 92

(-) 9- (3-Bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3e] pyridin-8 (2H) -one, 1,1-dioxide

From the above-described diastereomer chromatography in Example 91, 824 mg of the impure polar diastereomer is obtained. This material was flash chromatographed on a 6x36 cm silica gel column (ether / hexane 9/1) to give 695 mg of the more polar diastereomers. The diastereomer as a slurry in methanol (10 mL) under nitrogen was treated with a catalytic amount of sodium methoxide, stirred at room temperature for 5 days, treated with glacial acetic acid (3 drops), the solid precipitate was combined, washed with ethanol and dried to give 120 mg of the desired compound as a white solid. The filtrate was flash chromatographed on a silica gel column (5-15% ethanol / methylene chloride) and the product triturated with ethyl acetate to give an additional 186 mg of the desired compound.

[Α] ²³ d -60.8 (MeCN) 1 H NMR (DMSO-d ₆ ) 2.15-2.30 (m, 4H), 2.47-2.70 (m, 4H), 3.20 ( m, 2H), 4.83 (s, 1H), 7.25 (m, 2H), 7.41 (dd, 1H), 9.96 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 410 (M-H) &lt; - &gt;; Anal Calcd For C 18 H 18 BrFNO 3 S: C, 49.53; H, 3.67; N, 3.40. Found: C, 49.61; H, 3.58; N, 3.34.

Example 93

(+) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2b] quinolin-9 (5H) -one 1,1-dioxide

The product of Example 4 (1.646 g, 3.86 mmol) was treated according to the procedure of Example 91 to give 223 mg of the desired compound as a white solid.

[] ²³ d +7.3 (DMSO);

1 H NMR (DMSO-d 6) 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 1H), 2H); 5.01 (s, 1H), 7.15-7.28 (m, 2H), 7.88 (dd, 1H), 9.39 (br s, 1H);

MS (APCI-) m / z 424 (M-H) &lt; - &gt;;

Anal Calcd For C 18 H 18 BrFNO 5 S: C, 50.71; H, 4.02; N, 3.29. Found: C, 50.73; H,

4.24, N, 3.26.

Example 94

(-) 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinoline 1,1-dioxide

9 (5H) -on ¹ i wwwwwiwmawwwaHW ·

The product of Example 4 (1.646 g, 3.86 mmol) was treated according to the procedure of Example 91 and Example 92 to give 148 mg of the desired compound as a white solid.

[D] ²³ D-5.2 (DMSO);

1 H NMR (DMSO-d 6) 1.73 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H), 2.50 (m, 4H), 3.20 (m, 2H) 1.01 (s, 1H), 7.15-7.27 (m, 2H), 7.38 (dd, 1H), 9.40 (br s, 1H);

MS (APCI-) m / z 424 (M-H) &lt; - &gt;;

Calcd for C 18 H 11 BrFNO 5 S: C, 50.71; H, 4.02; N, 3.29. Found: C, 50.68; H, 4.17; N, 3.22.

Example 95

(+) (9R) -9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

The title compound of Example 29 (1.65 g, 4.30 mmol) as a slurry in THF (20 mL) under nitrogen at 5 ° C was treated dropwise with a solution of 1.0 M potassium tert-butoxide in THF (3.9 ml), allowed to warm to room temperature over 20 minutes, then treated with a solution of (-) - 8-phenylmenthylchloroformate (4.3 mmol) in THF (5 ml), stirred at room temperature over The mixture was extracted with diethyl ether (3x), the organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to give a mixture of diastereomeric carbamates. This mixture was flash chromatographed on a 6x40 cm silica gel column (chloroform: hexane: ether 7: 2: 1) to give 664 mg of less polar diastereomers. This material in the form of a slurry in methanol (10 ml) under nitrogen was treated with a catalytic amount of sodium methoxide, stirred at room temperature overnight, treated with glacial acetic acid (2 drops), the solid precipitate was combined, washed with ethyl alcohol and dried to give 295 mg of the desired compound as a white solid.

[Α] ²³ D + 70.9 ° (DMSO);

1 H NMR (DMSO-d 6) 1.75-1.95 (m, 2H), 2.23 (m, 2H), 2.54 (m, 2H), 2.83 (dt, 1H), 3.02 (dt,

1H), 3.45 (m, 2H), 4.84 (s, 1H), 7.16 (dd, 1H), 7.34 (d, 1H), 7.49 (d, 1H), 9, 82 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 382 (M-H) &lt; - &gt;;

Calcd for C17H15Cl2NO3S: C, 53.14; H, 3.93; N, 3.64. Found: C, 53.38; H,

4.19; N, 3.61.

· «· · · * · · · ·

Example 96

(-) (9S) 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

The contaminated, more polar diastereomer is obtained from the above-described diastereomer chromatography in Example 95. This material was flash chromatographed on a 6x40 cm silica gel column (chloroform: hexane: ether 7: 2: 1) to give 628 mg of the more polar diastereomers. This diastereomer in the form of a slurry in methanol (10ml) under nitrogen is treated with a catalytic amount of sodium methoxide, stirred at room temperature overnight, treated with glacial acetic acid (2 drops), the solid precipitate is combined, washed with ethanol and dried. to give 228 mg of the desired compound as a white solid. [Α] ²³ D -68.6 ° (DMSO);

^! 1 H NMR (DMSO-d 6) 1.75-1.95 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.73 (dt, 1H), 3.03 (dt, 1H), 3.35 (m, 2H), 4.84 (s, 1H), 7.17 (dd, 1H), 7.35 (d, 1H), 7.50 (d, 1H) , 9.85 (br s, 1H);

MS (APCI &lt; - &gt;) m / z 382 (M-H) &lt; - &gt;;

Calcd for C17H15Cl2NO3S: C, 53.14; H, 3.93; N, 3.64. Found: C, 53.11; H, 4.01; N, 3.59.

Example 97

(+) (9R) -9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinoline 1,1-dioxide ( 4H) -one

The product of Example 88 (1.34 g) was treated according to the methods of Example 95 to give 120 mg of the desired compound as a white solid.

[Α] ²³ D + 43.3 ° (DMSO);

1 H NMR (DMSO-d 6) 1.9 (m, 2H), 2.23 (m, 2H), 2.56 (m, 2H), 2.88 (m, 1H), 3.05 (m, ÍH),

3.4 (m, 2H), 5.0 (s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d, 1H), 9.95 (s) , 1H);

MS (ESI -) m / z 356 (M-H) &lt; - &gt;;

Calcd for C17H15N3O4S: C, 57.13; H, 4.23; N, 11.75. Found: C, 56.98; H,

4.28; N, 11.76.

Example 98

(-) (9S) -9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinoline 1,1-dioxide ( 4H) -one

The product of Example 88 (1.34 g) was treated according to the methods of Example 95 and Example 96 to give 110 mg of the desired compound as a white solid.

[Α] ²³ D -41.7 ° (DMSO);

^! 1 H NMR (DMSO-d 6) 1.9 (m, 2H), 2.25 (m, 2H), 2.57 (m, 2H), 2.9 (m, 1H), 3.05 (m, 1H) ), 3.4 (m, 2H), 5.0 (s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d, 1H), 9.95 (s, 1H);

MS (ESI -) m / z 356 (M-H) &lt; - &gt;;

Calcd for C17H15N3O4S: C, 57.13; H, 4.23; 11, 11.75. Found: C, 56.97; H, 4.43; N, 11.71.

Example 99

(+) (9R) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

The product of Example 34 (1.64 g) was treated according to the methods of Example 95 to give 300 mg of the title compound.

[Α] ²³ D + 41.04 ° (DMSO);

¹ H NMR (DMSO-d 6) 1.90 (m, 2H), 2.25 (m, 2H), 2.52 (m, 2H), 2.85 (m, 1H), 3.02 (m, 1H), 3.35 (m, 2H), 4.95 (s, 1H), 7.54 (dd, 1H, J = 3 Hz), 7.65 (d, 1H, J = 9 Hz), 7 80 (d, 1H, J = 3Hz)

9.90 (s, 1H);

MS (ESI -) for m / z 393 (M-H);

Calcd for C17H15ClN2O5S: C, 51.71; H, 3.83; N, 7.10. Found: C, 51.72; H, 3.85; N, 7.10.

Example 100

(9S) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide

The product of Example 34 (1.64 g) was treated according to the procedures of Example 95 and Example 96 to obtain 424 mg of the desired compound as a white solid. [Α] ²³ D-31.74 ° (DMSO);

1 H NMR (DMSO-d 6) 1.92 (m, 2H), 2.24 (m, 2H), 2.52 (m, 2H), 2.86 (m, 1H), 3.02 (m, 1H) )

3.38 (m, 2H), 4.95 (s, 1H), 7.54 (dd, 1H, J = 3Hz), 7.66 (d, 1H, J = 9Hz), 7.79 ( d, 1H, J = 3 Hz), 9.89 (s, 1H);

MS (ESI -) m / z 393 (M-H) ';

Calcd for C17H15ClN2O5S: C, 7.10; H, 3.83; N, 7.10. Found: C, 51.70; H, 3.83; N, 7.08.

Example 101

11- (3-bromo-4-fluorophenyl) -2,3,4,5,7,8,9,11-octahydrothiepino [3,2-b] quinolin-10 (6H) -one 1,1-dioxide

A solution of 3-bromo-4-fluorobenzaldehyde (1.22 g, 6.00 mmol), 3-amino-2-cyclohexen-one (667 mg, 6.00 mmol) and thiacycloheptan-3-one 1,1-dioxide ( 973 mg, 6.00 mmol) (prepared according to the method described in J. Heterocycl. Chem. (1990,27,1453)) in ethanol (10 mL) with triethylamine (0.4 mL) was heated at 80 ° C in sealed vessel for 3 days, cooled, solid precipitate collected, washed with ethanol and dried to give 1.8 g of the desired compound as a white solid

1 H NMR (DMSO-d 6) 1.65 (m, 1H), 1.75 (m, 2H), 1.90 (m, 1H), 2.02 (m, 2H), 2.52 (m, 2H) 2.75 (m, 3H), 3.15 (m, 1H), 4.95 (s, 1H), 7.20 (m, 1H), 7.25 (m, 1H), 7.40 (dd, 1H, J = 3 Hz),

9.44 (s, 1H);

MS (ESI +) m / z 441 (M + H) ^&lt; ^{+ &gt};;

Anal Calcd For C 11 H 18 BrFNCl 2 S: C, 51.83; H, 4.35; N, 3.18. Found: C, 51.59; H, 4.35; N, 3.18.

¹ U ··· »· * *» - - · * ''' Λ · «·“ ““ “

Example 102

10- (3-bromo-4-fluorophenyl) -2,3,4,5,6,7,8,10-octahydro-9H-cyclopenta [b] thiepino [2,3-e] pyridin-9-one

3-Bromo-4-fluorobenzaldehyde solution (639 mg, 3.14 mmol); 3-amino-2-cyclopenten-one (305 mg, 3.14 mmol) and thiacycloheptan-3-one 1,1-dioxide (510 mg, 3.14 mmol) in ethanol (10 mL) were heated at 80 ° C in a sealed vessel for 3 days, cooled, the solid precipitate was collected, washed with ethanol and dried to give 700 mg of the desired compound as a white solid.

Melting point 210 ° C;

1 H NMR (DMSO-d 6) 1.60 (m, 1H), 1.82 (m, 1H), 2.05 (m, 2H), 2.32 (m, 2H), 2.62 (m, 1H), 3H), 2.92 (m, 2H), 3.20 (m, 1H), 4.75 (s, 1H), 7.25 (dd, 1H, J = 3 Hz), 7.32 (m, 1H), 7.45 (dd, 1H, J = 3 Hz), 10.02 (s, 1H);

MS (ESI &^lt; ^{+ &gt};) m / z 427 (M + H) ^&lt; ^{+ &gt};;

Calcd for C ₁₈ H ₁₇ BrFNO ₃ S: C, 50.71; H, 4.02; N, 3.29. Found: C, 50.71; H,

4.10, N, 3.20.

Determination of potassium channel opening activity

Determination of membrane hyperpolarization

Compounds were evaluated for potassium channel opening activity using rat A10 thoracic aorta smooth muscle cell line or guinea pig primary cultured bladder cells (GPB).

The A10 cell line was purchased from the American Type Culture Collection (Rockville,

MD; Cat # 30-2002 Cells were cultured in 96-bottomed black plates (Packard) in culture medium (composition: Dulbecco's modified Eagle's medium supplemented with 20% fetal bovine serum, 100 units / ml penicillin, 100 units / ml streptomycin and 0.25 mg / ml amphotericin B) at 37 ° C with 5% CO 2 in a humidified chamber to form a confluent layer consisting of a single row of cells.

For the preparation of smooth muscle cells of the bladder, the bladder is removed from male guinea-pigs (Hartley, Charles River, Wilmington, MA) weighing 300-400 g and placed in Krebs solution, depleted in Ca ²⁺ cooled with ice (the composition. MM: KCl, 2.7 KH2PO4, 1.5;

NaCl, 75; Na ₂ HPO ₄ , 9.6; Na ₂ HPO4 * 7H ₂ O, 8; MgSO ₄ , 2; glucose, 5; HEPES, 10; pH 7.4).

♦ ·

Cells were isolated by the above enzymatic dissociation with minor modifications (Klockner, U. and Isenberg, G., Pflugers Arch. 1985, 405, 329-339). The bladder was divided into several small parts and incubated in 5 ml Krebs solution containing 1 mg / ml collagenase (Sigma, St. Louis, MO) and 0.2 mg / ml pronase (Calbiochem, La Jolla, CA) with stirring in cell incubator for 30 minutes. The mixture was then centrifuged at 1300 xg for 5 minutes and the pellets were resuspended in Dulbecco's PBS (GIBCO, Gaithersburg, MD) and centrifuged again to remove residual enzyme. Cell pellets were resuspended in 5 ml growth medium (composition: Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 units / ml penicillin, 100 units / ml streptomycin and 0.25 mg / ml amphotericin B) and further dissociated by pipetting the suspension using fire-sterilized Pasteur pipettes and passing through a polypropylene mesh membrane (Spectrum, Houston, TX). Cell density was adjusted to 100,000 cells / ml by resuspension in growth medium. For membrane potential studies, cells were placed in black plates of 96 clear bottom tubes (Packard) at a density of 20,000 cells / tube and kept in a cell incubator with 90% air: 10% CO ₂ until they coincide. Verification was made of smooth muscle cell type by cytoskeletal labeling using monoclonal antihuman smooth muscle actin obtained from mice (Biomeda, Foster City, CA).

Functional activity in potassium channels was measured by evaluating changes in membrane potential using bis-oxonal DiBAC (4) 3 (Molecular Probes) in a 96-tube Fluorescent Imaging Plate Reader (FLIPR) kinetic assay system ( KS Schroeder et al., J. Biomed. Screen., V. 1, 75-81 (1996)). DIBAC (4) 3 is an anionic potentiometric sensor that divides between two phases, depending on the membrane potential, between the cell phase and the extracellular solution phase. With increasing membrane potential (eg, K ⁺ depolarization), the sensor is further subdivided into the cell phase; this is measured as an increase in fluorescence due to dye interactions with intracellular lipids and proteins. Conversely, decreasing membrane potential (hyperpolarization with potassium channel opener) causes a decrease in fluorescence.

Continuous smooth muscle A10 cells or guinea-bladder cells cultured in 96 black tube plates were rinsed with 2 x 200 ml assay buffer (composition, mM: HEPES, 20; NaCl, 120; KCl, 2; CaCl ₂ , 2; MgCl ₂ 1 glucose

5; pH 7.4 at 25 ° C), which contained 5 M DIBAC (4) ₃ and incubated with 180 ml buffer • 9W ·· - · *?

solution in a cell incubator for 30 minutes at 37 ° C to ensure distribution of dye across the membrane. After recording the baseline fluorescence for 5 minutes, reference or test compounds prepared at 10-fold concentration in assay buffer were added directly to the tubes. Fluorescence changes were monitored for an additional 25 minutes. Hyperpolarization responses were corrected for any intrinsic noise and corrected for the responses observed with the 10 M reference compound P1075 (determined as 100%), a potent kanály _Α · π> smooth muscle channel opener (Quast et al., Mol. Pharmacol., V. 43, 474-481 (1993)).

Five concentrations of P1075 or test compounds (logarithmic or half logarithmic dilution) and maximum stationary hyperpolarization state values (expressed as% relative to P1075) plotted as a function of concentration were calculated. EC 50 values (the concentration that elicits 50% of the maximum response for the test sample) were calculated by non-linear regression analysis using four variables of the sigmoidal equation. The maximum responses of each compound (expressed as% relative to P1075) are shown below.

Compound stock solutions were prepared in 100% DMSO and further dilutions were made in assay buffer and added to 96-well plates.

Table 1

Membrane hyperpolarization (MHP) in A10 cells and guinea pig bladder (GPB) cells MHP in A10 MHP cells in GPB cells

Example number Maximal response (% P1075) EC50 (M) Maximal response (% P1075) EC50 (M) .—- ¹ 93 2.1 -50- 2 73 -0770- 77 2.1 3 90 -E6- 110 1J 4 ”110 030 120 038 5 78 5.5 41 18 6 ' 48 - _n - 31 17 7 94 -O- 100 ALIGN! 2.8 8 -56- -73- —ΓΟΟ 2.5 IN 39 16 67 7.2 10 61 4.0 —Ioo— 15 Dec 11 42 - _n - 29 20 May

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Functional models in vitro

Compounds were evaluated for functional potassium channel opening activity using portions of tissues obtained from bladders of Landras pig and human subjects.

Landrasse bladder bladders were obtained from female Landras pigs weighing 9-30 kg. These subjects were sacrificed by intraperitoneal injection of a pentobarbital solution, Somlethal®, JA Webster Inc, Sterling MA. The whole bladder was removed and immediately placed in Krebs physiological bicarbonate solution (composition, mM: NaCl, 120; NaHCO 3, 20; dextrose, 11; KCl, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 1.5; KH ₂ PO ₄ , 1.2; K ₂ EDTA, 0.01, equilibrated with 5% CO ₂ /95% O ₂ pH 7.4 at 37 ° C). Propanolol (0.004 mM) was included in all assays to block adrenoceptors. The triangular and upper portions were removed. Stripes 3-5 mm wide and 20 mm long were prepared from the remaining tissue, cut radially, and the mucous layer was removed. One end was attached to a solid glass rod and the other to the Grass FT03 transducer at a preliminary basal load of 1.0 grams. The solid glass rod contained two parallel platinum electrodes to provide a field stimulation of 0.05 Hz, 0.5 milliseconds at 20 volts. This low frequency stimulation was stable

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response rate of contractions of 100-500 centigrams. Tissues were allowed to equilibrate for at least 60 minutes and treated with 80 mM KCl. A control (cumulative) response curve was generated for each tissue using P1075, a potassium channel opener, as a control agonist. P1075 fully eliminated dose-dependent stimulated contractions over a range of 10 ⁹ - 10 ⁵ M concentrations at 1/2 log increments. After a 60 minute wash, a concentration (cumulative) response curve was generated for the agonists tested in the same manner as the control agonist P1075. The maximum activity of each compound (expressed as% relative to P1075) is shown below. The amount of agent required to achieve 50% of the maximum response (ED50) for the test sample was calculated using "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)) and agonist potency expressed as pD2 (negative). logarithm). The agonist potency was also expressed as an index relative to P1075. The index was calculated by dividing the ED50 for P1075 by the ED50 of the agonist tested in said tissue. Each tissue was used for only one agonist tested, and the data obtained from each tissue was averaged to obtain an average potency index. These data are shown in Table 2.

Bladders from human subjects were obtained from women over 45 years of age. Human tissue was provided by Anatomy Gift Foundation, Phoenix AZ and was delivered the next day on wet ice placed in Krebs saline bicarbonate (composition: mM: NaCl, 120; NaHCO ₃ , 20; dextrose, 11 ,; KCl, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 1.5; KH ₂ PO ₄ , 1.2; K ₂ EDTA, 0.01; equilibrated with 5% CO 2/95% O ₂ pH 7.4 at 37 ° C). Propanolol (0.004 mM) was included in all assays to block adrenoceptors. The triangular and upper portions were removed.

Stripes 3-5 mm wide and 20 mm long were prepared from the remaining tissue, cut radially, and the mucous layer was removed. For human detrusor bands, the tissues were concentrated with 25 mM KCl, which induced a steady state pressure of approximately 400 centigrams. For each tissue, a control (cumulative) response curve was generated using P1075, a potassium channel opener, as a control agonist. P1075 fully relaxed stimulated contractions over a range of 10 ⁹ - 10 ⁴ M concentrations at 1/2 log step. After a 60 minute wash, a concentration (cumulative) response curve was generated for the agonists tested in the same manner as the control agonist P1075. The maximum activity of each compound (expressed as% relative to P1075) is shown below. The amount of agent necessary to achieve 50% maximum response (ED 50) for the test sample was calculated by "ALLFIT" (DeLean et al., Am. J. Physiol., 235, E97 (1980)) and agonist potency was expressed as pD ₂ ( negative logarithm). The agonist potency was also expressed as an index relative to P1075.

Μ · - - <- '

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The index was calculated by dividing the ED50 for P1075 by the ED50 of the agonist tested in said tissue. Each tissue was used for only one agonist tested, and the data obtained from each tissue was averaged to obtain an average potency index. These data are shown in Table 2.

Number example Landrace pig bladder Human bladder Efficiency (% P1075) ρϋ2 Index Efficiency (% Ρ1075) ρϋ2 index 19 ” 94 6.0 07Π ΓΟΟ 578 Ο7Τ5 2 96 537 0.15 1 Γ00 5.5 0.022 “' 16 Γ00 5.0 ~ (Π) Π— 11 —Ιοο— 4.1 0.ΟΟ21 5 96 4.8 0.0076 3 85 6.0 0.11 8 95- 5.0 “07025” 4 93 6.2 —07Γ8— 36 97 5.5 07040 26 78 4.5  0.0099 ” 25 -88- 5.4 '0038 23 81 4.4 “070053” 22nd ΊΊ 4.5 “00059” 34 —100— 6.8 032 38 98 6.2 0714 40 98 6.9 045 30 99 5.5 '' 0.018 ....... 44 99 6.2 '0715 43. '98 6.6 041 51 99 5.4 0.023 ” 52 —Roo— -575- 'ϋΟΙ'8 ”' 53 —Roo— -50- —0717— 54 89 —Ο— O7OT5 56 97 -77Γ- '' 0788 "

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As shown in Tables 1 and 2, the compounds of the present invention reduce stimulated bladder contractions by opening potassium channels and are therefore effective in treating disease prevention or ameliorating the disease.

The present invention also provides pharmaceutical compositions comprising the compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of the present invention can be administered to humans or other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, or locally (dusting, ointments, drops), buccally, or as an oral or nasal spray. The term "parenteral" as used herein refers to routes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.

Pharmaceutical compositions of the invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile dusting powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings, such as lecithin, in the case of dispersions, by the maintenance of the desired particle size and by the use of surfactants.

These compositions may also contain adjuvants such as stabilizers, detergents, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by incorporating various antibacterial agents and fungicides, eg, paraben, chlorobutanol, phenol sorbic acid, etc. Also, it may be desirable to include isotonic agents such as sugar, sodium chloride, etc. Prolonged absorption of the injectable pharmaceutical form may be caused. admixtures with agents (such as aluminum monostearate and gelatin) that delay absorption.

In some cases, in order to prolong the effects of the drug, it is desired to slow the absorption of the drug from subcutaneous or intramuscular injection, which may be achieved using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The rate of drug absorption is then determined by the degree of solubility of the drug, which depends on the crystalline size and crystalline form.

Alternatively, delayed absorption of the parenterally administered drug may be achieved by dissolving or suspending the drug in an oil carrier.

Injectable depot forms are made by molding microscopically encapsulated drug matrices into biodegradable polymers such as polylactide polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the origin of the polymer particles used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

Injectable formulations may be sterilized, for example, by filtration through a bacterial retention filter or by incorporation of a sterilizing agent in the form of sterile solid preparations which, before use, may be dissolved or dispersed in sterile water or other sterile injectable medium.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and orthosilicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid certain silicates and calcium carbonate; e) solution inhibitors such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) detergents such as cetyl alcohol and glycerol monostearate; h) adsorbents such as e.g. for example, kaolin and bentonite kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent.

Solid compositions of a similar type may also be employed as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Dosages in solid form, such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulations. Dosages in solid form may optionally contain a opacifying agent and may also be free of such formulations that release only or preferably the active ingredients in a particular portion of the intestinal tract, optionally delayed to some extent. Examples of embedding compositions that can be used include polymeric substances and waxes.

The active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,

1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, groundnuts, corn, germs, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.

Compared to inert diluents, oral preparations may also include adjuvants such as detergents, emulsifiers and suspending agents, sweeteners, flavoring agents and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitols and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and traganth, and mixtures thereof.

Formulations for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with suitable, non-irritating excipients or carriers, such as cocoa butter, polyethylene glycols or wax suppositories, which are solid at room temperature but liquid at body temperature and therefore, they thaw in the rectum or vaginal cavity to release the active compound.

The compounds of the present invention may also be administered in the form of liposomes.

As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolamellar or multilamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and useful lipid capable of forming liposomes can be used. The present liposome formulations may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are synthetic or natural phospholipids and phosphatidylcholines (lecithins) used together or separately. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., (1976), page 33 et seq.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" as used herein refers to those salts that are within the scope of reasonable medical judgment suitable for use in contact with human or lower animal tissues without toxic action, irritation, allergic reactions, and the like, and they are proportional to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art, e.g., S. M. Berge, et al., Describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base with a suitable organic acid. Examples of pharmaceutically acceptable, non-toxic acid addition salts include, but are not limited to, adipate, alginate, citrate, aspartate, benzenesulfonate, benzoate, bisulfate, butyrate, camphate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloro, hydrogen chloride, , hydrogen iodide, 2-hydroxyethane sulfonate (isethionate), lactate, maleate, methanesulfonate,

2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, nitrogen-containing basic groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. Thus, water-soluble or oil-soluble or dispersible products are obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid, and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid.

Base addition salts may be prepared in situ during the final isolation and purification of the compounds of the present invention by reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate, bicarbonate of a pharmaceutically acceptable metal cation or ammonia or an organic primary, secondary or tertiary amine . Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as lithium, sodium, potassium, calcium, magnesium or aluminum salts and the like, and non-toxic quaternary ammonium salts and amine cations including ammonia, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Preferred salts of the compounds of the present invention include phosphate, tris- and acetate. salts.

Dosage forms for topical administration of a compound of this invention include dusting powders, sprays, inhalants and creams. The active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative, buffer, or propellant as desired. Ophthalmic formulations, eye ointments, dusting powders and solutions are also contemplated within the scope of the present invention.

Thus, the actual dosage level of the active compound component in the pharmaceutical compositions of the invention may be varied to provide an amount of active compound (s) that is effective to achieve the desired therapeutic response for the individual patient, formulations and route of administration. The selected dosage level will depend upon the activity of the individual compound, the mode of administration, the strength of the condition being treated and the condition prior to the medical history of the patient being treated. However, to achieve the desired therapeutic effect, it is known in the art to start doses of the compound at lower levels than desired and gradually increase the doses until the desired effect is achieved.

The compounds of the present invention, including but not limited to those specified in the examples, have potassium channel opening activity in mammals (particularly humans). As potassium channel opener, the compounds of the present invention are useful for treating and preventing such diseases as asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.

The ability of the compounds of the present invention to treat asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke can be demonstrated according to the methods described (DE Nurse et al., Br. J Urol., 1991, 68, 27-31, BB Howe et al., J.

Pharmacol. Exp. Ther., V. 274 884-890 (1995); K. Lawson, Pharmacol. Ther., V. 70, 39-63 (1996); D.R. Gehlert et al., Neuro-Psychopharmacol & Biol. Psychiat., V. 18, 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28 95-127 (1993); J.E. Freedman et al., The Neuroscientist, v. 2145-152 (1996); D. Spanswick et al., Nature, v. 390,521-25 (December 4, 1997)).

The aqueous liquid formulations of the present invention are particularly effective for treating and preventing diseases such as asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.

When the compounds of the present invention are used to treat the aforementioned diseases or to treat other diseases, a therapeutically effective amount of one of the compounds of the present invention in pure form or in the form of a pharmaceutically acceptable salt, ester or prodrug can be used. Alternatively, the compound may be administered as a pharmaceutical composition comprising the desired compound in combination with one or more pharmaceutically acceptable excipients. By "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to treat a disease at a reasonable efficacy / risk ratio applicable to any medical treatment. However, it is clear that the overall daily use of the compounds and compositions of the present invention is at the discretion of the attending physician after reasonable medical judgment. The specific, therapeutically effective dose level for any individual patient will depend on various factors including the disease being treated and the severity of the disease; the activity of the specific compound used; use of a specific preparation; the patient's age, body weight, general health, sex and lifestyle; the time of administration, the mode of administration and the rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or in accordance with the specific compound used; and similar factors well known in medical practice. For example, to achieve the desired therapeutic effect, it is known in the art to start doses of the compound at lower levels than desired and gradually increase the doses until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to humans or lower mammals may range from about 0.003 to 10 mg / kg / day. For oral administration, dosages in the range of about 0.01 to about 5 mg / kg / day are more preferred. If necessary, the effective daily dose for administration may be divided into several doses; as a result, a single dose may contain such amounts or proportions thereof to form a daily dose.

Claims (40)

A compound of formula (I) or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein R ¹ is alkyl; R ² is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; index n is 0-2; A is selected from the group consisting of hydrogen, alkyl and -X-R; R ³ is alkyl or haloalkyl; X is -C (O) - or -S (O) _P -, wherein the index p is 1-2; R ⁴ and R ⁵ are independently selected from the group consisting of hydrogen, alkyl or haloalkyl; or R ¹ and R ⁵ joined together form to the ring to which they are attached, A 5-membered, 6-membered or 7-membered one containing a sulfur atom with 1-2 double bonds and 0 2 oxo substituents; or the substituents A and R ⁴ taken together form to the ring to which they are attached a ring selected from the group consisting of a 5-membered, 6-membered or 7-membered carbocyclic ring with 1-2 double bonds and 0-1 oxo substituents az A 5-membered, 6-membered or 7-membered sulfur-containing ring with 1-2 double bonds and 0-2 oxo substituents, provided that at least one of R ¹ and R ⁵ or A and R ⁴ forms a ring. A compound according to claim 1, wherein the substituents A and R ⁴ together with the ring to which they are attached form a 6-membered carbocyclic ring with one double bond and one oxo substituent. V · ',: / T ... The compound of claim 2, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 3, wherein R ² is optionally substituted aryl. A compound according to claim 4 selected from the group consisting of: 3,4,6,7,8,10-Hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9- (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-Fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-difluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- [3-fluoro-5- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H79-thiopyrano [3,2-b] quinolin-9 (5H) - 1,1-dioxide onu; 10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ; 3,4,6,7,8,10-Hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide. The compound of claim 3, wherein R ² is optionally substituted heteroaryl. A compound according to claim 6 selected from the group consisting of. 10- (3-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-Pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide. The compound of claim 2, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 5-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 8, wherein R ² is optionally substituted aryl. The compound of claim 9 selected from the group consisting of. 9- (3-cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 3,4,5,6,7,9-hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; and 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide. The compound of claim 2, wherein R ¹ and R ⁵ are alkyl. The compound of claim 11, wherein R ² is optionally substituted aryl. A compound according to claim 12 selected from the group consisting of: 4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4 (3-nitrophenyl) -5 (1H) -quinolinone; 4.6.7.8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone; 4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4.6.7.8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3 (methylsulfonyl) -5 (1H) -quinolinone; 4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; and 4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; The compound of claim 1, wherein the substituents A and R ⁴ together with the ring to which they are attached form a 5-membered carbocyclic ring with one double bond and one oxo substituent. The compound of claim 14, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 15, wherein R ² is optionally substituted aryl. A compound according to claim 16 selected from the group consisting of: 9- (3-cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; and 9- (4-Methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide. The compound of claim 14, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 5-membered ring containing a sulfur atom with one double bond and two oxo substituents. The compound of claim 18, wherein R ² is optionally substituted aryl. A compound according to claim 19 selected from the group consisting of: • · · 8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide; and 8- (3-Bromo-4-fluorophenyl) 3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide. The compound of claim 1, wherein A is -XR, X is -C (O) -, and R ³ and R ⁴ are alkyl. The compound of claim 21, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom, with one double bond and two oxo substituents. The compound of claim 22, wherein R ² is optionally substituted aryl. The compound of claim 23 selected from the group consisting of: 1- [8- (3,4-Dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone; 1- [8- (4-Chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone . The compound of claim 1, wherein the substituents A and R ⁴ together with the ring to which they are attached form a 6-membered carbocyclic ring containing a sulfur atom with one double bond and 0-2 oxo substituents. The compound of claim 25, wherein R ¹ and R ⁵ together with the ring to which they are attached form a 6-membered ring containing a sulfur atom with one double bond and 0-2 oxo substituents. The compound of claim 26, wherein R ² is optionally substituted aryl. A compound according to claim 27 which is 10,9- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bisthiopyrano [3,2- b: 2 ', 3'-e] pyridine; • A ¹ '* ...... ^{1 Ι} '. ··! .Φ · ¹ II I ', H'. 29. A compound selected from the group consisting of. 3,4,6,7,8,10-Hexahydro-10-phenyl-2H-thiopyrano [3,2-b] quinolin-9- (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3-nitrophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-cyanophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [3- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-Fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- [4- (trifluoromethyl) phenyl] -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-bromophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-dichlorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-chloro-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3,4-difluorophenyl) -3,4,6,7,8,14-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- [3-Fluoro-5- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ; 10- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide ; 3,4,6,7,8,10-hexahydro-10- (4-methyl-3-nitrophenyl) 2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-chloro-3-nitrophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 3,4,6,7,8,10-Hexahydro-10- (3,4,5-trifluorophenyl) -2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (3-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 10- (4-pyridyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) -one, 1,1-dioxide; 9- (3-cyanophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- [4-fluoro-3- (trifluoromethyl) phenyl] -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 3,4,5,6,7,9-hexahydro-9- (4-methyl-3-nitrophenyl) thieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one 1,1-dioxide; 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-e] quinolin-8 (2H) -one 1,1-dioxide; 4- (3-cyanophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4 (3-nitrophenyl) -5 (1H) -quinolinone; 4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -4- [4- (trifluoromethyl) phenyl] -5 (1H) -quinolinone; 4- (3,4-dichlorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; .. .... »• .... .... .... .... .... .... .... .... .... 4,6,7,8-tetrahydro-2-methyl-4- (4-methyl-3-nitrophenyl) -3 (methylsulfonyl) -5 (1H) -quinolinone 1,1-dioxide; 4- (4-chloro-3-nitrophenyl) -4,6,7,8-tetrahydro-2-methyl-3 (methylsulfonyl) -5 (1H) -quinolinone; 4- (3-bromo-4-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4- (4-chloro-3-fluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 4- (3,4,5-trifluorophenyl) -4,6,7,8-tetrahydro-2-methyl-3- (methylsulfonyl) -5 (1H) -quinolinone; 9- (3-cyano) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-chloro-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-fluoro-3-trifluoromethyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 9- (4-methyl-3-nitro) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 8- (4-Chloro-3-nitrophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7- (4H) -one, 1,1-dioxide; 8- (3-bromo-4-fluorophenyl) -3,5,6,8-tetrahydro-2H-cyclopenta [b] thieno [2,3-e] pyridin-7 (4H) -one, 1,1-dioxide; 1- [8- (3,4-dichlorophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone; 1- [8- (4-Chloro-3-nitrophenyl) -3,4,5,8-tetrahydro-6-methyl-1,1-dioxido-2H-thiopyrano [3,2-b] pyridin-7-yl] ethanone ; 10- (4-chloro-3-nitrophenyl) -3,4,6,7,10-hexahydro-2H, 5H-bis-thiopyrano [3,2-b: 2 ', 3 ^, -e] 1,1,9,9-tetraoxide ] pyridine; Or pharmaceutically acceptable salts, esters, amides or prodrugs thereof. 30. A method of treating a disease comprising administering an effective amount of a compound of claim 1. The method of claim 30, wherein the disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, bowel functional disorders, neurodegeneration and stroke. or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein R ² is selected from the group consisting of aryl and heteroaryl; aryl or heteroaryl may be optionally substituted; n is 1 or 2; X is selected from the group consisting of -CH 2 -, -C (O) -, -S (O) -, or -S (O) ₂ -; and n and n are independently 1-3. The compound of claim 32, wherein R ² is optionally substituted aryl. The compound of claim 33, wherein said substituted aryl is substituted with substituents selected from the group consisting of halogen, nitro, cyano, and haloalkyl. The compound of claim 32, wherein R is optionally substituted heteroaryl. The compound of claim 35, wherein said substituted heteroaryl is substituted with substituents selected from the group consisting of halogen, nitro, cyano, and haloalkyl. A compound according to claim 32 selected from the group consisting of: 9- (3,4-difluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 8- (4-Chloro-3-nitrophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3i-e] pyridine, 1,1,7,7-tetraoxide; 8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine, 1,1,7,7-tetraoxide; 10- (3-bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H, 5H-dithiopyrano [3,2-b: 2H, 3i-e] 1,1,9,9-tetraoxide ] pyridine; 3,4,5,6,7,9-hexahydro-9- (3-nitrophenyl) cyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one, 1,1-dioxide; 8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 2,3,4,5,6,8-hexahydro-8- (3-nitrophenyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 3,4,6,7,8,10-hexahydro-10- (3-nitrophenyl) -2H, 5H-dithiopyrano [3,2b: 2H, 3i-e] pyridine 1,1,9,9-tetraoxide; 8- (3,4-dichlorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3-Cyanophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide; 8- (2-Cyano-4-pyridinyl) -2,3,4,5,6,8-hexahydro-88-dioxide 7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one; 8- (3-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (4-fluoro-3-trifluoromethylphenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2b: 2H, 3i-e] pyridine, 1,1,7,7-tetraoxide; 8- (4-bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide; 8- (5-bromo-2-thienyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide ; 2,3,4,5,6,8-Hexahydro-8- (5-nitro-3-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-thienyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one 1,1-dioxide ; 2,3,4,5,6,8-Hexahydro-8- (5-nitro-2-furyl) -7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3,4-Dibromophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 2,3,4,5,6,8-Hexahydro-8- (3-nitrophenyl) dithieno [3,2-b: 2H, 3H-e] pyridine 1,1,7,7-tetraoxide 8- (3-Chloro-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2,1-e] pyridine 1,1,7,7-tetraoxide ; 8- (3,4-Chloro-phenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3H-pyridine] 1,1,7,7-tetraoxide; 8- (4-Bromo-phenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (3,4-Difluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 8- (4-Chloro-3-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; 9- (3-chloro-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide; 8- (3-Cyano-4-fluorophenyl) -2,3,4,5,6,8-hexahydrodithieno [3,2-b: 2H, 3e] pyridine, 1,1,7,7-tetraoxide; - * · (► (+) (9R) -9- (3-bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) 1,1-dioxide -one; (-) (9S) -9- (3-Bromo-4-fluorophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) 1,1-dioxide -one; 8- (2,1,3-Benzoxadiazol-5-yl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-1,1-dioxide -one; (-) (8S) -8- (3-bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] 1,1-dioxide pyridin-7-one; (+) (8R) -8- (3-Bromo-4-fluorophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridine-7 -one; 9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide; 9- (4-fluoro-3-iodophenyl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) -one, 1,1-dioxide; 8- (4-fluoro-3-iodophenyl) -2,3,4,5,6,8-hexahydro-7H-cyclopenta [b] thieno [2,3-e] pyridin-7-one, 1,1-dioxide; (+) 9- (3-Bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one; (-) 9- (3-bromo-4-fluorophenyl) -3,4,5,6,7,9-hexahydrocyclopenta [b] thiopyrano [2,3-e] pyridin-8 (2H) -one; (+) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) 1,1-dioxide -one; (-) 10- (3-Bromo-4-fluorophenyl) -3,4,6,7,8,10-hexahydro-2H-thiopyrano [3,2-b] quinolin-9 (5H) 1,1-dioxide -one; (+) (9R) -9- (3,4-Dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ; (-) (9S) -9- (3,4-dichlorophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ; (+) (9R) -9- (2,1,3-Benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 1,1-dioxide ( 4H) -one; (-) (9S) -9- (2,1,3-benzoxadiazol-5-yl) -2,3,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (4H) - he; (+) (9R) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,990 hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide; (-) (9S) -9- (4-Chloro-3-nitrophenyl) -3,4,5,6,7,9-hexahydrothieno [3,2-b] quinolin-8 (2H) -one, 1,1-dioxide ; 11- (3-bromo-4-fluorophenyl) -2,3,4,5,7,8,9,11-octahydrothiepino [3,2-b] quinolin-10 (6H) -one, 1,1-dioxide; and 10- (3-bromo-4-fluorophenyl) -2,3,4,5,6,7,8,10-octahydro-9H-cyclopenta [b] thiepino [2,3-e] pyridin-9-one or their pharmaceutically acceptable salts, esters, amides or prodrugs. 38. A method of treating a disease comprising administering an effective amount of a compound of claim 32. 39. The method of claim 38, wherein the disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, bowel functional disorders, neurodegeneration and stroke. 40. A method of treating a disease comprising administering an effective amount of a compound of claim 37. 41. The method of claim 40, wherein the disease is selected from the group consisting of asthma, epilepsy, hypertension, Raynaud's syndrome, impotence, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.