U.S. patent application number 12/172380 was filed with the patent office on 2008-11-06 for novel substituted 2-aminoimidazoles, process for their preparation, their use as medicament or diagnostic aid.
This patent application is currently assigned to SANOFI-AVENTIS DEUTSCHLAND GMBH. Invention is credited to Uwe HEINELT, Armin HOFMEISTER, Hans-Willi JANSEN, Hans-Jochen LANG, Klaus WIRTH.
Application Number | 20080275098 12/172380 |
Document ID | / |
Family ID | 32667986 |
Filed Date | 2008-11-06 |
United States Patent
Application |
20080275098 |
Kind Code |
A1 |
HEINELT; Uwe ; et
al. |
November 6, 2008 |
NOVEL SUBSTITUTED 2-AMINOIMIDAZOLES, PROCESS FOR THEIR PREPARATION,
THEIR USE AS MEDICAMENT OR DIAGNOSTIC AID
Abstract
The present invention comprises novel substituted
2-aminoimidazoles of formula I, processes for their preparation,
pharmaceutical compositions thereof, and methods for their use in
the treatment of disorders of the central nervous system,
cardiovascular disorders, stroke and pulmonary disorders, urinary
disorders such as acute or chronic renal failure, disorders of
biliary function, respiratory disorders such as snoring or sleep
apnea. ##STR00001## wherein the substitutents R1-R8 are further
defined herein.
Inventors: |
HEINELT; Uwe; (Wiesbaden,
DE) ; LANG; Hans-Jochen; (Hofheim, DE) ;
HOFMEISTER; Armin; (Oppenheim, DE) ; WIRTH;
Klaus; (Kriftel, DE) ; JANSEN; Hans-Willi;
(Niedernhausen, DE) |
Correspondence
Address: |
ANDREA Q. RYAN;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206, MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
SANOFI-AVENTIS DEUTSCHLAND
GMBH
Frankfurt am Main
DE
|
Family ID: |
32667986 |
Appl. No.: |
12/172380 |
Filed: |
July 14, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10771185 |
Feb 3, 2004 |
|
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12172380 |
|
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60477570 |
Jun 11, 2003 |
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Current U.S.
Class: |
514/388 ;
514/392; 548/307.4; 548/333.1; 549/341; 549/451 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
11/00 20180101; A61P 43/00 20180101; A61P 3/00 20180101; A61P 3/12
20180101; A61P 5/08 20180101; A61P 25/08 20180101; A61P 7/08
20180101; A61P 9/12 20180101; A61P 7/00 20180101; A61P 39/00
20180101; A61P 9/02 20180101; A61P 25/18 20180101; A61P 25/20
20180101; A61P 3/06 20180101; A61P 3/10 20180101; A61P 25/22
20180101; C07D 233/50 20130101; A61P 37/02 20180101; A61P 33/02
20180101; A61P 9/06 20180101; A61P 13/12 20180101; A61P 11/16
20180101; A61P 25/24 20180101; A61P 1/10 20180101; A61P 33/00
20180101; A61P 17/00 20180101; A61P 33/06 20180101; A61P 33/14
20180101; A61P 9/00 20180101; A61P 7/02 20180101; A61P 25/00
20180101; A61P 9/10 20180101; A61P 1/00 20180101 |
Class at
Publication: |
514/388 ;
548/333.1; 514/392; 548/307.4; 549/451; 549/341 |
International
Class: |
C07D 233/50 20060101
C07D233/50; A61K 31/4168 20060101 A61K031/4168; C07D 235/30
20060101 C07D235/30; C07D 317/72 20060101 C07D317/72; A61P 9/10
20060101 A61P009/10; A61P 3/00 20060101 A61P003/00; A61P 3/10
20060101 A61P003/10; C07D 317/10 20060101 C07D317/10; A61K 31/4184
20060101 A61K031/4184 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 4, 2003 |
DE |
10304374.8 |
Claims
1. A compound of formula I, or a pharmaceutically acceptable salt
or trifluoroacetic acid salt of said compound: ##STR00027## where:
R1 and R2 are independently selected from the group consisting of
hydrogen, alkyl which has 1, 2, 3 or 4 carbon atoms and is
substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, CN
and phenyl, provided that R1 and R2 are not both simultaneously
hydrogen; R3, R4, R5, R6 and R7 are independently selected from the
group consisting of hydrogen, F, Cl, Br, I, alkyl with 1, 2, 3 or 4
carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9
fluorine atoms, and alkoxy with 1, 2, 3 or 4 carbon atoms and
substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms,
provided that R3 and R7 are not both simultaneously hydrogen; R8 is
selected from the group consisting of H, alkyl with 1, 2, 3 or 4
carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9
fluorine atoms, and cycloalkyl with 3, 4 or 5 carbon atoms and
substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms;
provided, when R3 is C1 and R4, R5, R6, R7 and R8 are hydrogen, R1
and R2 are not both simultaneously methyl; and further provided
that said compound is not
(2,6-dichlorphenyl)-(4-methyl-1H-imidazol-2-yl)-amine.
2. The compound or a salt thereof as recited in claim 1, wherein:
R3 and R7 are independently selected from the group consisting of
F, Cl, Br and alkyl has 1, 2, 3 or 4 carbon atoms and is
substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms; R4,
R5 and R6 are H; R8 is H or alkyl with 1, 2, 3 or 4 carbon atoms
and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine
atoms;
3. The compound or salt thereof as recited in claim 1, wherein: R1
and R2 are independently selected from the group consisting of
hydrogen, alkyl which has 1, 2, 3 or 4 carbon atoms and is
substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms, CN
and phenyl, provided that R1 and R2 are not both simultaneously
hydrogen; and R3, R4, R5, R6 and R7 are independently selected from
the group consisting of hydrogen, F, Cl, Br, and alkyl with 1, 2, 3
or 4 carbon atoms and substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9
fluorine atoms, provided that R3 and R7 are not both simultaneously
hydrogen.
4. The compound or salt thereof as recited in claim 3, wherein: R1
and R2 are independently selected from the group consisting of
either H or alkyl with 1, 2, 3 or 4 carbon atoms, provided that R1
and R2 are not both simultaneously hydrogen; R3 and R7 are
independently selected from the group consisting of F, Cl, Br and
alkyl with 1, 2, 3 or 4 carbon atoms and substituted by 0, 1, 2, 3,
4, 5, 6, 7, 8 or 9 fluorine atoms; R4, R5 and R6 are hydrogen; R8
is selected from the group consisting of H or an alkyl which has 1,
2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6,
7, 8 or 9 fluorine atoms.
5. A pharmaceutical composition comprising the compound or a salt
thereof as recited in claim 1 in combination with one or more
additional pharmaceutically acceptable carrier compounds.
6. A pharmaceutical composition comprising the compound or a salt
thereof as recited in claim 1 in combination with one or more
additional pharmaceutically acceptable carrier compounds . . .
alone or in combination with one or more other drugs or active
ingredients, in a pharmaceutically acceptable formulation for the
treatment or prophylaxis of disorders of respiratory drive, of
respiratory disorders, sleep-related respiratory disorders, of
chronic renal failure, of disorders of intestinal function, of high
blood pressure, of essential hypertension, of disorders of the
central nervous system, of disorders which result from CNS
overexcitability, epilepsy and centrally induced convulsions or of
anxiety states, depressions and psychoses, of ischemic states of
the peripheral or central nervous system or of stroke, of acute and
chronic damage to and disorders of peripheral organs or limbs
caused by ischemic or by reperfusion events, of atherosclerosis, of
disorders of lipid metabolism, of thromboses, of disorders of
biliary function, of infestation by ectoparasites, of disorders
resulting from endothelial dysfunction, of protozoal disorders, of
malaria, for preservation and storage of transplants for surgical
procedures, for use in surgical operations and organ
transplantations or for the treatment of states of shock or of
diabetes and late damage from diabetes or of disorders in which
cellular proliferation represents a primary or secondary cause,
7. The composition of claim 6, wherein said drug is for the
treatment or prophylaxis of disorders of respiratory drive and/or
of sleep-related respiratory disorders and sleep apneas.
8. The composition of claim 7, wherein said drug is for the
treatment or prophylaxis of snoring.
9. The composition of claim 8, wherein said drug is for the
treatment or prophylaxis of acute and chronic renal disorders, of
acute renal failure or of chronic renal failure.
10. The composition of claim 9 wherein said drug is for the
treatment or prophylaxis of disorders of intestinal function.
11. A method for the treatment of disorders of the central nervous
system, cardiovascular disorders, respiratory disorders,
sleep-related respiratory disorders, chronic renal failure,
disorders of intestinal function, high blood pressure, of essential
hypertension, and the like comprising the administration of a
compound of formula I or a pharmaceutically acceptable salt
thereof: ##STR00028## where: R1 and R2 are independently selected
from the group consisting of hydrogen, alkyl which has 1, 2, 3 or 4
carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9
fluorine atoms, CN and phenyl, provided that R1 and R2 are not both
simultaneously hydrogen; R3, R4, R5, R6 or R7 are independently
selected from the group consisting of hydrogen, F, Cl, Br, I, alkyl
with 1, 2, 3 or 4 carbon atoms, (C.sub.2-C.sub.4)-alkenyl,
cycloalkyl with 3, 4, 5 or 6 carbon atoms, OH, alkoxy with 1, 2, 3
or 4 carbon atoms, CN, NO.sub.2, NH.sub.2, alkylamino with 1, 2, 3
or 4 carbon atoms and dialkylamino with two alkyl parts each having
1, 2, 3 or 4 carbon atoms, said alkyl, alkenyl, cycloalkyl, alkoxy,
alkylamino and dialkylamino being unsubstituted or substituted
independently by 1, 2, 3, 4, 5, 6, 7, 8 or 9 fluorine atoms,
provided that R3 and R7 are not simultaneously hydrogen; R8 is H,
alkyl with 1, 2, 3 or 4 carbon atoms, or cycloalkyl with 3, 4 or 5
carbon atoms, said alkyl and cycloalkyl being independently
unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 F
atoms.
12. The method of treatment as recited in claim 11, wherein said
disorder is sleep apnea or another sleep-related respiratory
disorder.
13. The method of treatment as recited in claim 12, wherein said
disorder is snoring.
14. The method treatment as recited in claim 11, wherein said
disorder is an acute and chronic renal disorder, acute renal
failure, or chronic renal failure.
15. The method of treatment as recited in claim 11, wherein said
disorder is intestinal dysfunction.
16. The method of treatment as recited in claim 11, wherein said
disorder is high blood pressure or hypertension.
17. The method of treatment as recited in claim 11, wherein said
disorder is a disorder of the central nervous system, CNS
over-excitability, epilepsy, or centrally induced convulsions.
18. The method of treatment as recited in claim 11, wherein said
disorder is selected from the group consisting of anxiety,
depression or psychoses.
19. The method as recited in claim 11, wherein said disorder is
ischemia of the peripheral and central nervous system or
stroke.
20. The method of treatment of claim 11, wherein said disorder is
diabetes.
21. The method of treatment of claim 11, wherein said disorder is
atherosclerosis.
22. The method of treatment of claim 11, wherein said disorder is
lipid metabolism.
23. The method of treatment of claim 11, wherein said disorder is a
disorder where cellular proliferation is a primary or secondary
cause.
24. The method of treatment of claim 11, wherein said disorder is
thromboses.
25. A method of treatment of claim 11, wherein said disorder is
biliary dysfunction.
26. A process for the preparation of .alpha.-amino ketals of the
formula V ##STR00029## wherein: R1 and R2 are independently
selected from the group consisting of hydrogen, alkyl which has 1,
2, 3 or 4 carbon atoms and is substituted by 0, 1, 2, 3, 4, 5, 6,
7, 8 or 9 fluorine atoms, CN and phenyl, provided that R1 and R2
are not both simultaneously hydrogen; E is alkyl with 1, 2, 3 or 4
carbon atoms, or forms a cyclic ketal with another E where E-- E is
(C.sub.2-C.sub.4)-alkylene; Hal is Cl, Br, or I; which comprises a)
converting an .alpha.-halo ketone or aldehyde of the formula VI
with an azide by azide-halogen exchange into a corresponding
.alpha.-azide ketone or aldehyde of the formula VII ##STR00030## b)
reacting said .alpha.-azide ketone or aldehyde with mono- or
dihydric alcohols through ketalization or acetalization to give
.alpha.-azide ketal or acetal of the formula VIII ##STR00031## c)
reducing said .alpha.-azide ketal or acetal to a compound of the
formula V. ##STR00032##
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
10/771,185 filed Feb. 3, 2004, now allowed, which is incorporated
herein by reference in its entirety; which claims the benefit of
German patent application No. 10304374.8, filed Feb. 4, 2003 and
the benefit of U.S. Provisional patent application No. 60/477,570,
filed Jun. 11, 2003.
FIELD OF THE INVENTION
[0002] The invention relates to compounds of 2-aminoimidazoles,
which inhibit the sodium proton exchanger, in particular subtype 3
(NHE3), and which can be used in the prevention or treatment of
various disorders. Thus, the compounds can be employed inter alia
for renal disorders such as acute or chronic renal failure, for
disorders of biliary function, for respiratory disorders, for
snoring or sleep apneas or for stroke.
SUMMARY OF THE INVENTION
[0003] The invention relates to compounds of the formula I
##STR00002##
in which
[0004] R1 and R2 [0005] independently of one another H, alkyl with
1, 2, 3 or 4 carbon atoms CN or phenyl [0006] where the carbon
chains are unsubstituted or substituted independently of one
another by 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms, [0007] where R1 and
R2 do not both correspond simultaneously to hydrogen;
[0008] R3, R4, R5, R6, and R7 [0009] independently of one another
H, F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms, or alkoxy
with 1, 2, 3 or 4 carbon atoms, [0010] where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms, [0011] where R3 and R7 do not both
correspond simultaneously to hydrogen;
[0012] R8 [0013] H, alkyl with 1, 2, 3 or 4 carbon atoms or
cycloalkyl with 3, 4 or 5 carbon atoms, where the carbon chains or
cycloalkyl radicals are unsubstituted or substituted by 1, 2, 3, 4,
5, 6, 7, 8 or 9 F atoms; and the pharmaceutically acceptable salts
and trifluoroacetic acid salts thereof; where R1 and R2 are not
both simultaneously methyl when R3 is Cl and R4, R5, R6, R7 and R8
are hydrogen, where
(2,6-Dichlorphenyl)-(4-methyl-1H-imidazol-2-yl)-amine is
excluded.
[0014] Preference is given to compounds of the formula I in which
the meanings are
[0015] R1 and R2 [0016] together with the two carbon atoms to which
they are bonded a five-, six-, seven- or eight-membered carbon ring
comprising one or two double bonds, where the ring is unsubstituted
or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 F atoms
and/or by one or two radicals from the group of CH.sub.3 or
OCH.sub.3;
[0017] R3, R4, R5, R6 and R7 [0018] independently of one another H,
F, Cl, Br, alkyl with 1, 2, 3 or 4 carbon atoms or alkoxy with 1,
2, 3 or 4 carbon atoms, [0019] where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms, [0020] where R3 and R7 do not both
correspond simultaneously to hydrogen;
[0021] R8 [0022] H, alkyl with 1, 2, 3 or 4 carbon atoms or
cycloalkyl with 3, 4 or 5 carbon atoms, where the carbon chains or
cycloalkyl radicals are unsubstituted or substituted by 1, 2, 3, 4,
5, 6, 7, 8 or 9 F atoms; and the pharmaceutically acceptable salts
and trifluoroacetic acid salts thereof.
[0023] Particular preference is given to compounds of the formula I
in which the meanings are:
[0024] R1 and R2 [0025] together with the two carbon atoms to which
they are bonded a five-, six- or seven-membered carbon ring
comprising a double bond,
[0026] R3 and R7 [0027] independently of one another F, Cl, Br or
alkyl with 1, 2, 3 or 4 carbon atoms, where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms;
[0028] R4, R5 and R6 [0029] H
[0030] R8 is H or alkyl with 1, 2, 3 or 4 carbon atoms, [0031]
where the carbon chains are unsubstituted or substituted by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms; and the pharmaceutically acceptable
salts and trifluoroacetic acid salts thereof.
[0032] Very particular preference is given to: [0033]
(2,6-dichlorophenyl)(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)amine
or [0034]
(2,6-dichlorophenyl)methyl(4,5,6,7-tetrahydro-1H-benzoimidazol-2-y-
l)amine and the pharmaceutically acceptable salts and
trifluoroacetic acid salts thereof. [0035] Preference is further
given to compounds of the formula I in which R1 and R2 are
independently of one another H, alkyl with 1, 2, 3 or 4 carbon
atoms, CN or phenyl where the carbon chains are unsubstituted or
substituted independently of one another by 1, 2, 3, 4, 5, 6, 7, 8
or 9 F atoms, [0036] where R1 and R2 do not both correspond
simultaneously to hydrogen;
[0037] R3, R4, R5, R6 and R7 [0038] independently of one another H,
F, Cl, Br or alkyl with 1, 2, 3 or 4 carbon atoms where the carbon
chains are unsubstituted or substituted independently of one
another by 1, 2, 3, 4, 5, 6, 7, 8 or 9 F atoms, [0039] where R3 and
R7 do not both correspond simultaneously to hydrogen;
[0040] R8 [0041] H, alkyl with 1, 2, 3 or 4 carbon atoms or
cycloalkyl with 3, 4 or 5 carbon atoms, where the carbon chains or
cycloalkyl radicals are unsubstituted or substituted by 1, 2, 3, 4,
5, 6, 7, 8 or 9 F atoms; and the pharmaceutically acceptable salts
and trifluoroacetic acid salts thereof; where R1 and R2 are not
both simultaneously methyl when R3 is Cl and R4, R5, R6, R7 and R8
are hydrogen, where
(2,6-Dichlorphenyl)-(4-methyl-1H-imidazol-2-yl)-amine is
excluded.
[0042] Particular preference is given to compounds of the formula I
in which the meanings are:
[0043] R1 and R2 are independently of one another H or alkyl with
1, 2, 3 or 4 carbon atoms;
where R1 and R2 do not both correspond simultaneously to
hydrogen;
[0044] R3 and R7 [0045] independently of one another F, Cl, Br or
alkyl with 1, 2, 3 or 4 carbon atoms, where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms;
[0046] R4, R5 and R6 [0047] H
[0048] R8 [0049] H or alkyl with 1, 2, 3 or 4 carbon atoms, [0050]
where the carbon chains are unsubstituted or substituted by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms; and the pharmaceutically acceptable
salts and trifluoroacetic acid salts thereof, where
(2,6-Dichlorphenyl)-(4-methyl-1H-imidazol-2-yl)-amine is
excluded.
[0051] Very particular preference is given to: [0052]
(2,6-dichlorophenyl)(4,5-dimethyl-1H-imidazol-2-yl)amine and the
pharmaceutically acceptable salts and trifluoroacetic acid salts
thereof.
[0053] In one embodiment, preferred compounds of the formula I are
those in which R1 and R2 form together with the two carbon atoms to
which they are bonded a five-, six-, seven or eight-membered carbon
ring comprising one or two double bonds, where the ring is
unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
11 F atoms and/or by one or two radicals from the group of CH.sub.3
or OCH.sub.3; particularly preferred compounds are those in which
R1 and R2 form together with the two carbon atoms to which they are
bonded a five-, six- or seven-membered, unsubstituted carbon ring
comprising one double bond.
[0054] In a further embodiment, preferred compounds of the formula
I are those in which R1 and R2 are described independently of one
another by H or alkyl with 1, 2, 3 or 4 carbon atoms.
[0055] In a further embodiment, preferred compounds of the formula
I are those in which R3 and R7 are not described by hydrogen;
particularly preferred compounds are those in which R3 and R7 are
described independently of one another by F, Cl, Br or alkyl with
1, 2, 3 or 4 carbon atoms, where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms; very particularly preferred
compounds are those in which R3 and R7 are described independently
of one another by Cl or methyl, in particular Cl. In a further
embodiment, preferred compounds of the formula I are those in which
R4, R5 and R6 are described by hydrogen.
[0056] In a further embodiment, preferred compounds of the formula
I are those in which R8 is described by hydrogen or alkyl with 1,
2, 3 or 4 carbon atoms, and particularly preferred compounds are
those in which R8 is described by hydrogen or methyl.
[0057] The invention further relates to the use of compounds of the
formula I
##STR00003##
for producing a medicament for the treatment of diseases which can
be influenced by inhibition of the sodium/hydrogen exchanger (NHE),
in particular of NHE3, in which the meanings are:
[0058] R1 and R2 [0059] independently of one another H, F, Cl, Br,
I, CN, alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, alkenyl with 2,
3, 4, 5 or 6 carbon atoms, alkynyl with 2, 3, 4, 5 or 6 carbon
atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, cycloalkenyl with
4, 5 or 6 carbon atoms or phenyl, [0060] where phenyl is
unsubstituted or substituted independently of one another by one or
two radicals from the group of F, Cl, Br, I, OH, NR9R10, alkyl with
1, 2, 3 or 4 carbon atoms, CN, CF.sub.3 or alkoxy with 1, 2, 3 or 4
carbon atoms, with R9, R10 independently of one another H, alkyl
with 1, 2, 3 or 4 carbon atoms; and [0061] where the carbon chains
or rings are unsubstituted or substituted independently of one
another by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 F atoms
and/or one or two radicals from the group of OH, NR9R10, alkyl with
1, 2, 3 or 4 carbon atoms, CN, CF.sub.3 or alkoxy with 1, 2, 3 or 4
carbon atoms, with [0062] R9, R10 independently of one another H,
alkyl with 1, 2, 3 or 4 carbon atoms; [0063] where R1 and R2
preferably do not correspond simultaneously to phenyl; or
[0064] R1 and R2 [0065] together with the two carbon atoms to which
they are bonded a five-, six-, seven- or eight-membered carbon ring
comprising one or two double bonds, where the ring is unsubstituted
or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 F atoms
and/or one or two radicals from the group of NR9R10, alkyl with 1,
2, 3 or 4 carbon atoms, OH, CN, CF.sub.3 or alkoxy with 1, 2, 3 or
4 carbon atoms, with R9, R10 being independently of one another H,
alkyl with 1, 2, 3 or 4 carbon atoms;
[0066] R3, R4, R5, R6 or R7 [0067] independently of one another H,
F, Cl, Br, I, alkyl with 1, 2, 3 or 4 carbon atoms,
(C.sub.2-C.sub.4)-alkenyl, cycloalkyl with 3, 4, 5 or 6 carbon
atoms, OH, alkoxy with 1, 2, 3 or 4 carbon atoms, CN, NO.sub.2,
NH.sub.2, alkylamino with 1, 2, 3 or 4 carbon atoms or dialkylamino
with, in each case, 1, 2, 3 or 4 carbon atoms, [0068] where the
carbon chains or rings are unsubstituted or substituted
independently of one another by 1, 2, 3, 4, 5, 6, 7, 8 or 9 F
atoms; [0069] where R3 and R7 do not correspond simultaneously to
hydrogen;
[0070] R8 [0071] H, alkyl with 1, 2, 3 or 4 carbon atoms or
cycloalkyl with 3, 4 or 5 carbon atoms, where the carbon chains or
rings are unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8 or
9 F atoms; and the pharmaceutically acceptable salts thereof.
[0072] It is preferred in one embodiment to use compounds of the
formula I in which R1 and R2 form together with the two carbon
atoms to which they are bonded a five-, six-, seven- or
eight-membered carbon ring comprising one or two double bonds,
where the ring is unsubstituted or substituted by 1, 2, 3, 4, 5, 6,
7, 8, 9, 10 or 11 F atoms and/or by one or two radicals from the
group of CH.sub.3 or OCH.sub.3; it is particularly preferred to use
compounds in which R1 and R2 form together with the two carbon
atoms they are bonded a five-, six- or seven-membered,
unsubstituted carbon ring comprising one double bond.
[0073] It is preferred in a further embodiment to use compounds of
the formula I in which R1 and R2 are described independently of one
another by H or alkyl with 1, 2, 3 or 4 carbon atoms.
[0074] It is preferred in a further embodiment to use compounds of
the formula I in which R3 and R7 are not described by hydrogen; it
is particularly preferred to use compounds in which R3 and R7 are
described independently of one another by F, Cl, Br or alkyl with
1, 2, 3 or 4 carbon atoms, where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms; it is very particularly preferred to
use compounds in which R3 and R7 are described independently of one
another by Cl or methyl, in particular Cl. It is preferred in a
further embodiment to use compounds of the formula I in which R4,
R5 and R6 are described by hydrogen. It is preferred in a further
embodiment to use compounds of the formula I in which R8 is
described by hydrogen or alkyl with 1, 2, 3 or 4 carbon atoms; it
is particularly preferred to use compounds in which R8 is described
by hydrogen or methyl.
[0075] If the substituents R1, R2, R3, R4, R5, R6, R7 or R8 contain
one or more centers of asymmetry, these may have, independently of
one another, both the S and the R configuration. The compounds may
be in the form of optical isomers, of diastereomers, of racemates
or of mixtures thereof on all ratios.
[0076] The present invention encompasses all tautomeric forms of
the compounds of the formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definition
[0077] Carbon chains are all radicals which comprise carbon atoms
in straight-chain or branched arrangement, for example 1, 2, 3, 4,
5 or 6 carbon atoms. Examples are alkyl radicals, alkoxy radicals,
alkynyl radicals, alkynyl radicals, alkylamino radicals or
dialkylamino radicals. Carbon rings are all radicals which comprise
carbon atoms which form a ring, for example of 3, 4, 5 or 6 carbon
atoms. Examples of carbon rings are cycloalkyl radicals or
cycloalkenyl radicals. Carbon chains or rings may be unsaturated
and also polyunsaturated in various positions, and one or more, for
example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, hydrogen atoms
in carbon chains or rings may be replaced by fluorine atoms.
Substituted carbon chains may be substituted in any positions.
[0078] Alkyl radicals may be straight-chain or branched. This
applies also when they have substituents or occur as substituents
of other radicals, for example in fluoroalkyl radicals or alkoxy
radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl,
isopropyl (=1-methylethyl), n-butyl, isobutyl (=2-methylpropyl),
sec-butyl (=1-methylpropyl), tert-butyl (=1,1-dimethylethyl),
n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl,
3-methylpentyl, isohexyl, neohexyl. Preferred alkyl radicals are
methyl, ethyl, isopropyl. One or more, for example 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12 or 13, hydrogen atoms in alkyl radicals may
be replaced by fluorine atoms. Examples of such fluoroalkyl
radicals are trifluoromethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, heptafluoroisopropyl. Substituted alkyl radicals
may be substituted in any positions.
[0079] Alkenyl radicals may be straight-chain or branched. This
applies also when they have substituents, for example in
fluoroalkenyl radicals. The alkenyl radicals may be unsaturated in
various positions and also polyunsaturated. Examples of alkenyl
radicals are ethenyl, n-prop-1-enyl, n-prop-2-enyl, isoprop-1-enyl
(=1-methylethenyl), n-but-1-enyl, n-but-2-enyl, n-but-3-enyl,
n-buta-1,3-dienyl, isobut-1-enyl (=2-methylprop-1-enyl),
isobut-2-enyl (=2-methylprop-2-enyl), sec-but-1-enyl
(=1-methylprop-1-enyl) pentenyl, hexenyl. Preferred alkenyl
radicals are ethenyl, n-prop-1-enyl, n-prop-2-enyl, n-but-1-enyl,
n-but-2-enyl, n-pentenyl, n-pentadienyl, isopentenyl,
tert-pentenyl, neopentenyl, n-hexenyl, n-hexadienyl, n-hexatrienyl,
3-methylpentenyl, isohexenyl, neohexenyl. One or more, for example
1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, hydrogen atoms in alkenyl
radicals may be replaced by fluorine atoms. Substituted alkenyl
radicals may be substituted in any positions.
[0080] Alkynyl radicals may be straight-chain or branched. This
applies also when they have substituents, for example in
fluoroalkynyl radicals. The alkynyl radicals may be unsaturated in
various positions and also polyunsaturated. Examples of alkynyl
radicals are ethynyl, n-prop-1-ynyl, n-prop-2-ynyl, n-but-1-ynyl,
n-but-2-ynyl, n-but-3-ynyl, n-buta-1,3-diynyl, sec-but-2-ynyl
(=1-methylprop-2-ynyl), n-pentynyl, n-pentadiynyl, isopentynyl,
tert-pentynyl, neopentynyl, n-hexynyl, n-hexadiynyl, n-hexatriynyl,
3-methylpentynyl, isohexynyl, neohexynyl. Preferred alkynyl
radicals are n-prop-1-ynyl, n-prop-2-ynyl, n-but-1-ynyl,
n-but-2-ynyl. One or more, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9,
hydrogen atoms in alkynyl radicals may be replaced by fluorine
atoms. Substituted alkynyl radicals may be substituted in any
positions.
[0081] Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. One or more, for example 1, 2, 3, 4, 5,
6, 7, 8, 9, 10 or 11 hydrogen atoms in cycloalkyl radicals may be
replaced by fluorine atoms. Substituted cycloalkyl radicals may be
substituted in any positions.
[0082] The cycloalkenyl radicals may be unsaturated in various
positions and also polyunsaturated. Examples of cycloalkenyl
radicals are cyclobut-1-enyl, cyclobut-2-enyl, cyclopentenyl,
cyclopentadienyl, cyclohexenyl or cyclohexadienyl. One or more, for
example 1, 2, 3, 4, 5, 6, 7, 8 or 9, hydrogen atoms in cycloalkenyl
radicals may be replaced by fluorine atoms. Substituted
cycloalkenyl radicals may be substituted in any positions.
[0083] Phenyl radicals may be unsubstituted or mono- or
polysubstituted, for example mono-, di- or trisubstituted, by
identical or different radicals. In monosubstituted phenyl
radicals, the substituent may be in position 2, position 3 or
position 4. Disubstituted phenyl may be substituted in position
2.3, position 2.4, position 2.5, position 2.6, position 3.4 or
position 3.5.
[0084] A method for preparing the compounds used is also described.
Thus, compounds described by formula I can be prepared under acidic
conditions in a manner known to the skilled worker from the
underlying guanidines of the formula II or a tautomeric form of the
formula II
##STR00004##
where the radicals R1 to R8 are defined in accordance with formula
I, while E corresponds to an alkyl radical having 1 to 4 carbon
atoms, it being possible for the two E radicals also to be
connected to form a ring.
[0085] Compounds of the formula II can be obtained in a manner
known from the literature from the cyanamides of the formula III or
compounds of the formula IV and the appropriate amino ketals or
acetals of the formula V, where the radical R in formula IV
corresponds to an alkyl group, preferably methyl.
##STR00005##
[0086] Access to the above intermediates of the formulae III, IV
and V for R8=hydrogen is disclosed in the literature (J. Med. Chem.
1975, 18, 90-99; GB 1, 131, 191).
[0087] It has been found that compounds of the formula V can
advantageously be prepared, in a modification of the above
literature, starting from .alpha.-halo ketones or aldehydes via the
sequence of halogen-azide exchange (preferably with sodium azide),
ketalization or acetalization (preferably with ethylene glycol) and
reduction (preferably with hydrogen in the presence of palladium on
carbon or platinum dioxide) (scheme 1):
##STR00006##
[0088] The present invention thus further relates to a process for
preparing .alpha.-amino ketals of the formula (V)
##STR00007##
in which the meanings are:
[0089] R1 and R2 [0090] H, alkyl with 1, 2, 3, 4, 5 or 6 carbon
atoms, alkenyl with 2, 3, 4, 5 or 6 carbon atoms, alkynyl with 2,
3, 4, 5 or 6 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon
atoms, cycloalkenyl with 4, 5 or 6 carbon atoms or phenyl, [0091]
where phenyl is unsubstituted or substituted independently of one
another by one or two radicals from the group of F, Cl, Br, I,
NR11R12, alkyl with 1, 2, 3 or 4 carbon atoms, CN, CF.sub.3 or
alkoxy with 1, 2, 3 or 4 carbon atoms, with R11, R12 being
independently of one another alkyl with 1, 2, 3 or 4 carbon atoms,
benzyl, 4-methoxybenzyl; and [0092] where the carbon chains are
unsubstituted or substituted independently of one another by 1, 2,
3, 4, 5, 6, 7, 8 or 9 F atoms and/or by one or two radicals from
the group of NR11R12, alkyl with 1, 2, 3 or 4 carbon atoms, CN,
CF.sub.3 or alkoxy with 1, 2, 3 or 4 carbon atoms, with R11, R12
being independently of one another alkyl with 1, 2, 3 or 4 carbon
atoms, benzyl, 4-methoxybenzyl; or
[0093] R1 and R2 [0094] together with the two carbon atoms to which
they are bonded a five- to eight-membered carbon ring which is
saturated or comprises a double bond, [0095] where the ring is
unsubstituted or substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11
or 12 F atoms and/or by one or two radicals from the group of
NR11R12, alkyl with 1, 2, 3 or 4 carbon atoms, CN, CF.sub.3 or
alkoxy with 1, 2, 3 or 4 carbon atoms, with R11, R12 independently
of one another alkyl with 1, 2, 3 or 4 carbon atoms, benzyl,
4-methoxybenzyl;
[0096] E [0097] alkyl with 1, 2, 3 or 4 carbon atoms, or the two E
radicals form a cyclic ketal in which E-E is
(C.sub.2-C.sub.4)-alkylene;
[0098] Hal [0099] Cl, Br, I which comprises converting an
.alpha.-halo ketone or aldehyde of the formula VI with an azide,
for example NaN.sub.3, by halogen-azide exchange into the
corresponding .alpha.-azide ketone or aldehyde of the formula
VII
##STR00008##
[0099] which is subsequently reacted with mono- or dihydric
alcohols by ketalization or acetalization to give the .alpha.-azide
ketal or acetal of the formula VIII
##STR00009##
which is then reduced, preferably with hydrogen in the presence of
a catalyst for example palladium on carbon or platinum dioxide, to
compounds of the formula V.
##STR00010##
[0100] Compounds of the formula I can also be prepared starting
from cyanamides of the formula III and .alpha.-amino ketones of the
formula IX in protic solvents such as alcohols, for example
ethanol.
##STR00011##
[0101] A suitable alternative is also the two-stage reaction of
suitable 1,2-diaminoalkylene derivatives of the formula X with
isothiocyanates of the formula XI.
##STR00012##
[0102] The thiourea of the formula XII which is formed as
intermediate is then cyclized preferably with
N,N'-dicyclohexylcarbodiimide or methyl iodide to give compounds of
the formula I.
[0103] The starting compounds of the formulae IX and X are
commercially available or can be prepared by, or in analogy to,
processes described in the literature and known to the skilled
worker.
[0104] It was surprisingly possible to show in the present
invention that the described compounds are potent inhibitors of the
sodium/hydrogen exchanger (NHE), in particular of NHE3.
[0105] NHE3 is found in the body of various species preferentially
in the bile, the intestine and the kidney (Fliegel et al, Biochem.
Cell. Biol. 76: 735-741, 1998), but has also been detected in the
brain (E. Ma et al. Neuroscience 79: 591-603).
[0106] Known NHE3 inhibitors are derived, for example, from
compounds of the acylguanidine type (EP 825 178), norbornylamine
type (DE 199 60 204), 2-guanidinoquinazoline type (WO 01 79 186, WO
02 20496) or benzamidine type (WO 01 21582, WO 01 72 742).
Squalamine, which is likewise described as NHE3 inhibitor (M.
Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45: C136-C144),
does not act directly like the compounds of formula I but reaches
its maximum strength of effect only after one hour.
[0107] NHE3 inhibitors of the imidazolidine type are described in
German patent application DE 10163239 and of the thiophene type in
German patent application DE 10224892. WO 02 46169 A1 describes
NHE3 inhibitors of the 2-phenylaminobenzimidazole type. It has now
been found, surprisingly, that the imidazole derivatives of the
formula I described herein are likewise potent inhibitors of NHE3
and moreover have advantageous pharmacological properties.
[0108] Clonidine, which is similar to the compounds described
herein, is known as a weak NHE inhibitor. Its effect on the rat
NHE3 is indeed extremely moderate, with an IC.sub.50 of 620 .mu.M.
Instead, it shows a certain selectivity for NHE2, for which it has
an IC.sub.50 of 42 .mu.M (J. Orlowski et al J. Biol. Chem. 268,
25536). It should therefore rather be referred to as an NHE2
inhibitor. Besides the weak NHE effect, clonidine has a high
affinity for the adrenergic .alpha.2 receptor and imidazoline I1
receptor, mediating a strong blood pressure-lowering effect
(Ernsberger et al Eur. J. Pharmacol. 134, 1, 1987). Compounds of
the formula I are distinguished by an increased NHE3-inhibiting
effect compared with clonidine.
[0109] On the basis of these unexpected NHE-inhibitory properties,
the compounds of the formula I are suitable for the prevention and
treatment of diseases caused by an activation or by an activated
NHE. The use of the compounds of the invention relates to the
prevention and treatment of acute and chronic diseases in
veterinary and human medicine.
[0110] Thus, NHE inhibitors of the invention are suitable for the
treatment of diseases caused by ischemia and/or by reperfusion.
[0111] The compounds described herein are, as a result of their
pharmacological properties, outstandingly suitable as
antiarrhythmic drugs with a cardioprotective component for
prophylaxis of infarction and for treatment of infarction, and for
the treatment of angina pectoris, in which connection they also
inhibit or greatly reduce in a preventive manner the
pathophysiological processes associated with the development of
ischemia-induced damage, in particular in the induction of
ischemia-induced cardiac arrhythmias. Because of their protective
effects against pathological hypoxic and ischemic situations, the
compounds of the formula I which are used according to the
invention can, as a result of inhibition of the cellular
Na.sup.+/H.sup.+ exchange mechanism, be used as drugs for the
treatment of all acute or chronic damage induced by ischemia or
disorders induced primarily or secondarily thereby. This relates to
the use thereof as drugs for surgical interventions, e.g. in organ
transplantations, in which cases the compounds can be used both to
protect the organs in the donor before and during removal, to
protect removed organs for example on treatment with or storage
thereof in physiological bath fluids, as well as during the
transfer into the recipient organism. The compounds are likewise
valuable drugs with a protective action during the performance of
angioplastic surgical interventions, for example on the heart as
well as peripheral vessels.
[0112] In accordance with their protective action against
ischemia-induced damage, the compounds are also suitable as drugs
for the treatment of ischemias of the nervous system, especially of
the CNS, in which connection they are suitable for example for the
treatment of stroke or of cerebral edema.
[0113] In addition, the compounds of the formula I which are used
according to the invention are likewise suitable for the treatment
of types of shock, such as, for example, of allergic, cardiogenic,
hypovolemic and bacterial shock.
[0114] In addition, the compounds induce an improvement in the
respiratory drive and are therefore used to treat respiratory
conditions associated with the following clinical conditions and
diseases: disturbance of central respiratory drive (e.g. central
sleep apneas, sudden infant death, postoperative hypoxia),
muscle-related breathing disorders, breathing disorders after
long-term ventilation, breathing disorders associated with altitude
adaptation, obstructive and mixed type of sleep apneas, acute and
chronic pulmonary disorders with hypoxia and hypercapnia.
[0115] The compounds additionally increase the tone of the muscles
of the upper airways, so that snoring is suppressed.
[0116] A combination of an NHE inhibitor with a carbonic anhydrase
inhibitor (e.g. acetazolamide), the latter inducing metabolic
acidosis and thus itself increasing respiratory activity, proves to
be advantageous due to an enhanced effect and reduced use of active
ingredient.
[0117] The compounds described herein are additionally suitable as
medicaments for the therapy and prophylaxis of disorders and
impairment induced by overexcitability of the central nervous
system, especially for the treatment of epileptiform disorders,
centrally induced klonic and tonic spasms, states of mental
depression, anxiety disorders and psychoses. The NHE inhibitors
described herein may moreover be used alone or in combination with
other substances having antiepileptic activity or antipsychotic
active ingredients, or carbonic anhydratase inhibitors, for example
with acetazolamide, and with other inhibitors of NHE or of the
sodium-dependent chloride-bicarbonate exchanger (NCBE).
[0118] It has emerged that the compounds used according to the
invention have a mild laxative effect and accordingly can be used
advantageously as laxatives or if there is a risk of
constipation.
[0119] The compounds of the invention can additionally be used
advantageously for the prevention and therapy of acute and chronic
disorders of the intestinal tract caused by ischemic states in the
intestinal region and/or by subsequent reperfusion. Such
complications may be induced for example by inadequate bowel
peristalsis, like those for example to be observed frequently after
surgical interventions, associated with constipation or greatly
reduced bowel activity.
[0120] There is also the possibility of preventing the formation of
gallstones.
[0121] The compounds of the formula I used according to the
invention are furthermore distinguished by a strong inhibitory
effect on the proliferation of cells, for example of fibroblast
cell proliferation and the proliferation of smooth vascular muscle
cells. The compounds of the formula I are therefore suitable as
valuable therapeutic agents for diseases in which cell
proliferation represents a primary or secondary cause, and can
therefore be used as antiatherosclerotic agents, agents to prevent
late complications of diabetes, agents to prevent chronic renal
failure, cancers, fibrotic disorders of the heart, and pulmonary
fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies
and hyperplasias, for example of the heart and prostate, and thus
be used for the prevention and treatment of (congestive) heart
failure or for prostate hyperplasia or prostate hypertrophy.
[0122] The compounds according to the invention are effective
inhibitors of the cellular sodium-proton antiporter (Na/H
exchanger) which is elevated in numerous disorders (essential
hypertension, atherosclerosis, diabetes, etc.), also in those cells
which are readily amenable to measurements, such as, for example,
in erythrocytes, platelets or leukocytes. The compounds used
according to the invention are therefore suitable as excellent and
simple scientific tools, for example in their use as diagnostic
aids for determining and distinguishing different types of
hypertension, but also of atherosclerosis, of diabetes and late
complications of diabetes, proliferative disorders etc.
[0123] The compounds of the formula I are moreover suitable for
preventive therapy to prevent the development and for the treatment
of high blood pressure, for example of essential hypertension,
because they reduce or completely inhibit the reabsorption of NaCl
in the tubular system of the kidneys. Accordingly, they are also
outstandingly suitable as combination and formulation partners for
drugs used for treating high blood pressure. Examples of possible
combinations are diuretics having a thiazide-like action, loop
diuretics, aldosterone and pseudoaldosterone antagonists, such as
hydrochlorothiazide, indapamide, polythiazide, furosemide,
piretanide, torasemide, bumetanide, amiloride, triamterene. The NHE
inhibitors of the present invention can further be used in
combination with ACE inhibitors such as, for example, ramipril,
enalapril or captopril. Further beneficial combination partners are
also p-blockers.
[0124] The described NHE inhibitors can likewise be used in the
prevention and for the treatment of thrombotic disorders because,
as NHE inhibitors, they are able to inhibit both platelet
aggregation itself and, in addition, able to inhibit or prevent the
excessive release of coagulation mediators, in particular of von
Willebrand factor. The NHE inhibitors of the present invention can
therefore be combined with further anticoagulant active ingredients
such as, for example, acetylsalicylic acid, thrombin antagonists,
factor Xa antagonists, drugs with fibrinolytic activity, factor
Vila antagonists etc. Combined use of the present NHE inhibitors
with NCBE inhibitors is particularly beneficial.
[0125] It has additionally been found that NHE inhibitors show a
beneficial effect on serum lipoproteins. It is generally
acknowledged that blood lipid levels which are too high, so-called
hyperlipoproteinemias, represent a considerable risk factor for the
development of arteriosclerotic vascular lesions, especially
coronary heart disease. The reduction of elevated serum
lipoproteins therefore has exceptional importance for the
prophylaxis and regression of atherosclerotic lesions. The
compounds used according to the invention can therefore be used for
the prophylaxis and regression of atherosclerotic lesions by
eliminating a causal risk factor. The NHE inhibitors of the
invention can also be combined in a beneficial manner with other
antiarterioscierotic active ingredients such as a substance from
the class of fibrates, an upregulator of LD2 receptor activity such
as MD-700 and LY295427 or a cholesterol or bile acid absorption
inhibitor or an antihypercholesterolemic agent from the class of
statins, such as, for example, pravastatin, lovastatin,
simvastatin.
[0126] With this protection of the vessels against the syndrome of
endothelial dysfunction, compounds of the formula I are valuable
drugs for the prevention and treatment of coronary vasospasms,
peripheral vascular diseases such as intermittent claudication, of
atherogenesis and of atherosclerosis, of left-ventricular
hypertrophy and of dilated cardiomyopathy, and thrombotic
disorders.
[0127] Said compounds can likewise be used for the treatment of
diseases caused by protozoa and are particularly suitable as
antimalarials.
[0128] The compounds are additionally suitable for controlling
sucking parasites such as mosquitoes, ticks, fleas and plant
pests.
[0129] In accordance with their protective effects, the compounds
are also suitable as drugs for maintaining health and prolonging
life.
[0130] The NHE inhibitors described herein can generally be
combined in a beneficial manner with other compounds regulating the
intracellular pH, suitable combination partners being inhibitors of
the carbonic anhydratase enzyme group, inhibitors of the
bicarbonate ion-transporting systems such as the sodium-bicarbonate
cotransporter or the sodium-dependent chloride-bicarbonate
exchanger, and other NHE inhibitors, for example having an
inhibitory effect on other NHE subtypes, because the
pharmacologically relevant pH-regulating effects of the NHE
inhibitors described herein can be enhanced thereby.
[0131] Said compounds are therefore advantageously used for
producing a medicament for the prevention and treatment of sleep
apneas and muscle-related respiratory disorders; for producing a
medicament for the prevention and treatment of snoring; for
producing a medicament for lowering blood pressure; for producing a
medicament with a laxative effect for the prevention and treatment
of intestinal blockages; for producing a medicament for the
prevention and treatment of disorders induced by ischemia and
reperfusion of central and peripheral organs, such as acute renal
failure, stroke, endogenous states of shock, intestinal disorders
etc.; for producing a medicament for the treatment of late damage
from diabetes and chronic renal disorders, in particular of all
inflammations of the kidneys (nephritides) which are associated
with increased protein/albumin excretion; for producing a
medicament for the treatment of hypercholesterolemia; for producing
a medicament for the prevention of atherogenesis and of
atherosclerosis; for producing a medicament for the prevention and
treatment of diseases induced by elevated cholesterol levels; for
producing a medicament for the prevention and treatment of diseases
induced by endothelial dysfunction; for producing a medicament for
the treatment of infestation by ectoparasites; for producing a
medicament for the treatment of said disorders in combinations with
hypotensive substances, preferably with angiotensin converting
enzyme (ACE) inhibitors, with diuretics, aldosterone antagonists
and angiotensin receptor antagonists. A combination of an NHE
inhibitor of the formula I with an active ingredient lowering the
blood lipid level, preferably with an HMG-CoA reductase inhibitor
(e.g. lovastatin or pravastatin), the latter bringing about a
hypolipidemic effect and thus increasing the hypolipidemic
properties of the NHE inhibitor of the formula I, proves to be a
beneficial combination with enhanced effect and reduced use of
active ingredient.
[0132] The administration of sodium-proton exchange inhibitors of
the formula I as novel drugs for lowering elevated blood lipid
levels, and the combination of sodium-proton exchange inhibitors
with hypotensive drugs and/or drugs with hypolipidemic activity is
claimed.
[0133] The invention also relates to a curative composition for
human, veterinary or phytoprotective use comprising an effective
amount of a compound of the formula I and/or of a pharmaceutically
acceptable salt thereof, as well as curative compositions for
human, veterinary or phytoprotective use comprising an effective
amount of a compound of the formula I and/or of a pharmaceutically
acceptable salt thereof alone or in combination with one or more
other pharmacological active ingredients or drugs.
[0134] Drugs which comprise a compound of the formula I can in this
connection be administered orally, parenterally, intravenously,
rectally, transdermally or by inhalation, the preferred
administration being dependent on the particular characteristics of
the disorder. The compounds of the formula I may moreover be used
alone or together with pharmaceutical excipients, both in
veterinary medicine and in human medicine, and in crop
protection.
[0135] The excipients suitable for the desired pharmaceutical
formulation are familiar to the skilled worker on the basis of his
expert knowledge. Besides solvents, gel formers, suppository bases,
tablet excipients, and other active ingredient carriers, it is
possible to use, for example, antioxidants, dispersants,
emulsifiers, antifoams, flavorings, preservatives, solubilizers or
colors.
[0136] For a form for oral administration, the active compounds are
mixed with additives suitable for this purpose, such as carriers,
stabilizers or inert diluents, and converted by conventional
methods into suitable dosage forms such as tablets, coated tablets,
hard gelatin capsules, aqueous, alcoholic or oily solutions.
Examples of inert carriers which can be used are gum arabic,
magnesia, magnesium carbonate, potassium phosphate, lactose,
glucose or starch, especially corn starch. It is moreover possible
for the preparation to take place both as dry granules and as wet
granules. Examples of suitable oily carriers or solvents are
vegetable or animal oils such as sunflower oil or fish liver
oil.
[0137] For subcutaneous or intravenous administration, the active
compounds used are converted, if desired with the substances
customary for this purpose, such as solubilizers, emulsifiers or
other excipients, into a solution, suspension or emulsion. Examples
of suitable solvents are: water, physiological saline or alcohols,
e.g. ethanol, propanol, glycerol, as well as sugar solutions such
as glucose or mannitol solutions, or else a mixture of the various
solvents mentioned.
[0138] Suitable as pharmaceutical formulation for administration in
the form of aerosols or sprays are, for example, solutions,
suspensions or emulsions of the active ingredient of the formula I
in a pharmaceutically acceptable solvent such as, in particular,
ethanol or water, or a mixture of such solvents. The formulation
may, if required, also contain other pharmaceutical excipients such
as surfactants, emulsifiers and stabilizers, and a propellant gas.
Such a preparation normally contains the active ingredient in a
concentration of about 0.1 to 10, in particular of about 0.3 to 3,
% by weight.
[0139] The dosage of the active ingredient of the formula I to be
administered, and the frequency of administration, depend on the
potency and duration of action of the compounds used; additionally
also on the nature and severity of the disorder to be treated and
on the sex, age, weight and individual responsiveness of the mammal
to be treated.
[0140] On average, the daily dose of a compound of the formula I
for a patient weighing about 75 kg is at least 0.001 mg/kg,
preferably 0.1 mg/kg, to a maximum of 50 mg/kg, preferably 1 mg/kg,
of body weight. For acute episodes of the disorder, for example
immediately after suffering a myocardial infarction, higher and, in
particular, more frequent dosages may also be necessary, e.g. up to
4 single doses a day. Up to 200 mg/kg a day may be necessary, in
particular on i.v. administration, for example for a patient with
infarction in the intensive care unit.
[0141] Pharmaceutically acceptable salts are prepared for example
via the following acids: from inorganic acids such as hydrochloric
acid, sulfuric acid or phosphoric acid or from organic acids such
as acetic acid, citric acid, tartaric acid, lactic acid, malonic
acid, methanesulfonic acid, fumaric acid. Suitable acid addition
salts in this connection are salts of all pharmacologically
acceptable acids, for example halides, especially hydrochlorides,
lactates, sulfates, citrates, tartrates, acetates, phosphates,
methylsulfonates, p-toluenesulfonates, adipates, fumarates,
gluconates, glutamates, glycerolphosphates, maleates and pamoates
(this group also corresponds to the physiologically acceptable
anions); but also trifluoroacetates.
DESCRIPTIONS OF EXPERIMENTS AND EXAMPLES
[0142] List of abbreviations used:
R.sub.t retention time TFA trifluoroacetic acid LCMS liquid
chromatography mass spectroscopy MS mass spectroscopy CI chemical
ionization ES electrospray
General:
[0143] Retention times (R.sub.t) stated below refer to LCMS
measurements with the following parameters:
TABLE-US-00001 Method A: stationary Merck Purospher, 3.mu., 2
.times. 55 mm phase: mobile phase: 95% H.sub.2O (0.05% TFA)
.fwdarw. 95% acetonitrile, 4 min; 95% acetonitrile, 1.5 min;
.fwdarw. 5% acetonitrile, 1 min; 0.5 ml/min. Method B: stationary
YMC J'sphere ODS H80, 2 .times. 33 mm phase: Mobile phase: 95%
H.sub.2O (0.05% TFA) .fwdarw. 95% acetonitrile, 2.3 min; 95%
acetonitrile, 1 min; .fwdarw. 5% acetonitrile, 0.1 min; 1 ml/min.
Method C: stationary YMC J'sphere ODS H80, 2 .times. 33 mm phase:
Mobile phase: 90% H.sub.2O (0.05% TFA) .fwdarw. 95% acetonitrile,
2.5 min; 95% acetonitrile, 0.8 min; .fwdarw. 10% acetonitrile, 0.05
min; 1 ml/min. Method D: stationary Merck Purospher, 3.mu., 2
.times. 55 mm phase: mobile phase: 95% H.sub.2O (0.1% HCOOH)
.fwdarw. 95% acetonitrile (0.1% HCOOH), 5 min; .fwdarw. 95%
acetonitrile (0.1% HCOOH), 2 min; .fwdarw. 95% H.sub.2O (0.1%
HCOOH), 1 min; 0.45 ml/min. Method E: stationary YMC J`sphere ODS
H80, 2 .times. 33 mm phase: mobile phase: 98% H.sub.2O (0.05% TFA)
+ 2% acetonitrile, 0.3 min; 98% H.sub.2O (0.05% TFA) .fwdarw. 95%
acetonitrile, 2 min; 95% acetonitrile, 0.4 min; 1 ml/min. The
preparative HPLC was carried out under the following conditions:
stationary Merck Purospher RP18 (10 .mu.M) 250 .times. 25 mm phase:
mobile phase: 90% H.sub.2O (0.05% TFA) .fwdarw. 90% acetonitrile,
40 min; 25 ml/min.
Example 1
(2,6-Dichlorophenyl)(1H-imidazol-2-yl)amine hydrochloride
##STR00013##
[0145] (2,6-Dichlorophenyl)(1H-imidazol-2-yl)amine hydrochloride
was prepared by a method disclosed in the literature (J. Med.
Chem., 1975, 18, 90-99; GB 1131191).
[0146] MS-CI+: 228.1; LCMS-R.sub.t (A)=2.92 min
Example 2
(2,6-Dichlorophenyl)(4-methyl-1H-imidazol-2-yl)amine
hydrochloride
##STR00014##
[0147] a) 2-(2-Oxopropyl)isoindole-1,3-dione
##STR00015##
[0149] Phthalimide (3 g) was dissolved in dry tetrahydrofuran (70
ml) and added dropwise at room temperature to a suspension of
sodium hydride (539 mg) in tetrahydrofuran (15 ml). This was
followed by heating at 40.degree. C. for one hour, and then a
solution of chloroacetone (1.99 g) dissolved in tetrahydrofuran (15
ml) was added dropwise. The mixture was then kept at the reflux
temperature for 15 hours. After cooling, it was added to an
ice/water mixture and extracted three times with ethyl acetate. The
combined organic phases were washed once with saturated sodium
chloride solution and then dried over magnesium sulfate. The
solvent was removed in vacuo and the residue was chromatographed on
silica gel (n-heptane/ethyl acetate 2:1). 2.9 g of the title
compound were isolated.
[0150] MS-CI+: 204.2; LCMS-R.sub.t (C)=1.60 min
b) C-(2-Methyl-[1,3]dioxolan-2-yl)methylamine
##STR00016##
[0152] 2-(2-Oxopropyl)isoindole-1,3-dione (2.9 g) was mixed in
toluene (60 ml) with ethylene glycol (1.71 ml) and
para-toluenesulfonic acid (271 mg) and heated with a water trap for
15 hours. The mixture was subsequently dried in vacuo and the
residue was dissolved in ethanol (120 ml). Addition of hydrazine (1
g) was followed by heating at 65.degree. C. for one hour and then
addition of a further gram of hydrazine. The heating was stopped
after a further 1.5 hours at 65.degree. C. After standing
overnight, the precipitate which had formed was filtered off with
suction and the filtrate was concentrated in vacuo. The residue was
suspended in ethanol and again filtered. Concentration of the
filtrate resulted in 1.9 g of the amine which could be employed
directly in the next stage.
[0153] MS-CI+: 118.2; LCMS-R.sub.t (B)=0.16 min
c)
N-(2,6-Dichlorophenyl)-N'-(2-methyl-[1,3]dioxolan-2-ylmethyl)guanidine
trifluoroacetic acid salt
##STR00017##
[0155] 2,6-Dichlorophenylcyanamide (100 mg, prepared as described
in J. Med. Chem., 1975, 18, 90-99) and
C-(2-methyl-[1,3]dioxolan-2-yl)methylamine (69 mg) were mixed in a
flask and heated at 150.degree. C. for 0.5 hours. Water and
dichloromethane were added to the cooled reaction mixture.
Separation of the phases was followed by extraction twice with
dichloromethane. The combined organic phases were dried over
magnesium sulfate, filtered and concentrated. The residue was
purified by preparative HPLC. The product-containing fractions were
combined, the acetonitrile was stripped off in a rotary evaporator
and freeze dried. 29 mg of the desired guanidine were obtained.
[0156] MS-CI+: 304.2; LCMS-R.sub.t (B)=1.51 min
d) (2,6-Dichlorophenyl)(4-methyl-1H-imidazol-2-yl)amine
hydrochloride
[0157]
N-(2,6-Dichlorophenyl)-N'-(2-methyl-[1,3]dioxolan-2-ylmethyl)guanid-
ine trifluoroacetic acid salt (29 mg) was mixed with 1 ml of
concentrated hydrochloric acid and heated at 90.degree. C. for 30
min. Cooling was followed by dilution with water and addition of
dichloromethane. The mixture was then made alkaline with saturated
sodium bicarbonate solution and extracted twice with
dichloromethane. The combined organic phases were dried over
magnesium sulfate, filtered and concentrated. The residue was mixed
with hydrochloric acid and freeze dried. 14 mg of the title
compound were obtained.
[0158] MS-CI+: 242.2; LCMS-R.sub.t (B)=1.42 min
Example 3
(2,6-Dichlorophenyl)(4,5-dimethyl-1H-imidazol-2-yl)amine
hydrochloride
##STR00018##
[0160] The title compound was prepared in analogy to Example 2
starting from 3-bromo-2-butanone.
[0161] MS-CI+: 256.2; LCMS-R.sub.t (C)=1.43 min
Example 4
(2,6-Dichlorophenyl)(4-methyl-5-phenyl-1H-imidazol-2-yl)amine
hydrochloride
##STR00019##
[0163] 1-Amino-1-phenylacetone hydrochloride (189 mg),
2,6-dichlorophenylcyanamide (187 mg, prepared as described in J.
Med. Chem., 1975, 18, 90-99) and triethylamine (101 mg) were kept
at the reflux temperature in ethanol (10 ml) for 3 hours. Cooling
was followed by drying in vacuo and purification by preparative
HPLC. The product-containing fractions were combined, the
acetonitrile was stripped in a rotary evaporator, and the aqueous
residue was neutralized with potassium carbonate and extracted
three times with ethyl acetate. Drying over magnesium sulfate was
followed by evaporation to dryness and, after addition of
hydrochloric acid, freeze drying. 26 mg of the title compound were
obtained.
[0164] MS-CI+: 318.2; LCMS-R.sub.t (A)=4.14 min
Example 5
(2,6-Dichlorophenyl)(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)amine
hydrochloride
##STR00020##
[0165] a) 1,4-Dioxaspiro[4.5]dec-6-ylamine
##STR00021##
[0167] 2-Chlorocyclohexanone (5 g) was dissolved in DMSO (10 ml),
and sodium azide (7.06 g) dissolved in DMSO (150 ml) was slowly
added dropwise at room temperature. The mixture was then stirred at
room temperature for 60 minutes. Ice-water was added to the
reaction mixture, which was then extracted three times with
n-pentane (100 ml). The combined organic phases were washed once
with water and dried over magnesium sulfate, and the solvent was
concentrated not quite to dryness. This was followed by
coevaporation with toluene to remove remaining pentane. The residue
was diluted with abs. toluene (120 ml), mixed with ethylene glycol
(4.8 g) and a catalytic amount of p-toluenesulfonic acid and heated
with a water trap for 5 hours. Standing overnight was followed by
heating with a water trap for a further 6 hours. In addition, a
further spatula tip of p-toluenesulfonic acid and ethylene glycol
(6 ml) were added. The reaction mixture was then washed with water,
and the organic phase was extracted once more with toluene. The
combined organic phases were dried over magnesium sulfate, and
solvent was very substantially removed. The residue was taken up in
methanol (40 ml), transferred into a shaking apparatus and, after
addition of platinum dioxide (15 mg) and introduction of hydrogen,
hydrogenated for 2 hours. The platinum dioxide was filtered off and
the solvent was concentrated. The crude product was chromatographed
on a silica gel column (mobile phase dichloromethane/methanol/conc.
ammonia: 10:0.5:0.1). 1.105 g of an oily product were obtained.
[0168] MS-ES+: 158.2; LCMS-R.sub.t (E)=0.38 min
b)
N-(2,6-Dichlorophenyl)-N'-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine
##STR00022##
[0170] 1,4-Dioxaspiro[4.5]dec-6-ylamine (500 mg) was reacted with
2,6-dichloro-phenylcyanamide (595 mg, prepared as described in J.
Med. Chem., 1975, 18, 90-99) at 130.degree. C. After 45 minutes,
the reaction was stopped and the reaction product was purified by
preparative HPLC. The product-containing fractions were combined,
the acetonitrile was stripped off in a rotary evaporator, and the
aqueous residue was neutralized with potassium carbonate and
extracted three times with dichloromethane. Drying over magnesium
sulfate was followed by evaporation to dryness. 476 mg of the
desired guanidine were obtained.
[0171] MS-ES+: 344.2; LCMS-R.sub.t (D)=2.10 min
c)
(2,6-Dichlorophenyl)(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)amine
hydrochloride
[0172]
N-(2,6-Dichlorophenyl)-N'-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine
(426 mg) was mixed with concentrated HCl (5 ml) and stirred at room
temperature for 5 minutes. The resulting precipitate was filtered
off and washed with concentrated hydrochloric acid.
[0173] On dilution of the filtrate with water, a further
precipitate separated out and was likewise filtered off. The
combined precipitates afforded 311 mg of the desired compound.
[0174] MS-ES+: 282.19; LCMS-R.sub.t (D)=2.01 min
Example 6
2-(2,6-Dichlorophenylamino)-1H-imidazole-4,5-dicarbonitrile
##STR00023##
[0176] Diaminomaleonitrile (500 mg) was dissolved in absolute
tetrahydrofuran (7.5 ml), and 2,6-dichlorophenyl isothiocyanate was
added. After stirring at room temperature for 3 hours and leaving
to stand overnight, the solvent was stripped off and the residue
was purified. The product-containing fractions were combined,
acetonitrile was stripped off in a rotary evaporator, and the
aqueous residue was neutralized with potassium carbonate and
extracted three times with ethyl acetate. Drying over magnesium
sulfate was followed by evaporation to dryness. 73 mg of the
desired thiourea intermediate were obtained. This product was
stirred with N,N'-dicyclohexylcarbodiimide (48 mg) in absolute
tetrahydrofuran at room temperature for 5 days. The solvent was
stripped off and the residue was purified by preparative HPLC. The
product-containing fractions were combined, the acetonitrile was
stripped off in a rotary evaporator, and the aqueous residue was
neutralized with potassium carbonate and extracted three times with
ethyl acetate. Drying over magnesium sulfate was followed by
evaporation to dryness, and the residue was freeze dried. 16 mg of
the desired imidazole were obtained.
[0177] MS-CI+: 278.2; LCMS-R.sub.t (B)=2.14 min
Example 7
(2,6-Dichlorophenyl)methyl
(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)amine hydrochloride
##STR00024##
[0178] a) (2,6-Dichlorophenyl)methylcyanamide
##STR00025##
[0180] 2,6-Dichlorophenylcyanamide (1 g, prepared as described in
J. Med. Chem., 1975, 18, 90-99) was dissolved in dry
dimethylformamide (25 ml), and powdered potassium carbonate (739
mg) was added. After stirring at room temperature for five minutes,
methyl iodide (1.52 g) was added dropwise, and the mixture was
stirred at room temperature for two hours. The residue after
stripping off the solvent was taken up with water and extracted
three times with ether. The combined organic phases were dried over
magnesium sulfate and filtered. The residue after stripping of the
solvent was purified by preparative HPLC. The product-containing
fractions were combined, the acetonitrile was stripped off in a
rotary evaporator, and the aqueous residue was neutralized with
potassium carbonate and extracted three times with ethyl acetate.
Drying over magnesium sulfate was followed by evaporation to
dryness. 600 mg of the desired product were obtained.
[0181] MS-ES+: 201.1; LCMS-R.sub.t (B)=2.23 min
b)
N-(2,6-Dichlorophenyl)-N'-(1,4-dioxaspiro[4.5]dec-6-yl)-N-methylguanidi-
ne
##STR00026##
[0183] A solution of (2,6-dichlorophenyl)methylcyanamide (25 mg)
dissolved in dry tetrahydrofuran (5 ml) was added dropwise to a
boiling solution of 1,4-dioxaspiro[4.5]dec-6-ylamine (195 mg,
Example 5) in dry THF (5 ml), and the tetrahydrofuran was removed
in vacuo. The residue was then heated in an oil bath at 130.degree.
C. for 15 minutes and subsequently purified by preparative HPLC.
The product-containing fractions were combined, acetonitrile was
stripped off in a rotary evaporator, and the aqueous residue was
neutralized with potassium carbonate and extracted three times with
ethyl acetate. Drying over magnesium sulfate was followed by
evaporation to dryness, and the residue was freeze dried. 18 mg of
the desired product were obtained.
[0184] MS-ES+: 358.4; LCMS-R.sub.t (E)=1.48 min
c)
(2,6-Dichlorophenyl)methyl(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)ami-
ne hydrochloride
[0185] Concentrated HCl (1 ml) was added to
N-(2,6-dichlorophenyl)-N'-(1,4-dioxaspiro[4.5]dec-6-yl)-N-methylguanidine
(18 mg). After 10 minutes, the mixture was diluted with water and
freeze dried. The resulting product was coevaporated with toluene
three times.
[0186] 16 mg of the title compound were obtained.
[0187] MS-ES+: 296.17; LCMS-R.sub.t (D)=2.12 min
Pharmacological Data:
Description of Test:
[0188] In this test, the recovery in the intracellular pH
(pH.sub.i) after an acidification was ascertained, which is
initiated if the NHE3 is capable of functioning, even under
bicarbonate-free conditions. For this purpose, the pH.sub.i was
determined using the pH-sensitive fluorescent dye BCECF
(Calbiochem, the precursor BCECF-AM is employed). The cells
(fibroblasts, LAP 1 cells) were initially loaded with BCECF. The
BCECF fluorescence was determined in a "Ratio Fluorescence
Spectrometer" (Photon Technology International, South Brunswick,
N.J., USA) at excitation wavelengths of 505 and 440 nm and an
emission wavelength of 535 nm and converted into the pH.sub.i using
calibration curves. The cells were incubated in NH.sub.4Cl buffer
(pH 7.4) (NH.sub.4Cl buffer: 115 mM NaCl, 20 mM NH.sub.4Cl, 5 mM
KCl, 1 mM CaCl.sub.2, 1 mM MgSO.sub.4, 20 mM Hepes, 5 mM glucose, 1
mg/ml BSA; a pH of 7.4 is adjusted with 1 M NaOH) even during the
BCECF loading. The intracellular acidification was induced by
adding 975 .mu.l of an NH.sub.4Cl-free buffer (see below) to 25
.mu.l aliquots of the cells incubated in NH.sub.4Cl buffer. The
subsequent rate of pH recovery was recorded for three minutes. To
calculate the inhibitory potency of the tested substances, the
cells were initially investigated in buffers with which a complete
or absolutely no pH recovery took place. For complete pH recovery
(100%), the cells were incubated in Na.sup.+-containing buffer
(133.8 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl.sub.2, 1.25 mM MgCl.sub.2,
0.97 mM Na.sub.2HPO.sub.4, 0.23 mM NaH.sub.2PO.sub.4, 5 mM Hepes, 5
mM glucose, a pH of 7.0 is adjusted with 1 M NaOH). To determine
the 0% value, the cells were incubated in an Na.sup.+-free buffer
(133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl.sub.2, 1.25 mM
MgCl.sub.2, 0.97 mM K.sub.2HPO.sub.4, 0.23 mM KH.sub.2PO.sub.4, 5
mM Hepes, 5 mM glucose, a pH of 7.0 is adjusted with 1 M KOH). The
substances to be tested were made up in the Na.sup.+-containing
buffer. The recovery of the intracellular pH at each test
concentration of a substance was expressed as a percentage of the
maximum recovery. The IC.sub.50 value for the particular substance
for the individual NHE subtypes was calculated from the pH recovery
percentages using the Sigma-Plot program.
Results:
TABLE-US-00002 [0189] IC.sub.50 [.mu.M], Example (rNHE3) Clonidine
620*) 1 7.7 2 1.7 3 0.84 5 0.24 6 98 7 0.28 *)Ref.: J. Orlowski et
al J. Biol. Chem. 268, 25536
* * * * *