IP Library › Granted Patent US 8,183,234

Granted Patent B2

US 8,183,234 · App. 12/827,277 · Granted May 22, 2012

Tricyclic guanidine derivatives as sodium-proton exchange inhibitors

Assignee: Piramal Life Sciences Limited

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Patent No.: US 8,183,234
App. No.: 12/827,277
Granted: May 22, 2012
Kind: B2

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Abstract

Guanidine derivatives having a condensed tricyclic ring of formula 1: are disclosed, wherein U is C(O), CR a R b , O, NR a or S(O) m ; V is CR a R b or NR a ; W is S(O) m ; wherein R a is H, alkyl, cycloalkyl, alkenyl or aralkyl; R b is H, alkyl, OH, OR a or OCOR a , and m is the integer 0, 1 or 2; R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein with the proviso that at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is guanidino or guanidinocarbonyl. These derivatives are sodium-proton exchange inhibitors and are useful as medicaments for the treatment of, for example, organ disorders associated with ischemia and reperfusion, cardiac arrhythmia, cardiac hypertrophy, hypertension, cell proliferative disorders and diabetes.

Claims (478)

1. A method for the treatment of disorders associated with abnormal sodium proton exchange activity in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of the formula 1;

or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein,

R1 is selected from: hydrogen, halogen, —(C 1 -C 4 )alkyl and guanidino carbonyl;

R2 is selected from: hydrogen, halogen, hydroxy, hydroxyalkyl, formyl, alkoxy, (C 3 -C 6 )cycloalkoxy, aryloxy, alkylthio, alkylcarbonyl, carboxy, alkylcarboxylate, alkyl, —(C 2 -C 4 )alkenyl, (C 3 -C 6 )cycloalkyl, aryl, aryloxycarbonyl, alkylaminoalkyl, aminocarbonyl, cyano, nitro, amidino, sulfonyl chloride, sulfonyl hydrazide, alkylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, sulfonamide, alkyl-NH—SO 2 —, cycloalkyl-NH—SO 2 —, heterocyclyl-NH—SO 2 —, heteroaryl-NH—SO 2 —, heteroaryl-alkyl-NH—SO 2 —, arylalkyl, heterocyclyl, heteroaryl, guanidino carbonyl, guanidino, —NR′R″ and N═R′″;

R3 is selected from hydrogen and halogen;

R4 is selected from hydrogen, halogen, —(C 1 -C 4 )alkyl and —NR′R″;

R5 is —(C 1 -C 4 )alkyl;

R6 is selected from hydrogen, halogen, (C 1 -C 4 )alkyl, heteroaryl;

R7 is guanidino or guanidino carbonyl;

R8 is hydrogen;

R′ and R″ are independently from each other selected from: hydrogen, alkyl, (C 3 -C 6 )cycloalkyl, aryl, arylalkyl, haloalkyl, thioalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, carboxyalkyl, aminoalkyl, mono- or di-alkyl-substituted aminoalkyl, (C 3 -C 6 )cycloalkylaminoalkyl, arylalkylaminoalkyl, alkoxyarylalkyl aminoalkyl, heterocyclylalkyl, heterocyclylaminoalkyl, heterocyclylalkylaminoalkyl, heterocyclylalkyl-N[(alkyl)]-alkyl, heteroarylalkyl, heteroarylalkylaminoalkyl, alkoxyarylalkyl-N[(alkyl)]-alkyl, arylalkyl-N[(alkyl)]-alkyl, alkoxycarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylcarbonyl, CHO and alkyl carbonyl;

R′″ is selected from: heterocyclyl, (C 3 -C 6 )cycloalkyl and alkyl;

where alkyl is (C 1 -C 4 )alkyl which is unsubstituted or substituted by one, two or three of the same or different substituents selected from: halo, hydroxy, alkoxy, alkylamino, (C 3 -C 6 )cycloalkyl amino, aryl and heterocyclyl);

where aryl is (C 6 -C 10 )aryl which is unsubstituted or substituted by one or two of the same or different groups selected from: nitro, alkyl, alkoxy, halogen, haloalkyl, amino, mono- or dialkylamino, and heterocyclylalkylaminoalkyl;

where heteroaryl is a 5 or 6 membered ring system containing one, two or three ring atoms selected from N, O and S, which is unsubstituted or substituted by one or two of the same or different groups selected from: halogen, nitro, amino, alkylamino, alkyl, alkoxy and alkylcarbonyl;

where heterocyclyl is a 5 or 6 membered ring system containing one, two or three ring atoms selected from N, O and S, which is unsubstituted or substituted by one or two of the same or different groups selected from: alkyl, (C 3 -C 6 )-cycloalkyl, hydroxyalkyl, alkylaminoalkyl, (C 3 -C 6 )cycloalkylalkyl, (C 3 -C 6 )cycloalkyl carbonyl, heterocyclylalkyl, heteroarylalkyl, heteroarylcarbonyl, arylalkyl, and oxo; guanidino and guanidinocarbonyl are unsubstituted or substituted by one, two or three of the same or different groups selected from: alkyl and alkylcarbonyl;

U is C(O), CR a R b , O or NR a ;

V is CR a R b or NR a ;

W is S(O) 2 ;

wherein,

R a is H, alkyl, (C 3 -C 6 )cycloalkyl or (C 2 -C 4 )alkenyl;

R b is H, alkyl, OH, or OR a ;

and wherein the disorders associated with abnormal sodium-proton exchange activity are selected from: ischemia or reperfusion induced tissue damage as occurring in (i) cardiovascular diseases selected from the group consisting of angina pectoris, acute coronary syndrome, myocardial infarction, myocardial stunning, arrhythmias, cardiac dysfunction, post-infarct remodeling, hypertension and vascular restenosis, (ii) cardiovascular surgical procedures selected from the group consisting of coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary intervention (PTCI), organ transplantation, and (iii) cerebrovascular disorders selected from the group consisting of cerebral ischemic stroke and edema; and thrombosis.

2. The method according to claim 1 , wherein in the compounds of formula 1,

R 1 is selected from: hydrogen, halogen, —(C 1 -C 4 )alkyl and guanidinocarbonyl;

R 2 is selected from: hydrogen, halogen, hydroxy, cyano, nitro, formyl, carboxy, guanidino, guanidinocarbonyl, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkoxycarbonyl, (C 6 -C 10 )aryloxycarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, amino, (C 1 -C 4 )alkylamino, thio-(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkoxy-substituted (C 1 -C 4 )alkylamino, di-(C 1 -C 4 -alkyl)amino, chloro(C 1 -C 4 )alkylamino, di-[chloro-(C 1 -C 4 )alkyl]amino, hydroxy(C 1 -C 4 )alkylamino, di-[hydroxy-(C 1 -C 4 )alkyl]amino, mono- or di-(C 1 -C 4 -alkyl) substituted-amino-(C 1 -C 4 )alkylamino, (C 6 -C 10 )aryloxy(C 1 -C 4 )alkylamino, (C 6 -C 10 )aryl(C 1 -C 4 )alkoxy(C 1 -C 4 )alkylamino, benzylamino, morpholinyl-(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkylsubstituted-thiophenyl-(C 1 -C 4 )alkylamino, pyrrolidinyl(C 1 -C 4 )alkylamino, pyridyl(C 1 -C 4 )alkylamino, piperidinyl(C 1 -C 4 )alkylamino, 3H-imidazolyl(C 1 -C 4 )alkylamino, piperazinyl(C 1 -C 4 )alkylamino, morpholinyl(C 1 -C 4 )alkylamino(C 1 -C 4 -alkyl), pyrrolidinyl(C 1 -C 4 )alkylamino(C 1 -C 4 -alkyl), piperidinyl(C 1 -C 4 )alkylamino(C 1 -C 4 -alkyl), furanyl(C 1 -C 4 )alkylamino, benzylamino(C 1 -C 4 )alkylamino, morpholinylamino(C 1 -C 4 )alkylamino, (C 3 -C 6 )cycloalkylamino(C 1 -C 4 )alkylamino, furanyl(C 1 -C 4 )alkyl-N[(C 1 -C 4 )alkyl]CH 2 CH 2 —N[(C 1 -C 4 )alkyl]-, thiophenyl(C 1 -C 4 )alkyl-N[(C 1 -C 4 )alkyl]-CH 2 CH 2 —N[(C 1 -C 4 )alkyl]-, benzyl-N[(C 1 -C 4 )alkyl]-CH 2 CH 2 —N[(C 1 -C 4 )alkyl]-, (C 1 -C 4 )alkylcarbonylamino, (C 1 -C 4 )alkoxycarbonylamino, (C 6 -C 10 )aryloxycarbonylamino, (C 6 -C 10 )aryl(C 1 -C 4 )alkoxycarbonylamino, morpholinylacetamido, morpholinyl(C 1 -C 4 )alkyl-N[C(O)CH 3 ]—, morpholinyl(C 1 -C 4 )alkyl-N(C(O)CH 2 CH 3 )—, morpholinyl(C 1 -C 4 )alkyl-N[C(O)CH 2 OCH 3 ]—, morpholinyl(C 1 -C 4 )alkyl-N[C(O)-isobutoxy]-, morpholinyl(C 1 -C 4 )alkyl-N[C(O)cyclopropyl]-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)CH 3 ]—, pyrrolidinyl-(C 1 -C 4 )alkyl-N[C(O)CH 2 CH 3 ]—, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)isobutoxy]-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)cyclopropyl)-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)CH 2 Cl]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)—CH 3 ], piperidinyl(C 1 -C 4 )alkyl-N[C(O)—CH 2 OCH 3 ]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)—CH 2 OH]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)C(CH 3 ) 3 ]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)-isobutoxy]-, piperidinyl(C 1 -C 4 )alkyl-N[C(O)-cyclopropyl]-, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-N[C(O)—CH 3 ], (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-N[C(O)C(CH 3 ) 3 ], halo(C 1 -C 4 )alkyl-N[C(O)—CH 2 Cl]—, (C 3 -C 6 )cycloalkyl-NH-acetamido, (C 1 -C 4 )alkyl-NH-acetamido, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkylacetamido, pyrrolidinyl acetamido, piperidinyl acetamido, piperazinyl acetamido, phenyl piperazinyl acetamido, imidazolyl acetamido, 1-carboxyalkyl pyrrolidinium-(C 1 -C 4 )alkylamino, 1-carboxy, 4-(C 1 -C 4 -alkyl)piperazinium-(C 1 -C 4 )alkylamino, sulfonylchloride, (C 1 -C 4 )alkylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, sulfonylhydrazide, sulfonamide, (C 1 -C 4 )alkyl-NH—SO 2 —, (C 3 -C 6 )cycloalkyl-NH—SO 2 —, heterocyclyl-NH—SO 2 —, heteroaryl-NH—SO 2 —and heterocyclyl=N—;

R3 is selected from hydrogen and halogen;

R4 is selected from hydrogen, halogen, —(C 1 -C 4 )alkyl, amino, and morpholinyl-(C 1 -C 4 )alkylamino;

R5 is —(C 1 -C 4 )alkyl;

R6 is selected from hydrogen, halogen, (C 1 -C 4 )alkyl, pyrrolyl and benzylamino;

R7 is guanidino or guanidinocarbonyl;

R8 is hydrogen;

where pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, benzyl and imidazolyl are each unsubstituted or substituted by one or two of the same or different groups selected from: (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, oxo, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl(C 1 -C 4 )alkyl, benzyl (where the benzyl is unsubstituted or substituted by one or two of the same or different groups selected from: (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, amino, mono- or di-substituted amino [where the substituents on the amino group may be independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 ) acyl, halo(C 1 -C 4 )acyl, heterocyclyl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy(C 6 -C 10 )aryl(C 1 -C 4 )alkyl}, nitro, halo, halo(C 1 -C 4 )alkyl, and heterocyclyl(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl;

where alkyl is unsubstituted or substituted by one or two of the same or different groups selected from: halo, hydroxy, mono- or di-substituted amino [where the substituents on the amino group may be independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )acyl, halo(C 1 -C 4 )acyl, heterocyclyl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy(C 6 -C 10 )aryl(C 1 -C 4 )alkyl}, benzyl amino, pyridyl, piperidinyl, pyrrole, furanyl, morpholinyl, thiophenyl, phenyl, (C 3 -C 6 )cycloalkyl, heterocyclyl and heteroaryl; and

where (C 6 -C 10 )aryl, or each of heteroaryl and heterocyclyl, which is a 5 or 6 membered ring system containing one, two or three ring atoms selected from N, O and S, are independently from each other unsubstituted or substituted by one or two of the same or different groups selected from: (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and halo(C 1 -C 4 )alkyl.

3. The method according to claim 1 , wherein the compounds of formula 1 has the structure of formula 1a,

wherein

R1, R2, R3, R4, R5, R6, R7, R8 and W are as defined in claim 1 ; and

V is CH 2 , CHCH 3 , C(CH 3 ) 2 , NH or NCH 3 .

4. The method according to claim 1 , wherein the compound of formula 1 has the structure of formula 1b,

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and W are as defined in claim 1 ;

R a is H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl or (C 2 -C 4 )alkenyl; and

V is CH 2 , CHCH 3 , C(CH 3 ) 2 , NH or NCH 3 .

5. The method according to claim 1 , wherein in the compounds of formula 1, U is C(O), CHOH or CH 2 , V is CH 2 and R 7 is guanidinocarbonyl.

6. The method according to claim 3 , wherein the compounds of formula 1a are selected from the group consisting of:

N-(10,10-Dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(2,4-Dichloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Chloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(3-Fluoro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(1-Fluoro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Fluoro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Isopropyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Amino-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(10,10-dioxo-4-pyrrol-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Methanesulfonyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(10,10-dioxo-7-piperidin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(10,10-dioxo-7-pyrrolidin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-1-fluoro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-2-fluoro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(10,10-Dioxo-7-pyrrol-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-4-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Methyl-10,10-dioxo-7-pyrrol-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-2-methanesulfonyl-4-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-4-isopropyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2,7-Dichloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Benzylamino-4-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-7-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4,7-Dimethyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-methanesulfonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Isopropyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-2-nitro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4,6-Dimethyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Isopropyl-6-methyl-2-nitro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Amino-4,6-dimethyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-iodo-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-10,10-dioxo-2-pyrrol-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[2-(2,5-Dimethyl-pyrrol-1-yl)-4,6-dimethyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Dimethylamino-4,6-dimethyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-dimethylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-2-methylamino-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-isobutylamino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4,6-Dichloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine,

N-(2-Amino-4,6-dichloro-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(6-Chloro-4-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Amino-6-chloro-4-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-sulfonic acid amide;

N-(6-chloro-4-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclopentene-8-carbonyl)-guanidine;

4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-sulfonic acid (5-cyclopropyl-[1,3,4]thiadiazol-2-yl)-amide;

4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-sulfonic acid (pyridin-3-ylmethyl)-amide;

N-[4-Chloro-6-methyl-10,10-dioxo-2-(piperazine-1-sulfonyl)-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-2-(4-methyl-piperazine-1-sulfonyl)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-2-(morpholine-4-sulfonyl)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-2-(4-cyclopropyl-2-oxo-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-2-(4-cyclopentyl-2-oxo-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-2-(4-isopropyl-2-oxo-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[2-(4-Benzyl-2-oxo-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-6-methyl-2-[2-(4-methylpiperazin-1-yl)-ethylamino]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

1-Carboxymethyl-1-[2-(4-chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-ylamino)-ethyl]-4-methylpiperazin-1-ium;

N-[4-Chloro-2-(2-imidazol-1-yl-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[2-(2-Amino-ethylamino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-2-(2-morpholin-4-yl-ethylamino)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-2-[ethyl-(2-morpholin-4-yl-ethyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-N-(2-morpholin-4-yl-ethyl)-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-methoxy-N-(2-morpholin-4-yl-ethyl)-acetamide;

N-(4-Chloro-2-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethylamino}-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo {a,d}cycloheptene-8-carbonyl)-guanidine;

N-[4-Chloro-6-methyl-2-(2-methylamino-ethylamino)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[4-Chloro-6-methyl-10,10-dioxo-2-(2-pyrrolidin-1-yl-ethylamino)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-2-[ethyl-(2-pyrrolidin-1-yl-ethyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-(2-pyrrolidin-1-yl-ethyl)-carbamic acid isobutylester;

1-Carboxymethyl-1-[2-(4-chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10-lambda*6*-thia-dibenzo[a,d]cycloheptene-2-ylamino)-ethyl]-pyrrolidinium;

Cyclopropanecarboxylic acid (4-chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-methoxy-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;

N-{4-Chloro-6-methyl-2-[2-(2-morpholin-4-yl-ethylamino)-ethylamino]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-2-[2-(2-morpholin-4-ylamino)-ethylamino]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-[4-Chloro-2-(2-cyclopropylamino-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-2-(3-morpholin-4-yl-propylamino)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[2-(2-pyridin-2-yl-ethylamino)-ethylamino]-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(4-Chloro-2-{2-[(furan-2-ylmethyl)-amino]-ethylamino-1-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-{ethyl-[2-(ethyl-furan-2-ylmethyl-amino)-ethyl]-amino-}-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-10,10-dioxo-2-{2-[(thiophen-2-ylmethyl)-amino]-ethylamino}-10,11-dihydro-5-oxa-10lambda*6*thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-{ethyl-[2-(ethyl-thiophen-2-ylmethyl-amino)-ethyl]-amino}-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[2-(2-Benzylamino-ethylamino)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-(2-{[2-(Benzyl-ethyl-amino)-ethyl]-ethyl-amino}-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-{4-Chloro-2-[2-(2-methoxy-benzylamino)-ethylamino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(4-Chloro-2-{2-[ethyl-(2-methoxy-benzyl)-amino]-ethylamino}-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[4-Chloro-6-methyl-10,10-dioxo-2-(2-piperidin-1-yl-ethylamino)-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-[ethyl-(2-piperidin-1-yl-ethyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-hydroxy-N-(2-piperidin-1-yl-ethyl)-acetamide;

Cyclopropanecarboxylic acid (4-chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-(2-piperidin-1-yl-ethyl)-amide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2,2-dimethyl-N-(2-piperidin-1-yl-ethyl)-propionamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-N-(2-piperidin-1-yl-ethyl)-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-methoxy-N-(2-piperidin-1-yl-ethyl)-acetamide;

N-[4-Chloro-2-(2-dimethylamino-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-8-carbonyl]-guanidine;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-N-(2-dimethylamino-ethyl)-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-N-(2-dimethylamino-ethyl)-2,2-dimethyl-propionamide;

N-[4-Chloro-6-methyl-2-(4-methylpiperazin-1-yl)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-(4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[4-Chloro-2-(4-decyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-10,10-dioxo-2-(4-pentyl-piperazin-1-yl)-10,11-dihydro-5-oxa-10-lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-2-(4-cyclopropanecarbonyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-2-[4-(4-dimethylamino-benzyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-2-[4-(2,4-dichloro-benzyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[4-(1H-pyrrole-2-carbonyl)-piperazin-1-yl]-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-2-[4-(5-methyl-furan-2-ylmethyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-2-[4-(2-methyl-benzyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-2-[4-(5-methyl-thiophen-2-ylmethyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-2-[4-(3,4-dimethoxy-benzyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[4-(4-trifluoromethyl-benzyl)-piperazin-1-yl]-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-[4-Chloro-2-(4-ethyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-2-morpholin-4-yl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[2-(4-Benzyl-piperazin-1-yl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-2-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-[4-Chloro-2-(4-isopropyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-6-methyl-2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[4-(2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-[4-Chloro-2-(4-cyclopropylmethyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[4-(2-piperazin-1-yl-ethyl)-piperazin-1-yl)-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-[4-Chloro-2-(4-cyclopropyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{2-[4-(3-Amino-benzyl)-piperazin-1-yl]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-[4-Chloro-6-methyl-10,10-dioxo-2-(4-pyridin-3-ylmethyl-piperazin-1-yl)-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-2-(4-cyclobutyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-2-(4-cyclohexyl-piperazin-1-yl)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-[4-Chloro-6-methyl-10,10-dioxo-2-(4-thiophen-2-ylmethyl-piperazin-1-yl)-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-2-[4-(2-methoxy-benzyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-2-pyperidin-1-yl-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-2-(2,2,2-trifluoro-ethylamino)-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-2-hydroxy-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-imidazol-1-yl-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-cyclopropylamino-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-cyclohexylamino-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-cyclopentylamino-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-isopropylamino-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-dimethylamino-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-2-cyclobutylamino-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-morpholin-4-yl-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclohepten-2-yl)-2-methylamino-acetamide dimesylate;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cyclohepten-2-yl)-2-pyrrolidine-1-yl-acetamide;

N-{2-[Bis-(2-hydroxy-ethyl)-amino]-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(2-Amino-4-chloro-6,11,11-trimethyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-2-yl)-2-cyclopropylamino-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;

N-(4-Chloro-8-guanidinocarbonyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclopenten-2-yl)-2-(4-methyl-piperazin-1-yl)-acetamide;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[4-(tetrahydro-furan-2-ylmethyl)-piperazin-1-yl]-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(6-Methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-11-aza-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[4-Chloro-6-methyl-2-(1-methyl-pyrrolidin-2-ylidineamino)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[4-Amino-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-[6-Methyl-4-(2-morpholin-4-yl-ethylamino)-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine;

N-{4-Chloro-2-[(3H-imidazol-4-ylmethyl)-amino]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-2-[(5-methyl-thiophen-2-ylmethyl)-amino]-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-6-methyl-10,10-dioxo-2-[(pyridin-3-ylmethyl)-amino]-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-{4-Chloro-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl}-guanidine;

N-(2-Aminomethyl-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-2-diethylaminomethyl-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-10,10-dioxo-2-pyrrol-1-ylmethyl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl)-guanidine; and

N-[2-(Benzylamino-methyl)-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carbonyl]-guanidine.

7. The method according to claim 4 , wherein the compounds of formula 1b are selected from the group consisting of:

N-(10,10-Dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Chloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(3-Chloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(1-Chloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(3-Fluoro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Fluoro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(2-Ethanesulfonyl-4-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4,7-Dichloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4-tert-Butyl-7-chloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-4-methyl 10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-1-fluoro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(2,7-Dichloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-2-fluoro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Chloro-2-ethanesulfonyl-4-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(1,7-Dichloro-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4,7-Dimethyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-7-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4,6-Dimethyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(1-Fluoro-6-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-6-methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(6-Methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(10,10-Dioxo-7-pyrrol-1-yl-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(7-Benzylamino-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(5-Methyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(5-Allyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(4-Chloro-5,6,11-trimethyl-10,10-dioxo-10,11-dihydro-5H-10lambda*6*-thia-5-aza-dibenzo[a.d]cycloheptene-8-carbonyl)-guanidine;

N-(10,10-Dioxo-10,11-dihydro-5H-10lambda 6-thia-5-aza-dibenzo[a.d]cycloheptene-2-carbonyl)-guanidine; and

N-(10,10-Dioxo-10,11-dihydro-5H-10lambda 6-thia-5-aza-dibenzo[a.d]cycloheptene 1-carbonyl)-guanidine.

8. A method for treating ischemia or reperfusion induced tissue damage in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula 1:

or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof;

wherein,

R1 is selected from: hydrogen, halogen, —(C 1 -C 4 )alkyl and guanidino carbonyl;

R3 is selected from hydrogen and halogen;

R4 is selected from hydrogen, halogen, —(C 1 -C 4 )alkyl and —NR′R″;

R5 is —(C 1 -C 4 )alkyl;

R6 is selected from hydrogen, halogen, (C 1 -C 4 )alkyl, heteroaryl;

R7 is guanidino or guanidino carbonyl;

R8 is hydrogen;

R′″ is selected from: heterocyclyl, (C 3 -C 6 )cycloalkyl and alkyl;

U is C(O), CR a R b , O or NR a ;

V is CR a R b or NR a ;

W is S(O) 2 ;

wherein,

R a is H, alkyl, (C 3 -C 6 )cycloalkyl or (C 2 -C 4 )alkenyl;

R b is H, alkyl, OH, or OR a .

9. The method of claim 8 , wherein in the compound of formula 1,

R1 is selected from: hydrogen, halogen, —(C 1 -C 4 )alkyl and guanidino carbonyl;

R2 is selected from: hydrogen, halogen, hydroxy, cyano, nitro, formyl, carboxy, guanidino, guanidino carbonyl, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkoxycarbonyl, (C 6 -C 10 )aryloxycarbonyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, amino, (C 1 -C 4 )alkylamino, thio-(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkoxy-substituted (C 1 -C 4 )alkylamino, di-(C 1 -C 4 -alkyl)amino, chloro(C 1 -C 4 )alkylamino, di-[chloro-(C 1 -C 4 )alkyl]amino, hydroxy(C 1 -C 4 )alkylamino, di-[hydroxy-(C 1 -C 4 )alkyl]amino, mono- or di-(C 1 -C 4 -alkyl) substituted-amino-(C 1 -C 4 )alkylamino, (C 6 -C 10 )aryloxy(C 1 -C 4 )alkylamino, (C 6 -C 10 ) aryl(C 1 -C 4 )alkoxy(C 1 -C 4 )alkylamino, benzylamino, morpholinyl-(C 1 -C 4 )alkylamino, (C 1 -C 4 )alkylsubstituted-thiophenyl-(C 1 -C 4 )alkylamino, pyrrolidinyl(C 1 -C 4 )alkylamino, pyridyl(C 1 -C 4 )alkylamino, piperidinyl(C 1 -C 4 )alkylamino, 3H-imidazolyl(C 1 -C 4 )alkylamino, piperazinyl(C 1 -C 4 )alkylamino, morpholinyl(C 1 -C 4 )alkylamino(C 1 -C 4 -alkyl), pyrrolidinyl(C 1 -C 4 )alkylamino(C 1 -C 4 -alkyl), piperidinyl(C 1 -C 4 )alkylamino(C 1 -C 4 -alkyl), furanyl(C 1 -C 4 )alkylamino, benzylamino(C 1 -C 4 )alkylamino, morpholinylamino(C 1 -C 4 )alkylamino, (C 3 -C 6 )cycloalkylamino(C 1 -C 4 )alkylamino, furanyl(C 1 -C 4 )alkyl-N[(C 1 -C 4 )alkyl]CH 2 CH 2 —N[(C 1 -C 4 )alkyl]-, thiophenyl(C 1 -C 4 )alkyl-N[(C 1 -C 4 )alkyl]-CH 2 CH 2 —N[(C 1 -C 4 )alkyl]-, benzyl-N[(C 1 -C 4 )alkyl]-CH 2 CH 2 —N[(C 1 -C 4 )alkyl]-, (C 1 -C 4 )alkylcarbonylamino, (C 1 -C 4 )alkoxycarbonylamino, (C 6 -C 10 )aryloxycarbonylamino, (C 6 -C 10 )aryl(C 1 -C 4 )alkoxycarbonylamino, morpholinylacetamido, morpholinyl(C 1 -C 4 )alkyl-N[C(O)CH 3 ]-, morpholinyl(C 1 -C 4 )alkyl-N(C(O)CH 2 CH 3 )—, morpholinyl(C 1 -C 4 )alkyl-N[C(O)CH 2 OCH 3 ]-, morpholinyl(C 1 -C 4 )alkyl-N[C(O)-isobutoxy]-, morpholinyl(C 1 -C 4 )alkyl-N[C(O)cyclopropyl]-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)CH 3 ]-, pyrrolidinyl-(C 1 -C 4 )alkyl-N[C(O)CH 2 CH 3 ]-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)isobutoxy]-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)cyclopropyl)-, pyrrolidinyl(C 1 -C 4 )alkyl-N[C(O)CH 2 Cl]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)—CH 3 ], piperidinyl(C 1 -C 4 )alkyl-N[C(O)—CH 2 OCH 3 ]-, piperidinyl(C 1 -C 4 )alkyl-N[C(O)—CH 2 OH]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)C(CH 3 ) 3 ]—, piperidinyl(C 1 -C 4 )alkyl-N[C(O)-isobutoxy]-, piperidinyl(C 1 -C 4 )alkyl-N[C(O)-cyclopropyl]-, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-N[C(O)—CH 3 ], (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-N[C(O)C(CH 3 ) 3 ], halo(C 1 -C 4 )alkyl-N[C(O)—CH 2 Cl]—, (C 3 -C 6 )cycloalkyl-NH-acetamido, (C 1 -C 4 )alkyl-NH-acetamido, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkylacetamido, pyrrolidinyl acetamido, piperidinyl acetamido, piperazinyl acetamido, phenyl piperazinyl acetamido, imidazolyl acetamido, 1-carboxyalkyl pyrrolidinium-(C 1 -C 4 )alkylamino, 1-carboxy, 4-(C 1 -C 4 -alkyl)piperazinium-(C 1 -C 4 )alkylamino, sulfonylchloride, (C 1 -C 4 )alkylsulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, sulfonylhydrazide, sulfonamide, (C 1 -C 4 )alkyl-NH—SO 2 —, (C 3 -C 6 )cycloalkyl-NH—SO 2 —, heterocyclyl-NH—SO 2 —, heteroaryl-NH—SO 2 — and heterocyclyl═N—;

R3 is selected from hydrogen and halogen;

R4 is selected from hydrogen, halogen, —(C 1 -C 4 )alkyl, amino, and morpholinyl-(C 1 -C 4 )alkylamino;

R5 is —(C 1 -C 4 )alkyl;

R6 is selected from hydrogen, halogen, (C 1 -C 4 )alkyl, pyrrolyl and benzylamino;

R7 is guanidino or guanidino carbonyl;

R8 is hydrogen;

where pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, benzyl and imidazolyl are each unsubstituted or substituted by one or two of the same or different groups selected from: (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, oxo, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl(C 1 -C 4 )alkyl, benzyl (where the benzyl is unsubstituted or substituted by one or two of the same or different groups selected from: (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, amino, mono- or di-substituted amino [where the substituents on the amino group may be independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )acyl, halo(C 1 -C 4 )acyl, heterocyclyl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy(C 6 -C 10 )aryl(C 1 -C 4 )alkyl], nitro, halo, halo(C 1 -C 4 )alkyl, and heterocyclyl(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl;

where alkyl is unsubstituted or substituted by one or two of the same or different groups selected from: halo, hydroxy, mono- or di-substituted amino [where the substituents on the amino group may be independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )acyl, halo(C 1 -C 4 )acyl, heterocyclyl(C 1 -C 4 )alkyl, heteroaryl(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy(C 6 -C 10 )aryl(C 1 -C 4 )alkyl], benzyl amino, pyridyl, piperidinyl, pyrrole, furanyl, morpholinyl, thiophenyl, phenyl, (C 3 -C 6 )cycloalkyl, heterocyclyl and heteroaryl; and

10. The method of claim 8 , wherein the compound of formula 1 has the structure of formula 1a

wherein

R1, R2, R3, R4, R5, R6, R7, R8 and W are as defined in claim 8 ;

and

V is CH 2 , CHCH 3 , C(CH 3 ) 2 , NH or NCH 3 .

11. The method of claim 8 , wherein the compound of formula 1 has the structure of formula 1b

wherein

R1, R2, R3, R4, R5, R6, R7, R8 and W are as defined in claim 8 ;

R a is H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl or (C 2 -C 4 )alkenyl; and

V is CH 2 , CHCH 3 , C(CH 3 ) 2 , NH or NCH 3 .

12. The method of claim 8 , wherein in the compound of formula 1 U is C(O), CHOH or CH 2 , V is CH 2 , and R7 is guanidino carbonyl.

13. The method of claim 9 , wherein the compound of formula 1a is selected from the group consisting of: