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

• US 20040044081A1
• Filed: 08/15/2003
• Published: 03/04/2004
• Est. Priority Date: 08/24/1993
• Status: Abandoned Application

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Kleemann, Heinz-Werner, Weichert, Andreas, Schwark, Jan-Robert, Albus, Udo, Crause, Peter, Scholz, Wolfgang, Lang, Hans-Jochen
• Application Number:
  US10/641,058
• Publication Number:
  US 20040044081A1
• Time in Patent Office: Days
• US Class Current: 514/616
• 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

Diacyl-substituted guanidines, a process for their preparation, their use as medicament or diagnostic aid, and medicament containing them.

Diacyl-substituted guanidines of the formula I

are described

where

X(1) and X(2) are

T1 is zero, 1, 2, 3 or 4,

R(A) and R(B) are hydrogen, Hal, CN, OR(106), (O) (cyclo)—(fluoro)alkyl, NR(107)R(108), phenyl or benzyl,

or

T2a and T2b are, independently of each other, zero, 1 or 2,

where the double bond can be in the E or Z configuration;

or

X(1) and X(2) are

as are the pharmaceutically tolerated salts thereof. They are outstandingly suitable for use as antiarrhythmic pharmaceuticals possessing a cardioprotective component for the prophylaxis and treatment of infarction and for the treatment of angina pectoris, in connection with which they also inhibit or strongly reduce, in a preventive manner, the pathophysiological processes associated with the genesis of ischemically induced damage, in particular associated with the elicitation of ischemically induced cardiac arrhythmias. On account of their protective effects against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention can, as a consequence of inhibiting the cellular Na⁺/H⁺ exchange mechanism, be used as pharmaceuticals for treating all acute or chronic damage elicited by ischemia, or diseases induced primarily or secondarily thereby.

Claims

1. A diacyl-substituted guanidine of the formula I

2. A compound of the formula I as claimed in claim 1, wherein X(1) is identical to X(2)

and wherein the remaining substituents are defined as in claim 1.

3. A compound of the formula I as claimed in claim 1, wherein:

X(1) and X(2) are

T1 is zero or 2,

R(A) and R(B) are, independently,

hydrogen, F, Cl, CN, OR(106), (C₁-C₄)-alkyl, (C₅-C₆)-cycloalkyl, CF₃ or NR(107)R(108),

R(106)

is hydrogen, (C₁-C₄)-alkyl, CF₃, phenyl or benzyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(111)R(112),

R(111) and R(112) being hydrogen, CH₃ or CF₃,

R(107) and R(108) are, independently of each other, defined as R(106),

or

R(107) and R(108) are together 4 or 5 methylene groups of which one CH₂ group can be replaced by oxygen, S, NH, N—

CH₃ or N-benzyl,

or

X(1) is

where the double bond can be in the E or Z configuration,

or

X(1) is

U, YY and Z are, independently of each other, C or N;

with, however, the restriction that only one of the positions U, YY and Z can be nitrogen;

where

U, YY and Z can carry the following number of substituents;

U, YYBonded to a doubleNumber of permit-or Zbond in the ringted substituentsCyes1Cno2Nyes0Nno1

R(D) is hydrogen,

R(U1), R(U2), R(Y1), R(Y2), R(Z1) and R(Z2) are, independently of each other,

hydrogen, F, Cl, CN, OR(114), CH₃, CF₃ or NR(115)R(116)

R(114)

is hydrogen, (C₁-C₄)-alkyl, CF₃, phenyl or benzyl, where the aromatic radicals are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(119)R(120),

R(119) and R(120) being hydrogen, CH₃ or CF₃,

R(115) and R(116) are, independently of each other, defined as R(114),

or

R(115) and R(116)

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

CH₃ or N-benzyl,

R(101)

is hydrogen, F, Cl, CH₃, OH, NH₂ or CF₃,

R(102)

is hydrogen, F, Cl, Br, —

C≡

N, —

C_zqaF_2zqaCF₃, R(110a)-SO₂R(110b)R(110c)N—

CO—

, R(111a)-CO—

or

R(112a)R(113a)N—

SO₂—

,

R(110a), R(110b), R(111a) and R(112a) are, independently,

(C₁-C₄)-alkyl, (C₃-C₄)-alkenyl, —

C_znH_2zn—

R(115a)

or CF₃,

zn is zero or 1,

zqa is zero, 1, 2, 3, 4 or 5,

R(115a)

is (C₃-C₆)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(116a)R(117a),

R(116a) and R(117a) being hydrogen or methyl,

or

R(110b), R(111a) and R(112a) are also hydrogen,

R(110c) and R(113a) are, independently, hydrogen or methyl,

R(103)

is —

Y-para-C₆H₄—

(CO)_zh—

(CHOH)_zi—

(CH₂)_zj—

(CHOH)_zk—

R(123),

—

Y-meta-C₆H₄—

(CO)_zad—

(CHOH)_zae—

(CH₂)_zaf—

(CHOH)_zag—

R(124) or

—

Y-ortho-C₆H₄—

(CO)_zah—

(CHOH)_zao—

(CH₂)_zap—

(CHOH)_zak—

R(125),

Y is oxygen, S or —

NR(83),

R(123), R(124), R(125) and R(83) are, independently, hydrogen or methyl,

zh, zad and zah are, independently,

zero or 1,

zi, zk, zae, zag, zao and zak are, independently,

zero, 1, 2 or 3,3

zj, zaf and zap are, independently,

zero or 1,

where, however, in each case, zh, zi and zk are not simultaneously zero,

zad, zae and zag are not simultaneously zero

and

zah, zao and zak are not simultaneously zero,

or

R(103) is hydrogen, F, Cl, Br, CN, (C₁-C₈)-alkyl, CF₃, (C₃-C₈)-alkenyl or —

C_zalH_2zalR(118a),

zal is zero, 1 or 2,

R(118a) is (C₃-C₆)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and

NR(119a)R(119b),

R(119a) and R(119b) being hydrogen or CH₃,

or

R(103)

is (C₁-C₉)-heteroaryl which is linked via C or N and which is unsubstituted or is substituted by 1-2 substituents from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

or

R(103)

is —

W-para-(C₆H₄)—

R(196), —

W-meta-(C₆H₄)—

R(197) or —

W-ortho-(C₆H₄)—

R(198),

R(196), R(197) and R(198) are, independently, pyrrolyl, imidazolyl, pyrazolyl or pyridyl which in each case is unsubstituted or substituted by 1 to 2 radicals selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, dimethylamino and benzyl,

W is oxygen, —

S—

or NR(136)—

,

R(136) being hydrogen or methyl,

or

R(103) is

—

SR (129), —

OR (130), —

NR (131)R(132) or —

CR(133)R(134)R(135),

R(129), R(130), R(131) and R(133) are, independently of each other,

—

C_zabH_2zab—

(C₁-C₉)-heteroaryl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

zab is zero or 1,

R(132), 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 —

C_znH_2zn—

R(115a),

zn is zero or 1,

R(115a) is

(C₃-C₆)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and

NR(116a)R(117a),

R(116a) and R(117a) being hydrogen or CH₃,

R(112a) is

hydrogen, (C₁-C₄)-alkyl, CF₃, (C₃-C₄)-alkenyl or —

C_zaH_2za—

R(115a),

za is zero or 1,

R(115a) is

(C₃-C₆)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and

NR(116a)R(117a),

R(116a) and R(117a) being 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 can be replaced by oxygen, S, NH, N—

CH₃ or N-benzyl,

or

R(103) is

R(146)X(1a)-,

X(1a) is oxygen, S, NR(147), (C═

O)A- or

NR(148)C=MN(%)R(149)-,

M is oxygen, and

A is oxygen or NR(150),

R(146) and R(147) are, independently, hydrogen, (C₁-C₆)-alkyl, (C₃-C₄)-alkenyl,

(CH₂)_zbzC_zdzF_2zdz+1 or C_zxaH_2zxa—

R(151),

zbz is zero or 1,

zdz is 1, 2, 3, 4, 5, 6 or 7,

zxa is zero or 1,

R(151)

is (C₃-C₆)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy or NR(152)R(153),

R(152) and R(153) being hydrogen or CH₃,

R(148)

is hydrogen or (C₁-C₄)-alkyl,

R(149) is defined as R(146),

or

20 R(146) and R(147), or R(146) and R(148), respectively, are together 4 or 5 methylene groups of which one CH₂ group can be replaced by oxygen, S, NH, N—

CH₃ or N-benzyl,

where A and N(*) are bonded to the phenyl nucleus of the benzoylguanidine parent substance,

or

R(103)

is —

SR(164), —

OR(165), —

NHR(166), —

NR(167)R(168), —

CHR(169)R(170), —

[CR(154)R(155)OH], —

C≡

CR(156), —

CR(158)=CR(157) or

—

[CR(159)R(160a)]_zz-(CO)-[CR(161)R(162)]_zv-R(163),

R(164), R(165), R(166), R(167) and R(169) are identical or different and are

—

(CH₂)_zy—

(CHOH)_zz—

(CH₂)_zaa—

(CHOH)_zt—

R(171) or

—

(CH₂)_zab—

O—

(CH₂—

CH₂O)_zac—

R(172),

R(171) and R(172) are hydrogen or methyl,

zu is 1 or 2,

zv is zero, 1 or 2,

zy, zz, zaa, zab and zac are identical or different and are

zero, 1 or 2,

zt is 1, 2 or 3,

R(168), R(170), R(154) and R(155) are identical or different and are

hydrogen or methyl,

or

R(169) and R(170), or R(154) and R(155), respectively, together with the carbon atom carrying them, are a (C₃-C₆)-cycloalkyl,

R(163) is

hydrogen, (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or

—

C_zebH_2zeb—

R(173),

zeb is zero, 1 or 2,

R(156), R(157) and R(173) are, independently of each other,

phenyl which is unsubstituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and

NR(174)R(175),

R(174) and R(175) being hydrogen or CH₃,

or

R(156), R(157) and R(173) are, independently of each other,

(C₁-C₉)-heteroaryl which is unsubstituted or is substituted as phenyl,

R(158), R(159), R(160), R(161) and R(162) are hydrogen or methyl,

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 hydrogen, (C₁-C₄)-alkyl, (C₃-C₄)-alkenyl or —

C_zfaH_2zfa—

R(180),

zfa is zero or 1,

R(180)

is (C₅-C₇)-cycloalkyl or phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methoxy or methyl,

or

R(177) and R(178) are together 4 or 5 methylene groups of which one CH₂ group can be replaced by oxygen, S, NH, N—

CH₃ or N-benzyl,

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

R(104)

is hydrogen, CF₃ (C₁-C₈)-alkyl or —

C_zalH_2zalR(118a),

zal is zero or 1,

R(118a)

is (C₃-C₆)-cycloalkyl or phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(119a)R(119b),

R(119a) and R(119b) being hydrogen or CH₃,

or

R(104)

is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl which are linked via C or N and which are unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino and dimethylamino,

or

R(104)

is R(110a)-SO₂ or R(112a)R(113a)N—

SO₂—

,

R(110a)

is (C₁-C₄)-alkyl or CF₃,

R(112a)

is hydrogen, (C₁-C₄)-alkyl, CF₃ or —

C_zaH_2za—

R(115a),

za is zero or 1,

R(115a)

is phenyl which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(116a)R(117a),

R(116a) and R(117a) being hydrogen or CH₃,

R(113a)

is hydrogen or CH₃,

or

R(104)

is —

C≡

CR(193),

R(193)

is phenyl which is unsubstituted or substituted by 1-2 substituents selected from the group consisting of F, Cl, CF₃, methyl, methoxy and NR(194)R(195),

R(194) and R(195) being hydrogen or CH₃,

R(105)

is hydrogen.

4. A process for preparing a compound I as claimed in claim 1, wherein

a) two equivalents of the compounds of the formula II are reacted with one equivalent of the guanidine,

where X(1) and X(2) have the given meaning and L is a leaving group which can readily be substituted nucleophilically, or

b) a compound of the formula Ia

is reacted with a compound of the formula III

with the participation of a base, where X(1) and X(2) have the given meaning and L is a leaving group which can readily be substituted nucleophilically,

and wherein conversion takes place, where appropriate, into a pharmaceutically tolerated salt.

5. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment of arrhythmias.

6. A method for treating arrhythmias, wherein an effective quantity of a compound I as claimed in claim 1 is treated with the customary additives and administered in a suitable form for administration.

7. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of cardiac infarction.

8. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of angina pectoris.

9. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of ischemic conditions of the heart.

10. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke.

11. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and limbs.

12. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment of shock conditions.

13. The use of a compound I as claimed in claim 1 for preparing a medicament for employment in surgical operations and organ transplantations.

14. The use of a compound I as claimed in claim 1 for preparing a medicament for the preservation and storage of transplants for surgical procedures.

15. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment of diseases in which cell proliferation represents a primary or secondary cause, and consequently its use as an anti-atherosclerotic agent, or as an agent against diabetic late complications, cancerous diseases, fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, and against hyperplasia of the prostate.

16. The use of a compound I as claimed in claim 1 for preparing a scientific tool for inhibiting the Na⁺/H⁺ exchanger and for diagnosing hypertension and proliferative diseases.

17. A medicine containing an effective quantity of a compound I as claimed in claim 1.