Dihydrothiaphenanthrenecarbonylguanidines: composition,...

Details Dihydrothiaphenanthrenecarbonylguanidines: composition,... Dihydrothiaphenanthrenecarbonylguanidines: composition,...

2003-01-23

2004-05-04

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S437000, C549S015000, C549S016000

Reexamination Certificate

active

06730697

ABSTRACT:

SUMMARY OF THE INVENTION
The Scope of Composition
This invention relates to dihydrothiaphenanthrenecarbonylguanidines of formula I, encompassing their composition, process of making, and use as medicament or diagnostic aid.
wherein,
R1 and R3 are independently selected from the group consisting of hydrogen, —(C1-C4)-alkyl, —(C1-C4)-alkoxy, —F, —Cl, —Br, —I, —CN, —NR10R11, —O
p
—(CH
2
)
n
—(CF
2
)
x
—CF
3
, and —(SO
m
)
p
—(CH
2
)
n
—(CF
2
)
x
—CF
3
, wherein:
R10 and R11 are independently selected from the group consisting of hydrogen, —(C1-C4)-alkyl and —(CH
2
)
n
—(CF
2
)
x
—CF
3
,
m=0, 1 or 2,
n=0, 1, 2, 3, 4, 5 or 6,
x=0 or 1, and
p=0 or 1;
R2 is selected from the group consisting of hydrogen, —F, —Cl, —Br, —I, —CN, —(C1-C4)-alkyl, methoxy, and —(C3-C8)-cycloalkyl;
R4 and R5 are independently selected from the group consisting of hydrogen and —(C1-C4) alkyl;
R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, —(C1-C4)-alkyl; —(C1-C4)-alkoxy, —F, —Cl, —Br, —I, —CN, —NR12R13, —O
q
—(CH
2
)
r
—(CF
2
)
s
—CF
3
and —(SO
w
)
t
—(CH
2
)
u
—(CF
2
)
v
—CF
3
, wherein:
R12 and R13 are independently selected from the group consisting of hydrogen and —(C1-C4)-alkyl,
w=0, 1 or 2,
r=0, 1, 2, 3, 4, 5, or 6,
u=0, 1, 2, 3, 4, 5, or 6,
q=0 or 1
s=0 or 1
t=0 or 1, and
v=0 or 1; or
R6 and R7, together with ring 1, form a naphthalene system and R8 and R9 remain as defined above; or
R7 and R8, together with ring 1, form a naphthalene system and R6 and R9 remain as defined above; or
R8 and R9, together with ring 1, form a naphthalene system and R6 and R7 remain as defined above; and
A is selected from the group consisting of —S—, —SO— and —SO
2
—.
Preference is given to compounds of formula I wherein,
R1 and R3 are independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, —F, —Cl, —CN, —NR10OR11, —O
p
—(CH
2
)
n
—CF
3
and —(SO
m
)
p
—(CH
2
)
n
—CF
3
, wherein:
R10 and R11 are independently selected from the group consisting of hydrogen, methyl, ethyl and —CH
2
—CF
3
,
m=0, 1 or 2,
n=0, 1, 2 or 3, and
p=0 or 1;
R2 is selected from the group consisting of hydrogen, —F, —Cl, —CN, —(C1-C4)-alkyl, methoxy, and —(C3-C6)-cycloalkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, methyl and ethyl;
R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, —(C1-C4)-alkyl, methoxy, ethoxy, —F, —Cl, —CN, —NR12R13, —O
q
—(CH
2
)
r
—CF
3
and —(SO
w
)
t
—(CH
2
)
u
—CF
3
, wherein:
R12 and R13 are independently selected from the group consisting of hydrogen, methyl and ethyl,
w=0, 1 or 2;
r=0, 1, 2, or 3,
u=0, 1,2, or 3,
q=0 or 1, and
t=0 or 1; or
R6 and R7, together with ring 1, form a naphthalene system and R8 and R9 remain as defined in the preceding section of this claim; or
R7 and R8, together with ring 1, form a naphthalene system and R6 and R9 remain as defined in the preceding section; or
R8 and R9, together with ring 1, form a naphthalene system and R6 and R7 remain as defined in the preceding section; and
A is selected from the group consisting of —S—, —SO— and —SO
2
—.
Particular preference is given to compounds of formula I, wherein:
R1 is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, —F, —Cl, —NR10R11, —O
p
—(CH
2
)
n
—CF
3
and —(SO
m
)
p
—(CH
2
)
n
—CF
3
, wherein R10 and R11 are independently selected from the group consisting of hydrogen, methyl, ethyl and —CH
2
—CF
3
;
m=0, 1 or 2; n=0 or 1; p=0 or 1;
R2 is selected from the group consisting of hydrogen, —F, —Cl, methyl, and —(C3-C6)-cycloalkyl;
R3, R4 and R5 are hydrogen;
R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, —F, —Cl, —NR(12)R(13), —O
q
—(CH
2
)
r
—CF
3
and —(SO
w
)
t
—(CH
2
)
u
—CF
3
, wherein
R12 and R13 are independently selected from the group consisting of hydrogen, methyl or ethyl; w=0, 1 or 2; q, r, t and u are independently zero or one; or
R6 and R7, together with ring 1, form a naphthalene system and R8 and R9 remain as defined in the preceding section; or
R7 and R8, together with ring 1, form a naphthalene system and R6 and R9 remain as defined in the preceding section; or
R8 and R9, together with ring 1, form a naphthalene system and R6 and R7 remain as defined in the preceding section; and
A is selected from the group consisting of —S—, —SO— and —SO
2
—.
Further particular preference is given to compounds of formula I, wherein:
R1 is selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, —Cl, —NR10R11, —O—CH
2
—CF
3
and —(SO
m
)
p
—(CH
2
)
n
—CF
3
, wherein R(10) and R(11) are independently selected from the group consisting hydrogen, methyl, ethyl and —CH
2
-CF
3
; m is 0, 1 or 2; p is 0 or 1;
R2 is selected from the group consisting of hydrogen, —F, —Cl and methyl;
R3, R4 and R5 are hydrogen;
R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, methyl; methoxy, ethoxy, —F, —Cl, —O—CH
2
—CF
3
and —(SO
w
)
t
—(CH
2
)
u
—CF
3
, wherein w is 0, 1 or 2; t and u are independently zero or one; or
R6 and R7, together with ring 1, form a naphthalene system and R8 and R9 remain as defined in the preceding section; or
R7 and R8, together with ring 1, form a naphthalene system and R6 and R9 remain as defined in the preceding section; or
R8 and R9, together with ring 1, form a naphthalene system and R6 and R7 remain as defined in the preceding section; and
A is —SO
2
—.
The present invention further encompasses any pharmaceutically suitable salts of the compounds of formula I.
It is also understood that compounds of formula I may, with appropriate substitution, exist in stereoisomeric forms. If the compounds of formula I contain one or more centers of asymmetry, these may have, independently of one another, the S configuration or the R configuration. All possible stereoisomers, e.g. enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, e.g. enantiomers and/or diastereomers, in any ratios, are contemplated in the present invention. For example, enantiomers are contemplated in the invention in enantiopure form, both as levorotatory and as dextrorotatory antipodes, and in the form of mixtures of the two enantiomers in various ratios or in the form of racemates. Individual stereoisomers can be prepared if desired by fractionation of a mixture by conventional methods or, for example, by stereoselective synthesis. If mobile hydrogen atoms are present, the present invention also encompasses all tautomeric forms of the compounds of formula I.
The term “—(C1-C4)-alkyl” is understood as meaning an alkyl that contains from 1 to 4 carbon atoms and may be straight-chain or branched, for example, methyl, ethyl, propyl, isopropyl, butyl or tertiary butyl. “—(C3-C8)-cycloalkyl” is understood as meaning a cycloalkyl that contains a 3 to 8-membered ring. Similarly, “—(C3-C6)-cycloalkyl” means a cycloalkyl having a 3 to 6-membered ring. “a naphthalene system” means a chemical group of a substituted or unsubstituted naphthalene ring.
Methods Of Preparing Compounds of Formula I
The invention further relates to a process for preparing compound I, which comprises reacting a compound of formula II
in which R1 to R9 and A are as defined above, and L is a leaving group amenable to easy nucleophilic substitution, with guanidine.
The activated acid derivatives of formula II in which L is an alkoxy group (preferably a methoxy), a phenoxy group, a phenylthio group, a methylthio group, a 2-pyridylthio group, or a nitrogen heterocycle group (preferably 1-imidazolyl), are advantageously obtained in a manner known to those skilled in the art from the underlying carbonyl chlorides (formula II, L═Cl), which in turn can be prepared in a manner known to those skilled in the art from the underlying carboxylic acids (formula II, L═OH), for example with thionyl chloride.
Besides the carbonyl chlorides of for

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