Monoacyl-substituted guanidines, a process for their preparation, their use as a medicament or diagnostic aid, and pharmaceutical compositions containing them

• US 6,632,840 B1
• Filed: 03/24/2000
• Issued: 10/14/2003
• Est. Priority Date: 08/24/1993
• Status: Expired due to Fees

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Scholz, Wolfgang, Lang, Hans-Jochen, Kleemann, Heinz-Werner, Weichert, Andreas, Schwark, Jan-Robert, Albus, Udo, Crause, Peter
• Primary Examiner(s): Davis, Brian J.
• Application Number:
  US09/534,036
• Time in Patent Office: 1,299 Days
• Field of Search: 564/237, 548/561
• US Class Current: 514/634
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 279/22 Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

Monoacyl-substituted guanidines of formula III, or a salt or acid thereof, and their use as medicine or diagnostic aid:

in which X(2) is

Claims

1. A compound of formula III or a salt or acid thereof:

in which

X(2) is

wherein R(101) is methyl;

R(102) is hydrogen;

R(103) is pyrrolyl;

R(104) is methylsulfonyl; and

R(105) is hydrogen.

2. A method of protecting at least one organ, comprising providing to said at least one organ an effective amount of a compound of claim 1.

3. The method of claim 2, wherein said at least one organ is treated prior to removal from a host.

4. The method of claim 2, wherein said at least one organ has been removed from a host.

5. The method of claim 2, wherein said at least one organ is the heart.

14. A method for inhibiting the Na+/H+ exchanger, comprising providing within a host an effective amount a compound of claim 1.

16. A method of treating at least one of arrhythmias and shock condition, comprising providing within a host an effective amount of a compound of claim 1.

18. A method of treating at least one of cardiac infarction, angina pectoris, ischemic conditions of the heart, ischemic conditions of the peripheral and central nervous system and of stroke, and ischemic conditions of peripheral organs and limbs, comprising providing within a host an effective amount of a compound of claim 1.

6. A compound of formula III or a salt or acid thereof:

in which X(2) is

R(101)

is F, Cl, CH3 or CF3;

R(102)

is hydrogen, F, Cl, Br, —

CN, R(110b)R(110c)N—

CO—

, or R(111a)—

CO—

;

R(110b) and R(111a)

are, independently, (C1-C4)-alkyl, (C3-C4)-alkenyl, —

CnH2n-R(115a) or CF3;

n is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a) are hydrogen or methyl;

or

R(110b) and R(111a)

are hydrogen;

R(110c)

is hydrogen or methyl;

R(103)

is —

Y-para-C6H4-(C═

O)h-(CHOH)i-(CH2)j-(CHOH)k-R(123),

-Y-m-C6H4-(C═

O)ad-(CHOH)ae-(CH2)af-(CHOH)ag-R(124) or

-Y-ortho-C6H4-(C═

O)ah-(CHOH)ao-(CH2)ap-(CHOH)ak-R(125);

Y is oxygen, S or —

NR(83);

R(123), R(124), R(125) and R(83)

are, independently, hydrogen or methyl;

h, ad and ah

are, independently, zero or 1;

i, k, ae, ag, ao and ak

are, independently, zero, 1, 2 or 3;

j, af and ap

are, independently, zero or 1;

with the proviso that, h, i and k are not simultaneously zero,

ad, ae and ag are not simultaneously zero and

ah, ao and ak are not simultaneously zero;

or

R(103)

is F, Br, CN, CF3 or —

CgH2gR(118a);

g is zero, 1 or 2;

R(118a) is phenyl,

in which R(118a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(119a)R(119b);

wherein R(119a) and R(119b)

are H or CH3;

or

R(103)

is pyrrolyl;

or

R(103)

is —

SR(129) or —

CR(133)R(134)R(135);

R(129) and R(133)

are -CaH2a-(C1-C9)-heteroaryl,

which is unsubstituted or is substituted by 1 to 3 substituents chosen from F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;

a is zero or 1;

R(134) and R(135)

are, independently of each other, hydrogen or CH3;

or

R(103)

is R(110a)-SO2- or R(112a)R(113a)N—

SO2-;

R(110a) is (C1-C4)-alkyl, CF3, (C3-C4)-alkenyl or -CsH2s-R(115a);

s is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a)

are hydrogen or CH3;

R(112a)

is (C1-C4)-alkyl, CF3, (C3-C4)-alkenyl or −

CwHw2w-R(115a);

w is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl, in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a) are hydrogen or CH3;

R(113a) is hydrogen or CH3;

or

R(112a) and R(113a)

are together 4 or 5 methylene groups of which one CH2 group is optionally replaced by oxygen, S, NH, N—

CH3 or N-benzyl;

or

R(103)

is R(176)—

NH—

SO2—

;

R(176) is R(177)R(178)N—

(C═

Y′

)—

;

Y′

is oxygen, S or N—

R(179);

R(177) and R(178) are identical or different and are (C1-C4)-alkyl, (C3-C4)-alkenyl or —

CfH2f-R(180);

f is zero or 1;

R(180) is (C5-C7)-cycloalkyl or phenyl,

in which R(180) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methoxy and methyl;

or

R(177) and R(178)

together form 4 or 5 methylene groups of which one CH2 group is optionally replaced by oxygen, S, NH, N—

CH3 or N-benzyl;

R(179) is defined as R(177);

R(104)

is R(110a)-SO2—

;

R(110a) is (C1-C4)-alkyl or CF3; and

R(105) is hydrogen.

7. A compound of claim 6, wherein

R(101) is F, Cl, CH3 or CF3;

R(102) is hydrogen, F, Cl, Br, —

CN, R(110b)R(110c)N—

CO—

, R(111a)—

CO—

;

R(110b) and R(111a)

are independently, (C1-C8)-alkyl, (C3-C4)-alkenyl, -CnH2n-R(115a) or CF3;

n is zero of 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a) are hydrogen or methyl;

or

R(110b) and R(111a)

optionally are hydrogen;

R(110c)

is hydrogen or methyl;

R(103) is F, Br, CN, CF3 or -CgH2gR(118a);

g is zero, 1 or 2;

R(118a) is or phenyl, in which R(118a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(119a) and R(119b);

wherein R(119a) and R(119b) are H or CH3;

or

R(103) is —

SR(129) or —

Cr(133)R(134)R(135);

or

R(103)

is R(110a)—

SO2—

or R(112a)R(113a)N—

SO2—

;

or

R(103)

is pyrrolyl;

R(104)

is R(110a)—

SO2—

;

R(110a) is (C1-C4)-alkyl or CF3; and

R(105) is hydrogen.

8. A method of protecting at least one organ, comprising providing to said at least one organ an effective amount of a compound of claim 6.

9. The method of claim 8, wherein said at least one organ has been removed from a host.

10. The method of claim 6, wherein said at least on organ is the heart.

11. The method of claim 8, wherein said at least on organ is treated prior to removal from a host.

15. A method for inhibiting the Na+/H+ exchanger, comprising providing within a host an effective amount a compound of claim 6.

17. A method of treating at least one of arrhythmias and shock condition, comprising providing within a host an effective amount of a compound of claim 6.

19. A method of treating at least one of cardiac infarction, angina pectoris, ischemic conditions of the heart, ischemic conditions of the peripheral and central nervous system and of stroke, and ischemic conditions of peripheral organs and limbs, comprising providing within a host an effective amount of a compound of claim 6.

12. A method for diagnosing hypertension and proliferative diseases, comprising providing within a host an effective amount of a compound of formula III or a salt or acid thereof:

in which X(2) is

R(101)

is F, Cl, CH3 or CF3;

R(102)

is hydrogen, F, Cl, Br, —

CN, R(110b)R(110c)N—

CO—

, or R(111a)—

CO—

;

R(110b) and R(111a)

are, independently, (C1-C4)-alkyl, (C3-C4)-alkenyl, —

CnH2n-R(115a) or CF3;

n is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a) are hydrogen or methyl;

or

R(110b) and R(111a)

optionally are hydrogen;

R(110c)

is hydrogen or methyl;

R(103)

is —

Y-para-C6H4-(C═

O)h-(CHOH)i-(CH2)j-(CHOH)k-R(123),

-Y-meta-C6H4-(C═

O)ad-(CHOH)ae-(CH2)af-(CHOH)ag-R(124) or

-Y-ortho-C6H4-(C═

O)ah-(CHOH)ao-(CH2)ap-(CHOH)ak-R(125);

Y is oxygen, S or —

NR(83);

R(123), R(124), R(125) and R(83)

are, independently, hydrogen or methyl;

h, ad and ah

are, independently, zero or 1;

i, k, ae, ag, ao and ak

are, independently, zero, 1, 2 or 3;

j, af and ap

are, independently, zero or 1;

with the proviso that, h, i and k are not simultaneously zero,

ad, ae and ag are not simultaneously zero and

ah, ao and ak are not simultaneously zero;

or

R(103)

is F, Br, CN, CF3 or —

CgH2gR(118a);

g is zero, 1 or 2;

R(118a) is phenyl,

in which R(118a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(119a)R(119b);

wherein R(119a) and R(119b) are H or CH3;

or

R(103)

is pyrrolyl;

or

R(103)

is —

SR(129) or —

CR(133)R(134)R(135);

R(129) and R(133)

are -CaH2a-(C1-C9)-heteroaryl,

which is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;

a is zero or 1;

R(134) and R(135)

are, independently of each other, hydrogen or CH3;

or

R(103)

is R(110a)—

SO2—

or R(112a)R(113a)N—

SO2—

;

R(110a) is (C1-C4)-alkyl, CF3, (C3-C4)-alkenyl or -CsH2s-R(115a);

s is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a)

are hydrogen or CH3;

R(112a)

is (C1-C4)-alkyl, CF3, (C3-C4)-alkenyl or −

CwHw2w-R(115a);

w is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a) are hydrogen or CH3;

R(113a) is hydrogen or CH3;

or

R(112a) and R(113a)

are together 4 or 5 methylene groups of which one CH2 group is optionally replaced by oxygen, S, NH, N—

CH3 or N-benzyl;

or

R(103)

is R(176)—

NH—

SO2—

;

R(176) is R(177)R(178)N—

(C═

Y′

)—

;

Y′

is oxygen, S or N—

R(179);

R(177) and R(178)

are identical or different and are (C1-C4)-alkyl, (C3-C4)-alkenyl or —

CfH2f-R(180);

f is zero or 1;

R(180) is (C5-C7)-cycloalkyl or phenyl,

in which R(180) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methoxy and methyl;

or

R(177) and R(178)

together form 4 or 5 methylene groups of which one CH2 group is optionally replaced by oxygen, S, NH, N—

CH3 or N-benzyl;

R(179) is defined as R(177);

R(104)

is R(110a)—

SO2—

;

R(110a) is (C1-C4)-alkyl or CF3; and

R(105) is hydrogen.

13. The method of claim 13, wherein

R(101) is F, Cl, CH3 or CF3;

R(102) is hydrogen, F, Cl, Br, —

CN, R(110b)R(110c)N—

CO—

, R(111a)—

CO—

;

R(110b) and R(111a)

are independently, (C1-C8)-alkyl, (C3-C4)-alkenyl, -CnH2n-R(115a) or CF3;

n is zero or 1;

R(115a) is (C3-C6)-cycloalkyl or phenyl,

in which R(115a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(116a)R(117a);

wherein R(116a) and R(117a) are hydrogen or methyl;

or

R(110b) and R(111a)

optionally are hydrogen;

R(110c)

is hydrogen or methyl;

R(103) is F, Br, CN, CF3, or -CgH2gR(118a);

g is zero, 1 or 2;

R(118a) is phenyl, in which R(118a) is unsubstituted or is substituted by 1 to 2 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(119a) and R(119b);

wherein R(119a) and R(119b) are H or CH3;

or

R(103) is —

SR(129) or —

CR(133)R(134)R(135);

or

R(103)

is R(110a)—

SO2—

or R(112a)R(113a)N—

SO2—

;

or

R(103)

is pyrrolyl;

R(104)

is R(110a)—

SO2—

;

R(110a) is (C1-C4)-alkyl or CF3; and

R(105) is hydrogen.