Indian Patents
Title of Invention

NITROSATED IMIDAZOPYRIDINES
Abstract Compounds of the formula 1 K3a pi (1*) Arom in which Rl is methyl R2 is hydrogen, methyl, or chloro, R3a is hydrogen, R3b is hydrogen, one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, methoxy, ethoxy, hydroxyethoxy, methoxyethoxy or methoxyethoxyethoxy, R5a is the radical R53, where R53 is -0-C(0)-CH2-(CH2)x-0-N02, -0-C(0)-0-(CH2)x-0-N02, -0-C(0)-C6H4-CH2-0- N02 or -0-C2H4-(CH2)x-0-N02, in which x is an integer from 2 to 4, R5b is hydrogen, Arom is a phenyl radical and X is O (oxygen) or NH, and their salts.
Full Text FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (See Section 10, rule 13)
NITROSATED IMIDAZOPYRIDINES
ALTANA PHARMA AG of BYK-GULDEN-STRASSE 2, D-78467 KONSTANZ, DEUTSCHLAND, GERMANY, GERMAN Company
The following specification particularly describes the nature of the invention and the manner in which it is to be performed : -





WO 03/091253 PCT/EP03/04134
!!
Nitrosated imidazopyrldines
Technical field
The invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments.
Prior art
In International patent applications WO98/42707 (= US Patent 6,197,783), W098/54188, WO00/17200,

WO00/26217, WO00/63211, WO01/72756, WO01/72754, WO01/72755 and WO01/72757,

tricyclic

imidazopyridine derivatives having a very specific substitution pattern are disclosed, which should be suitable for the treatment of gastric and intestinal diseases. In international patent applications WO94/04484, W094/12463, WO00/72838 and WO01/66088 various rfo-releasing nitric esters and their use for the manufacture of medicaments and for the treatment of diseases, e. g. bacterial infec¬tions, are disclosed. In international patent applications WOOO/50037 and WO02/00166 various ni¬trosated and nitrosyiated proton pump inhibitors are disclosed. In J. Med. Chem. 2001,44, 3463-3468.
I Marco L. Loili et al. describe NO-reieasing Ibuprofen derivatives with antiinflammatory properties.
i;
Summary of the invention

The invention relates to compounds of the formula 1

R33 po

in which .,
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1J4C-alkoxy-
1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl orhydroxy-1-4C-
alkyl, j
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alko'xycarbonyl,
hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, cyanomethyl or R21,
where
2.

Nitrosated imidazopyridines

Technical field
The invention relates to novel compounds, which are used in the pharmaceutical industry as active
compounds for the production of medicaments. j,
Prior art
In international patent applications WO98/42707 (= US Patent 6,197,783), W098/54188, WOOO/17200, WO00/26217, WO00/63211, WO01/72756, WO01/72754, WO01/72755 and WO01/72757, tricyclic
I!
imidazopyridine derivatives having a very specific substitution pattern are disclosed, which should be
I! suitable for the treatment of gastric and intestinal diseases. In international patent applications
WO94/04484, W094/12463, WO00/72838 and WO01/66088 various NO-releasing niUjic esters and
li
their use for the manufacture of medicaments and for the treatment of diseases, e. g. bacterial
II
infections, are disclosed. In international patent applications WO00/50037 and WO02/00166 various
v
nitrosated and nitrosylated proton pump inhibitors are disclosed. In J. Med. Chem. 200j1, 44, 3463-3468. Marco L Lolli et al. describe NO-releasing Ibuprofen derivatives with antiinflammatory properties.

Summary of the invention
The invention relates to compounds of the formula 1
R3a

R2

(D

in which
I' R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cy 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C-

l,
alkyl,
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, cyanpmethyl or R21, where


Nitrosated imidazopyridines
Technical field
The invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments.
Prior art
In international patent applications WO98/42707 (= US Patent 6,197,783), W098/54188! WOOO/17200,
WO00/26217, WO00/63211, WO01/72756, WO01/72754, WO01/72755 and WO01/72757, tricyclic
II imidazopyridine derivatives having a very specific substitution pattern are disclosed, which should be
suitable for the treatment of gastric and intestinal diseases. In international patent applications WO94/04484, W094/12463, WO00/72838 and WO01/66088 various NO-releasing nitric' esters and their use for the manufacture of medicaments and for trje treatment of diseases, e. g. bacterial infec¬tions, are disclosed. In international patent applications WO00/50037 and WO02/00166 various ni-trosated and nitrosylated proton pump inhibitors are disclosed. In J. Med. Chem. 2001, 44, 3463-3468. Marco L. Lolli et al. describe NO-releasing Ibuprofen derivatives with antiinflammatory properties.
Summary of the invention
The invention relates to compounds of the formula 1

in which :; |
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy| 1-4C-alkoxy-
1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C-
alkyl, ,•' v
it f ■
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7^C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl; *•* hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, cyanomethyl or R21,:» where
3

R21 is -CH2-0-C(0)-CH2-(CH2)x-NOy or -CH2-0-C2H4-(CH2)x-NOy, [;
in which ^
x is an integer from 2 to 6 and
y is an integer from 1 to 3, R3a is hydrogen, halogen, fluoro-1-4C-alkyl, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, -CO-
1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,
fluoro-1-4C-alkoxy-1-4C-alkyl or the radical -CO-NR31R32, I
R3b is hydrogen, halogen, fluoro-1-4C-alkyl, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, -CO- '
1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl,
fluoro-1-4C-alkoxy-1-4C-alkyl or the radical -CO-NR31R32, f
where
ii R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and j'
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, ||
|j or where
V R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino,
i' piperidino or morpholino radical,
. one of the substituents R4a and R4b is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alkyl
and the other is hydroxyl, 1-4C-alkoxy, oxo-subs'tituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-
cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-
alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy,|l-4C-alkoxy, 1-
4C-alkylcarbonyloxy, wholly or mainly halogen-substituted 1-4C-alkoxy, the radical R41 or the
radical R42, or in which R4a and R4b together afe O (oxygen) or are 1-7C-alkylidene,
where
R41 is a radical from which a hydroxy group is formed under physiological conditions,
and where
R42 is-0-(CH2)m-S(0)n-R6, -S(0)n-(CH2)m-OH;-S(0)n-(CH2)m-0-R6,
-S(0)n-(CH2)m-S(0)p-R6, -0-Alk1-S(0)n-R6, -S(0)„-R6, -S(0)„- Alk1-OH, h
-S(0)n- Alk1-0-R6 or -S(0)„- Alk1-S(0)p-R6 ,
in which '
R6 is 1-7C-alkyl, halo-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4G-alkyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl or di-1-4C-alkylamino-1ir4C-alkyl, Ar or

Ar-1-4C-alkyl, where Ar is phenyl or substituted phenyl having one)

two or three

identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino and nitro , Alk1 is substituted 2-7C-alkylene or 3-4C-alkenylene by 1-4C-alkyl, hydrpxyl, oxo, carboxyl, halogen, amino, 1-4C-alk

m is an integer from 2 to 7,
n is the number 0, 1 or 2 and
p is the number 0, 1 or 2, one of the substituents R5a and R5b is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alkyl
[j
and the other is hydrogen, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-
i cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-
alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C-alkoxy, 3-7C-cycloalkyl|1 -4C-alkoxy-1 -
4C-alkoxy, 1-4C-alkylcarbonyloxy, wholly or mainly halogen-substituted 1-4C-alkoxy, the radical
R51, the radical R52 or the radical R53, or in which R5a and R5b together are O (oxygen) or are
1-7C-alkylidene,
where i
R51 is a radical from which a hydroxy group is formed under physiological conditions,
R52 is-0-(CH2)q-S(0)rR7, -S(0)r(CH2)q-OH,-S(0)r(CH2)q-0-R7, !
-S(0)r(CH2)q-S(0),-R7, -0-Alk2-S(0)rR7,!"-S(0)rR7, -S(0)rAlk2-OH, j;
-S(0)rAlk2-0-R7 or -S(0)rAlk2-S(0),-R7 , ;
in which
\l R7 is 1-7C-alkyl, halo-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4G-alkyl, carboxy-
1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4£-alkyl or di-1-4C-alkylamino-1-4C-alkyl, Ar or
Ar-1-4C-alkyl, where Ar is phenyl or substituted phenyl having one, two or three
identical or different substituents selected from the group consisting of 1-4C-alkyl,
II 1-4C-alkoxy, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl,
difluoromethoxy, trifluoromethoxy, amino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-
1-4C-alkoxycarbonylamino and nitro, |
Alk2 is 2-7C-alkylene or 3-4C-alkenylene substituted by 1-4C-alkyl, hydroxyl, oxo,

one of the substituents R4a and R4b on the one hand and one of the substituents R5a and R5b on the
other hand is in each case hydrogen, 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-^C-alkyl, and the
i1


other substituents in each case together form a 1-4C-alkylenedioxy radical, which if desired, is wholly or partially halogen-substituted, Arom is a mono- or bicyclic aromatic radical substituted by R8, R9, R10 and R11, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyl (benzothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinolinyl and isoquinolinyl, where
R8 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-40-alkyl, halogen,
amino, mono- .
I
il-4C-alkoxy-1-
hydroxyl, aryl, aryl-1-4C-alkyl, aryloxy, aryl-1-HC-alkoxy, trifluoromethyl, nitro, or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 4C-alkoxycarbonylamino or sulfonyl,
R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or
hydroxyl, iS
R10 is hydrogen, 1-4C-alkyl or halogen and R11 is hydrogen, 1-4C-alkyl or halogen, where aryl is phenyl or substituted phenyl having one, two or three identical or different substituents from
the group consisting of 1-4C-alkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, halogen,
'I
trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano,
X is O (oxygen) or NH,
and their salts,
with the proviso that either
R2 has the meaning R21 or one of R5a and R5b have the meaning R53 or R2 has the meaning R21 and one of R5a and R5b have the meaning R53.
1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
r
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which
ll ■:
cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which L
substituted by one of the aforementioned 3-7C-cycloalkyl radicals. Examples which may be
l| mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl radical.


1-4C-Alkoxy represents radicals, which in addition to the oxygen atom contain a straight-chain or
branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy,
isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radical.
1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is substituted]
by one of the aforementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the
methoxymethyl, the methoxyethyl radical and the butoxyethyl radical.
1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the
,■01
methoxycarbonyl (CH30-C(0)-) and the ethoxycarbonyi radical (CH3CH20-C(0)-) .
2-4C-Alkenyl represents straight-chain or branched alkenyl radicals having 2 to 4 carbon atoms.
Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl radical
(allyl radical).
2-4C-Alkynyl represents straight-chain or branched alkynyl radicals having 2 to 4 carbon atoms.
Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, radical
(propargyl radical).
Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is substituted by one or more fluorine atoms. An example which may be mentioned is the trifluoromethyl radical.
Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl radicals, which are substituted by a hydroxy' group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radical.
Halogen within the meaning of the invention is bromo, chloro and fluoro.
The group -NOy with y being the number 1, 2 or 3 represents a group which is able to release nitrogen monoxide. The preferred group in this connection is the -N03 (-0-N02 = nitrate) group
1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy radicals, .which is substituted by a further 1-4C-alkoxy radical. Examples which may be mentioned are the radicals 2-(methoxy)ethoxy (CH3-0-CH2-CH2-0-) and 2-(ethoxy)ethoxy (CH3-CH2-0-CH2-CH2-Q-).
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkoxy-1-4C-alkyl radicals, which is substituted by one of the aforementioned 1-4C-alkoxy radicals. An example which may be mentioned is the radical 2-(methoxy)ethoxymethyl (CH3-0-CH2-CH2-0-CH2-).


Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is substituted by a fluoro-1-4C-alkoxy radical. Fluoro-1-4-alkoxy in this case represents one of the ; aforementioned 1-4C-alkoxy radicals, which is wholly or mainly substituted by fluorine. Examples of wholly or mainly fluoro-substituted 1-4C-alkoxy which may be mentioned are the 1,1,1,3,3,3-

hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the

perfluoro-tert-

butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-penta-
fluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy,'
the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radical.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples; which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl(2,2-dimethylpropyl), butyl,
isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.

2-7C-Alkenyl represents straight-chain or branched alkenyl radicals having 2 to 7 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-pro^enyl (allyl) and the vinyl radical. The aforementioned 2-4C-alkenyl radicals are preferred.
Phen-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is substituted by a phenyl radical. The phenethyl and in particular the benzyl radical are preferred.
Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy^group, which instead of a methylene group ; contains a carbonyl group. An example which may be mentioned is the 2-oxopropoxy group.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexylpxy and cyclo-heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy radicals, which is substituted by one of the aforementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethoxy, the cyclobutylmethoxy and the cyclohexylethoxy radical.
Hydroxy-1-4C-alkoxy represents aforementioned 1-4C-alkoxy radicals, which are substituted by a hydroxy group. A preferred example which may be mentioned is the 2-hydroxyethoxy radical.


1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkbxy radicals,
which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy radicals. A preferred
example which may be mentioned is the methoxyethoxyethoxy radical.





3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy radicals, which is substituted by one of the aforementioned 3-7C-cycloalkoxy radicals. Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutQjtymethoxy and the cyclohexyloxyethoxy

radical.



3-7C-Cycloalkyl-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy radicals,,
which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-alkoxy radicals! Examples,
which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobutylmethoxyethoxy and the
cyclohexylethoxyethoxy radical.


one of the' radical.
ins
1-4C-Alkylcarbonyl represents a radical, which in addition to the carbonyl group contai aforementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl

1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An ( example which may be mentioned is the acetoxy radical (CH3CO-O-).
Wholly or mainly halogen-substituted 1-4C-alkoxy which may primarily be mentioned are chloro- and/or
in particular fluoro-substituted 1-4C-alkoxy radicals. Examples of halogen-substituted 1]-4C-alkoxy
which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the [ . .
i
pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1,1,1-trichloro-2-methyl-2- . propoxy, the 1,1,1-trichloro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-propoxy, the 3-bromo-1,1,1- . trifluoro-2-butoxy, the 4-bromo-3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxyj the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-' butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3!3-pentafluoro-propoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluproethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy radical.

1-7C-Alkylidene represents one of the aforementioned 1-7C-alkyl radicals, but which is bonded with a double bond. Examples which may be mentioned are isopropylidene ((CH3)2C=) and in particular the methylene radical (H2C=) .
A radical R41 or R51 from which a hydroxy group is formed under physiological conditions is

understood as meaning a radical -OR' from which the group R' is removed hydrolytically in the human
or animal bodv with formation of the radicals -OH and the nontoxic compound R'OH. The radical R"cah
hydroxy
protective groups or "prodrug" raaicais are Known, inte©ana, rrom tne patent applications and patents ','. :.
DE 4308095, WO 95/14016, EP 694547, WO 95/11884, WO 94/05282 and US 5,432!
I which can be mentioned are radicals R' having the general structure -C(0)R, -C(0)NRaRb,
II '
-P(0)ORaORb or -S(0)2OR, where R, Ra and Rb represent any desired organic radicals or optionally
183. Examples, -


hydrogen. In one embodiment of the invention, R41 and R51 have a common hydroxy protective group
R', which can then have, for example, one of the structures -CRaRb-, -CRa(ORb)-, -C(ORa)(ORb)-\or~
-P(0)OR-. .. '.
The groups to be mentioned as radicals R' to be emphasized by way of example in the context of the
invention are
-C(0)-NR12R13,
-C(0)-alk-NR12R13,
-C(0)-alk-C(0)-NR12R13,
-P(0)(OH)2,
-S(0)2NR12R13,
-C(0)-R12,
-C(0)-C6H3R14R15,
-C(0)-OR12,
-C(0)-alk-C(0)-R12,
-C(0)-alk-C(0)-OR12,
-C(0)-C(0)-R12,
-C(0)-C(0)-OR12and
-CH2-ORI2,
where
Alk is 1-7C-alkylene, ' ,
R12 is hydrogen, 1-7C-alkyl or 1-4C-alkyl substituted by halogen, carboxyl, hydroxyl, sulfo (-SO3H),
sulfamoyl (-S02NH2), carbamoyl (-CONH2), 1-4C-alkoxy or 1-4C-alkoxycarbonyl,[ R13 is hydrogen or 1-4C-alkyl, R14 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl and R15 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy.
1-7C-Alkylene represents straight-chain or branched InJC-alkylene radicals, for example the
methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), tetramethylene
(-CH2CH2CH2CH2-), 1,2-dimethylethylene [-CH(CH3)-CH(CH3)-], 1,1-dimethylethylene [-C(CH3)2-CH2-],
ll ■ ■•
2,2-dimethylethylene [-CH2-C(CH3)2-], isopropylidene [-C(CH3)2-], 1-methylethylene [-GH(CH3)-CH2-],
I!
pentamethylene (-CH2CH2CH2CH2CH2-), hexamethylene (-CH2CH2CH2CH2CH2CH2-) and the
heptamethylene radical (-CH2CH2CH2CH2CH2CH2CH2-).
The groups to be mentioned as radicals R' to be particularly emphasized by way of example in this connection are -C(0)-N(CH3)2, -C(0)-N(C2H5)2, -C(0)-NHC2H5l -C(0)-CH2CH2NH2, -0(0)-(CH2)3NH2, -C(0)-C(CH3)2NH2, -C(0)-CH2N(CH3)2, -C(0)-CH(NH2)-CH(CH3)2, -C(0)-CH(NH2)CH(CH3)C2H5,
-C(0)-(CH2)6C(0)N(CH3)CH2CH2S03H, -P(0)(OH)2, -S(0)2NH2, -C(0)-H, -C(0)-C(CHJJ)3, -C(0)-CH2CH2COOH, -C(0)-CH3, -C(0)-C2H5, -C(0)-C6H5l -C(0)-C6H4-4-N02, -C(0)-C6H4-3-N02,


-C(0)-C6H4-4-OCH3, -C(0)-C6H4-4-C(0)-OCH3, -C(0)-OCH3, -C(0)-0-menthyl, -C(0)-CH2-C(0)-OCH3, -C(0)-CH2CH2-C(0)-OCH3l -C(0)-C(0)-OCH3, -C(0)-C(0)-OC2H5 and -CH2OCH(CH3)|, or (if R41 and R51 have a common hydroxy protective group) the groups -C(CH3)2-, -P(0)(OH)- and -CH[C(CH3)3]-.
'
trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, " '
ethoxyethyl, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonylmethyl, dimethylaminoethyl,
diethylaminoethyl, phenyl, benzyl, 4-chlorophenyl, 4-aminophenyl, 4-chlorobenzyl, 4-difluoromethoxy- ;
II
phenyl, 4-trifluoromethoxyphenyl, 4-methylbenzyl, 3-methylbenzyl, 2,4-diaminophenyl, 2-methyl-4-tert-butylphenyl, 2-nitro-4-acetylphenyl, 4-fluorobenzyl, 4-nitrophenyl, 3-nitrophenyl, 3-aminophenyl,' 2-methoxycarbonylamino-6-methylphenyl, 2-methoxyetjgoxycarbonylamino-6-methylphenyl, 2-methoxy;.. carbonylamino-6-methylbenzyl and 2-methoxyethoxycarbonylamino-6-methylbenzyl.
Exemplary alkylene and alkenylene groups Alk1 and Alk2 in the substituents R42 and R52 which may
be mentioned are: 1-methylethylene, 2-methylethylene, 1-phenylethylene, 2-phenylethylene,
1-propylpropylene, 3-propylpropylene, 2-aminopropylene, 2-tert-butyloxycarbonylaminopropylene, 2-hydroxypropylene, 2-oxopropylene, 2-carboxypropylene, 1-acetyl-1,2-dimethylethylene, 2-acetyl-1,2-dimethylethylene, 1,1-dimethyl-2-oxoethylene, 1-oxo-2,2-dimethylethylene, 1,3-dioxobutylene, 2,4-dioxobutylene, 1,2-dioxopropylene, 2,3-dioxopropylene, prop-1-enylene, prop-2-enylene, but-1-enylene, but-2-enylene, but-3-enylene, but-4-enylene, buta-1,3-dienylene, buta-2,4-dienylene, 1-oxobut-2-enylene, 4-oxobut-2-enylene, 1-oxo-2,2-difluoroethylene, 2-oxo-1,1-difluoroethylene, 1-oxopropylene, 3-oxopropylene, 1-carboxyethylene and 2-carboxyethylene.
Halo-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is substituted by one; of the aforementioned halogen atoms. An example which may be mentioned is the 3-chloropropyl radical.

Carboxy-1-4C-alkyl for example represents the carboxymethyl (-CH2COOH) or the carboxyethyl
(-CH2CH2COOH).

radical

1-4C-Alkoxycarbonyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is substituted by one of the aforementioned 1-4C-alkoxycarbonyl radicals. An example which may be mentioned is the ethoxycarbonylmethyl radical (CH3CH2OC(0)CH2-) .
Di-1-4C-alkylamino represents an amino radical, which is substituted by two identical or different radicals from the aforementioned 1-4C-alkyl radicals. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino radical.


Di-1-4C-alkylamino-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl radicals, which is

substituted by one of the aforementioned di-1-4C-alkylamino radicals. Examples which

may be

mentioned are the dimethylaminomethyl, the dimethylaminoethyl and the diethylaminoethyl radical.
Ar-1-4C-Alkyl represents one of the aforementioned, Ar-substituted 1-4C-alkyl radicals where Ar has the aforementioned meaning. Examples which may be mentioned are the phenethyl and the benzyl radical.
1-4C-Alkylcarbonyl represents a radical, which in addition to the carbonyl group contains one of the

aforementioned 1-4C-alkyl radicals. An example which may be mentioned is the acetyl

radical.



1-4C-Alkoxycarbonylamino represents an amino radical, which is substituted by one of

the

aforementioned 1-4C-alkoxycarbonyl radicals. Examples which may be mentioned arefhe ethoxycarbonylamino and the methoxycarbonylamino radical.
1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned!
'
1-4C-alkoxy-1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the 2-(methoxy)-•
ethoxycarbonyl (CH3-0-CH2CH2-0-CO-) and the 2-(ethoxy)ethoxycarbonyl radical (CH3CH2-0-
CH2CH2-O-CO-). v
1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino radical, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl radicals. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethpxycarbonylamino radical.
2-7C-Alkylene represents straight-chain or branched 2-7C-alkylene radicals, for example tne etnylene-(-CH2-CH2-), trimethylene (-CH2-CH2-CH2-), tetramethylene (-CH2-CH2-CH2-CH2-), 1,2-di-methylethylene [-CH(CH3)-CH(CH3)-], 1,1-dimethylethylene [-C(CH3)2-CH2-], 2,2-dimethylethylene [-CH2-C(CH3)2-], isopropylidene [-C(CH3)2-], 1-methylethylene [-CH(CH3)-CH2-], pentamethylene (-CH2-CH2-CH2-CH2-CH2-), hexamethylene (-CH2-CH2-CH2-CH2-CH2-CH2-) and the heptamethylene radical (-CHz-CHz-CHz-CHz-ChVCrVCHr).

3-4C-Alkenylene represents straight-chain 3-4C-alkenylene radicals, for example the 1 the 2-propenylene, the 2-butenylene and the 3-butenylene radical.

propenylene,

1-4C-Alkylenedioxy radicals which, if desired, are wholly or partially halogen-substituted and which > may be mentioned are, for example, the methylenedioxiy (-0-CH2-0-), the ethylenedioxy (-0-CH2-CH2-0-) or the propylenedioxy radical (-0-CH2-CH2-CH2-0-) as unsubstituted radicals, of the halogen-substituted radicals, in particular fluoro-substituted 1-2C-alkylenedioxy, for example the


difluoroethylenedioxy (-0-CF2-CH2-0-), the tetrafluoretRylenedioxy (-0-CF2-CF2-0-) an'cl in particular; the difluoromethylenedioxy (-0-CF2-0-), and the 1,1,2-trifluoroethylenedioxy radical (-0-CF2CHF-0-) and also the chlorotrifluoroethylenedioxy radical, may be mentioned.
2-4C-Alkenyloxy represents a radical, which in addition to the oxygen atom contains a 2-4C-alkenyl
radical. An example which may be mentioned is the allyloxy radical.
Aryl-1-4C-alkyl represents an aryl-substituted 1-4C-alkyl radical. An example which may be mentioried is the benzyl radical.

Aryl-1-4C-alkoxy represents an aryl-substituted 1-4C-alkoxy radical. An example which mentioned is the benzyloxy radical.

may be

Mono- or di-1-4C-alkylamino radicals contain, in addition to the nitrogen atom, one or two of the
aforementioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-
diethyl- or diisopropylamino. '|
1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl radical is bonded. Examples which may be mentioned are the propionylamino (C3H7C(0)NH-) and the acetylamino ' ' radical (acetamido radical) (CH3C(0)NH-).
0
Arom radicals which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl,:;
4-acetamidophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl,
4-benzyloxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl,
3,5-bis(trifluoromethyl)phenyl, 4-butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chloro'phenyl,
2-chloro-6-fluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3-(4-
chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 2,4-dihydroxyphenyl,
2,6-dimethoxyphenyl, 3,4-dimethoxy-5-hydroxyphenyl, 2,5-dimethylphenyl, 3-ethoxy-4-H'ydroxyphenyl, ;
2-fluorophenyl, 4-fluorophenyl, 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, 3-methoxy-2-nitrophenyl,,
3-nitrophenyl, 2,3,5-trichlorophenyl, 2,4,6-trihydroxyphenyl, 2,3,4-trimethoxyphenyl, 2-hydroxy-1-
II
naphthyl, 2-methoxy-1-naphthyl, 4-methoxy-1-naphthyl, 1-methyl-2-pyrrolyl, 2-pyrrolyl, 3-methyl-2-u
pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 4-(2-methoxycarbonylethyl)-3-methyl-2-pyrrolyl, 5-ethoxycarbonyl-2,4-
dimethyl-3-pyrrolyl, 3,4-dibromo-5-methyl-2-pyrrolyl, 2,5-dimethyl-1-phenyl-3-pyrrolyl, 5-carboxy-3- ,
ethyl-4-methyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 2,5-dimethyl-1-(4-trifluoromethylphenyl)-3-pyrrolyl,': ,
1-(2,6-dichloro-4-trifluoromethylphenyl)-2-pyrrolyl, 1-(2-nitrobenzyl)-2-pyrrolyl, 1-(2-fluorophenyl)-2-
pyrrolyl, 1-(4-trifluoromethoxyphenyl)-2-pyrrolyl, 1-(2-nitrobenzyl)-2-pyrrolyl, 1-(4-ethoxycarbonyl)-2,5
dimethyl-3-pyrrolyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl, ,

1-(4-chlorobenzyl)-5-pyrazolyl, 1,3-dimethyl-5-(4-chlorphenoxy)-4-pyrazolyl, 1-methyl-3-trifluomethyl-5-j
\3

(3-trifluoromethylphenoxy)-4-pyrazolyl, 4-methoxycarbonyl-1-(2,6-dichlorophenyl)-5-pyrazolyl, 5-allyl-
II
oxy-1-methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3,5-di-"j

methyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyl-1,2,3-triazol-
4-yl, 3-indolyl, 4-indolyl, 7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3-indolyl, 2-(4- l
chlorophenyl)-3-indolyl, 7-benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3Jindolyl, 4,5,6,7-
tetrafluoro-3-indolyl, 1-(3,5-difluorobenzyl)-3-indolyl, 1-methyl-2-(4-trifluorophenoxy)-3-indolyl,
1-methyl-2-benzimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl, 5-(2-nitro-4-
II
trifluoromethylphenyl)-2-furyl, 4-ethoxycarbonyl-5-methyl-2-furyl, 5-(2-trifluoromethoxyphenyl)-2-furyl, -
5-(4-methoxy-2-nitrophenyl)-2-furyl, 4-bromo-2-furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-
2-furyl, 2-benzofuryl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, '
II
5-nitro-2-thienyl, 5-methyl-2-thienyl, 5-(4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-
thienyl, 5-carboxy-2-thienyl, 2,5-dichloro-3-thienyl, 3-methoxy-2-thienyl, 2-benzothienyl, 3-methyl-2-
benzothienyl, 2-bromo-'5-chloro-3-benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2,4-dichlorb
5-thiazolyl, 2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
'■ ' 6-methyl-2-pyridyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2,6-dichloro-4-pyridyl! 3-chloro-5-

trifluoromethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 4-(4-chlprophenyl)-3-pyridyl, 2-chloro-5^methoxy-
carbonyl-6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6-(3-trifluoromethylphenoxy)-3Jpyridyl, 2-'(4f .'
chlorophenoxy)-3-pyridyl, 2,4-dimethoxy-5-pyrimidinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chlorb
I
3-quinolinyl, 2-chloro-6-methoxy-3-quinolinyl, 8-hydroxyl-2-quinolinyl and 4-isoquinolinyl!

Possible salts of compounds of the formula I - depending on substitution - are especially all acid
addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acidj phosphoric
acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4]j ;

hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid,
||
fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, •
II methanesulfonic acid or 3-hydroxy-2-naphthoic acid, wtjere the acids are used in salt preparation - •
depending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an
equimolar quantitative ratio or one differing there from.
Pharmacologically intolerable salts, which can initially be obtained, for example, as process products ir the production of the compounds according to the invention on the industrial scale, are converted into '-the pharmacologically tolerable salts by processes known to the person skilled in the ant. .
It is known to the person skilled in the art that the compounds according to invention and their salts, if,-for example, they are isolated in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the


formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the
formula I. '

The compounds of the formula I have up to three chiral centers in the parent structure. thus relates to all conceivable stereoisomers in any desired mixing ratio to one another. pure enantiomers, which are a preferred subject of the invention.

The invention i including the

One embodiment (embodiment 1) of the invention are compounds of the formula 1, in which
R2 isR2i,
one of the substituents R5a and R5b is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alkyl!
and the other is hydrogen, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3r7C-
1-7C-alkylidene, outset,
Icycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy,"l-4C-': alkoxy-1 -4C-alkoxy-1 -4C-alkoxy, 3-7C-cycloalkoxy-1 -4C-alkoxy, 3-7C-cycloalkyl-j1 -4C-alkoxy'M 4C-alkoxy, 1-4C-alkylcarbonyloxy, wholly or mainly halogen-substituted 1-4C-alkoxy, the radjbai',.
R51 or the radical R52, or in which R5a and R5b together are O (oxygen) or are and in which R1, R3a, R3b, R4a, R4b, Arom and X have the meanings indicated in the and their salts.

in which
Another embodiment (embodiment 2) of the invention are compounds of the formula 1,
R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl,
hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or cyanomethyl, ; one of the substituents R5a and R5b is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alkyl.
and the other is the radical R53,
outset,
and in which R1, R3a, R3b, R4a, R4b, Arom and X have the meanings indicated in the and their salts.

in which

A further embodiment (embodiment 3) of the invention are compounds of the formula 11 R2 isR21,
!'

one of the substituents R5a and R5b is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alky|
outset,
and the other is the radical R53, and in which R1, R3a, R3b, R4a, R4b, Arom and X have the meanings indicated in the and their salts.
Compounds to be emphasized are those of the formula 1, in which
R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkoxy-1-4C-alkyl, 2-4C-alkynyl orfluoro-1-4C-
alkyl,
R2 is hydrogen, 1-4C-alkyl, aryl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1- '
4C-alkylorR21,


where
R21 is -CH2-0-C(0)-CH2-(CH2)x-NOy or -CH2-0-C2H4-(CH2)x-NOy,
in which
x is an integer from 2 to 6 and
y is an integer from 1 to 3, R3a is hydrogen, R3b is hydrogen, halogen, 1-4C-alkyl or the radical -CO-NR31R32,
where
R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl$r 1-4C-alkoxy-1-4C-alkyl and
R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
or where
R31 and R32 together, including the nitrogen atom to which both are bonded, arje a pyrrolidine
piperidino or morpholino radical,
one of the substituents R4a and R4b is hydrogen or 1-4C-alkyl and the other is hydroxyl, 1-4C-alkoxy
oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-
alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, or in which R4a ano ;
R4b together are O (oxygen),
one of the substituents R5a and R5b is hydrogen or 1-4C-alkyl and the other is hydrogen, hydroxyl,
1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy,
hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-a|koxy, or the
radical R53, or in which R5a and R5b together aYe O (oxygen),
where
R53 is -0-C(0)-CH2-(CH2)x-NOy, -0-C(0)-0-(CH2)x-NOy, -0-C(0)-C6h4-uri2-i\iuy or -u-u2(-
(CH2)x-NOy,
in which
x is an integer from 2 to 6 and
y is an integer from 1 to 3,
Arom is a mono- or bicyclic aromatic radical substituted by R8, R9, R10 and R11, which is selected
from the group consisting of phenyl, furanyl (furyl) and thiophenyl (thienyl),
where
R8 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-
alkoxycarbonyl, halogen, hydroxyl, trifluoromethyl, 1-4C-alkylcarbonylamino, 1|-4C-
alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl,
R9 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or
hydroxyl,
R10 is hydrogen and
R11 is hydrogen,
X is O (oxygen) or NH,


and their salts,
with the proviso that either
R2 has the meaning R21 or one of R5a and R5b have the meaning R53 or R2 has the meaning R21 and one of R5a and R5b have the meaning R53.



Compounds to be particularly emphasized are those of the formula 1, in which
R1 is 1-4C-alkylor1-4C-alkoxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, phenyl, hydroxy-1-4C-alkyl, halogen or R21,
where
R21 is -CH2-0-C(0)-CH2-(CH2)x-NOy or -CH2-0-C2H4-(CH2)x-NOy,
in which
x is an integer from 2 to 4 and
y is an integer from 1 to 3, R3a is hydrogen, R3b is hydrogen, one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, hydroxy-lT4C
alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkoxyT1-4C-alkoxy-1-4C-alkoxy, or in which R4a and
R4b together are O (oxygen), one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, jj-4C-alkoxy,;i-*.

4C-alkoxy-1-4C-alkoxy or the radical R53,
where

R53 is -0-C(0)-CH2-(CH2)x-NOy, -0-C(0)-0-(CH2)x-NOy, -0-C(0)-C6H4-CH2-Npy or -0-C2H4-(CH2)x-NOy,
in which
x is an integer from 2 to 4 and
y is an integer from 1 to 3, Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl), X is O (oxygen) or NH, and their salts, with the proviso that either
R2 has the meaning R21 or one of R5a and R5b have the meaning R53 or R2 has the meaning R21 and one of R5a and R5b have the meaning R53.
Compounds of embodiment 1 to be particularly emphasized are those of the formula 1]J in which R1 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 isR21, where
R21 is -CH2-0-C(0)-CH2-(CH2)x-NOy or -CH2-0-C2H4-(CH2)x-NOy


in which

x is an integer from 2 to 4 and

y is an integer from 1 to 3,
R3a is hydrogen,
R3b is hydrogen,
ii one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, hydroxy-1-4C
alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, or in which R4a and
I
1-4C-alkoxy or
R4b together are O (oxygen), one of the substituents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl
1-4C-alkoxy-1-4C-alkoxy, Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl), X is O (oxygen) or NH, and their salts.

Compounds of embodiment 2 to be particularly emphasized are those of the formula 1 !| in which
R1 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, phenyl, hydroxy-1-4C-alkyl or halogen,
R3a is hydrogen,

R3b is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, hydroxy-iT4U-
alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, or in which R4a and
R4b together are O (oxygen), one of the substituents R5a and R5b is hydrogen and the other is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-NOy, -0-C(0)-0-(CH2)x-NOy, -0-C(0)-C6H4-CH2-Npy or -0-C2H4-(CH2)x-NOy,
in which
x is an integer from 2 to 4 and
y is an integer from 1 to 3, Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl), v X is O (oxygen) or NH, and their salts.

Compounds of embodiment 3 to be particularly emphasized are those of the formula 1 Ji in which R1 is 1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 isR21,
where
R21 is -CH2-0-C(0)-CH2-(CH2)x-NOy or -CH2-0-C2H4-(CH2)x-NOy,





in which
x is an integer from 2 to 4 and
y is an integer from 1 to 3, R3a is hydrogen, R3b is hydrogen, one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, hydroxy- 1-4C-
alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, or in which R4a and ;
R4b together are O (oxygen), one of the substituents R5a and R5b is hydrogen and the other is the radical R53, where
R53 is -0-C(0)-CH2-(CH2)x-NOy, -0-C(0)-0-(CH2)x-NOy, -0-C(0)-C6H4-CH2-Nlpy or -0-C2H4-(CH2)x-NOy,
in which
x is an integer from 2 to 4 and

y is an integer from 1 to 3, Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl), X is O (oxygen) or NH, and their salts.
Among the compounds according to the invention, including the embodiments 1 to 3 arid the compounds to be emphasized and to be particularly emphasized, the optically pure compounds of the formula 1*






are preferred, those with R5b = hydrogen being particularly preferred.



Preferred compounds of the formula 1 * are those in which
R1 is1-4C-alkylor1-4C-alkoxy-1-4C-alkyl,
R2 is hydrogen, 1-4C-alkyl, phenyl, hydroxy-1-4C-alkyl, halogen or R21,
where
R21 is -CH2-0-C(0)-CH2-(CH2)x-NOy or-CH2-0-C2H4-(CH2)x-NOy,


in which
x is an integer from 2 to 4 and
y is an integer from 1 to 3, R3a is hydrogen, R3b is hydrogen, one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, hydroxy-1-4C-
alkoxy, 1-4C-alkoxy-1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, R5a is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical R53
where

R53 is -0-C(0)-CH2-(CH2)x-NOy, -0-C(0)-0-(CH2)x-NOy„ -0-C(0)-C6H4-CH2-Nlpy or -O-C2I7U-:' (CH2)x-NOy,
in which
x is an integer from 2 to 4 and
y is an integer from 1 to 3, R5b is hydrogen,
Arom is phenyl, furanyl (furyl) or thiophenyl (thienyl), X is O (oxygen) or NH, and their salts, with the proviso that either
R2 has the meaning R21 or R5a has the meaning R53 or R2 has the meaning R21 and R5a has the meaning R53.
Compounds with exemplary substituents to be particularly emphasized are those of the' formula 1*, in
which
R1 is hydrogen, methyl, cyclopropyl, methoxymethyl or trifluoromethyl,

R2 is hydrogen, methyl, phenyl, hydroxymethyl, chloro, bromo, ethynyl, trifluoromethyl or R21,
where
R21 is -CH2-0-C(0)-CH2-(CH2)x-N03 or-CH2-0-C2H4-(CH2)x-N03,
in which
x is the integer 2 or 3, R3a is hydrogen,
R3b is hydrogen, fluorine, methyl or the radical -CO-N(CH3)2, one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, methoxy, ejhoxy, propoxy,
isopropoxy, butoxy, hydroxyethoxy, methoxyethoxy, methoxypropoxy, methoxyethoxyethoxy,;2-
oxopropoxy, cyclopropyloxy or cyclopropylmethoxy, R5a is hydrogen, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methoxyethoxy,
methoxypropoxy, methoxyethoxyethoxy, 2-oxopropoxy, cyclopropyloxy, cyclopropylmethoxy or
the radical R53,


where
R53 is -0-C(0)-CH2-(CH2)x-N03, -0-C(0)-0-(CH2)x-N03, -0-C(0)-C6H4-CH2-N03 or -0-C2H4-
(CH2)x-N03, in which

x is an integer from 2 to 4, R5b is hydrogen, Arom is a phenyl radical and X is O (oxygen) or NH, and their salts, with the proviso that either
R2 has the meaning R21 or R5a has the meaning R53 or R2 has the meaning R21 and R5a has the meaning R53.
Preferred compounds are those of embodiment 2.
Preferred exemplary compounds of the formula 1* are accordingly those, in which
R1 is methyl,
R2 is hydrogen, methyl, or chloro,
R3a is hydrogen,
R3b is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, methoxy, ethoxy,
hydroxyethoxy, methoxyethoxy or methoxyethoxyethoxy, R5a is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-N03, -0-C(0)-0-(CH2)x-N03, -0-C(0)-C6H4-CH,-NO-, or -O-CKU (CH2)x-N03,
in which
x is an integer from 2 to 4, R5b is hydrogen, Arom is a phenyl radical and X is 0 (oxygen) or NH, and their salts.
Particularly preferred exemplary compounds of the formula 1* are those, in which
R1 is methyl,
R2 is hydrogen, methyl, or chloro,
R3a is hydrogen,
R3b is hydrogen,


one of the substituents R4a and R4b is hydrogen and the other is methoxyethoxy, R5a is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-N03 or -0-C(0)-0-(CH2)x-N03,
in which
x is an integer from 2 to 4, R5b is hydrogen, Arom is a phenyl radical and X is 0 (oxygen) or NH, and their salts.
Preferred compounds of the formula 1* according to the invention are those, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3a is hydrogen,
R3b is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy-1-4C-alkoxy,
R5a is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-0-N02, -0-C(0)-C6H4-CH2-0-N02 or -0-C(0)-0-(CH2)x-0-N02;|
in which
x is an integer from 2 to 4, R5b is hydrogen, Arom is a phenyl radical and X is O (oxygen) or NH, and their salts.
Particularly preferred compounds of the formula 1* according to the invention are those, in which
R1 is 1-4C-alkyl,
R2 is 1-4C-alkyl,
R3a is hydrogen,
R3b is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy-1
R5a is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-0-N02 or -0-C(0)-0-(CH2)x-0-N02,
in which
x is an integer from 2 to 4,



R5b is hydrogen, Arom is a phenyl radical and X is O (oxygen) or NH, and their salts.

Particularly preferred exemplary compounds are those of formula 1* in which R1 is methyl, R3a is hydrogen, R3b is hydrogen, R5b is hydrogen and Arom is phenyl, and the substituentsjand groups R4a, R4b, R5a and X have the meaning given in the following table 1,




R2 R4a R4b R5a X
CH3 H OCH2CH2OCH3 0C(O)(CH2)3-NO3 NH
H H OCH2CH2OCH3 OC(0)(CH2)3-N03 NH
CI H OCH2CH2OCH3 OC(0)(CH2)3-N03 NH
CH3 H OCH2CH2OCH3 OC(0)(CH2)4-N03 NH
H H OCH2CH2OCH3 ®C(0)(CH2)4-N03 NH
CI H . OCH2CH2OCH3 OC(0)(CH2)4-N03 NH
CH3 H OCH2CH2OCH3 OC(0)(CH2)3-N03 0
H H OCH2CH2OCH3 OC(0)(CH2)3-N03 0
CI H OCH2CH2OCH3 OC(0)(CH2)3-N03 0
CH3 H OCH2CH2OCH3 OC(0)(CH?)4-N03 0
H H OCH2CH2OCH3 OC(0)(CH2)4-N03 0
CI H OCH2CH2OCH3 OC(0)(CH2)4-N03 0
CH3 H OCH2CH2OCH3 OC(0)0(CH2)2-N03 NH
H H OCH2CH2OCH3 OC(0)0(CH2)2-N03 NH
CI H OCH2CH2OCH3 OC(0)0(CH2)2-N03 NH
CH3 H OCH2CH2OCH3 OC(0)0(CH2)3-N03 NH
H H OCH2CH2OCH3 OC(0)0(CH2)3-N03 NH
CI H OCH2CH2OCH3 OC(0)0(CH2)3-N03 NH
CH3 H OCH2CH2OCH3 OC(0)0(CH2)2-N03 0
H H OCH2CH2OCH3 OC(0)0(CH2)2-N03 0
CI H OCH2CH2OCH3 '8c(0)0(CH2)2-N03 0
CH3 H OCH2CH2OCH3 OC(0)0(CH2)3-N03 0
H H OCH2CH2OCH3 OC(0)0(CH2)3-N03 0
CI H OCH2CH2OCH3 OC(0)0(CH2)3-N03 0
and the salts of these compounds.


Particularly preferred are the compounds given as final products in the examples, and their salts,
|iincluding those intermediates which are within the scope of the invention, and their salts.

The compounds according to the invention can be synthesised from the corresponding! starting compounds of formula 1, in which either R2 is a hydroxymethyl group or R5a or R5b are a hydroxyl-
group, or R2 is a hydroxymethyl group and R5a or R5b are a hydroxyl group. The synthesis is carried
out in a manner known to the expert and described for example in international patent
application WOOO/50037. For obtaining the preferred nitrate compounds according to the invention (with y = 3)) the starting compounds are in a first step esterified or etherified in an appropriate manner by reaction with; the compounds L-C(0)-(CH2)x-Hal or L-CH2-(CH2)x-Hal
' ,$ i . -,..4
in which L is a hydroxy group or a suitable leaving group and Hal is a halogen atom, and the resulting ,.
intermediate compounds are then reacted with a suitable: nitrate, in particular with silver nitrate, to yield
the compounds according to the invention. j i • The starting compounds of formula 1, in which either R2 is a hydroxymethyl group or R5a or R5b are a hydroxyl group, or R2 is a hydroxymethyl group and R5a or R5b are a hydroxyl group, can be prepared as described by way of example in the following examples below, or starting from corresponding starting compounds using analogous process steps (see, for example, WO 98/42707, WO 98/54188, • WO00/17200, WO00/26217, WO00/63211, WO01/72756, WO01/72754, WO01/72755iand WO01/72757), or as outlined very generally in the following schemes.

Scheme 1:
V
Preparation of compounds 1 where X = NH, R4a or R4b = hydroxyl, R5a/R5b = H and substituents R3a and R3b

any desired ,"







Prot in the above scheme represents any desired protective group, for example a pivalbyl group. The •
introduction of the acetyl group, the condensation with the aldehyde Arom-CHO, the ring closure and '
the reduction are carried out in a manner known per se. The derivatization, if desired, fpllowing this' ..",
II
(e.g. conversion of the hydroxy group into an alkoxy group) is likewise carried out in a manner known ,
I ■. ■)
per se, for example as described by way of example in international patent application WO 00/17200.

Scheme 2: i ;.

Preparation of compounds 1 where X = NH, R4a or R4b = hydroxyl, R5a or R5b = hydroxyl and any .. j desired substituents R3a and R3b



The 7-acetyl-8-aminoimidazopyridine used as a startihgjmaterial is prepared as outlined in scheme
The additional epoxidation compared with scheme 1. is likewise carried out in a manner known per se,*.
for example using hydrogen peroxide as an epoxidizing agent. Alternatively to schemes 1 and 2,'th,e'"i'i
compounds where X = NH can also be prepared according to scheme 8 of international patent
application WO98/42707, advantageously with protection of the hydroxy group of the phenylisoserine '
ester, for example using a suitable silyl group, or - if compounds where R5a/R5b = H are desired -
using the corresponding propionic acid derivative without a 2-hydroxy group.
While compounds 1 where X = O, R4a or R4b = hydroxyl, R5a/R5b = H and any desired substituents
R3a and R3b can be prepared in analogy to scheme 1, compounds where X = O, R4a or R4b = .'
hydroxyl, R5a or R5b = hydroxyl and any desired substituents R3a and R3b are advantageously
prepared according to reaction scheme 3 below.

Scheme 3:



1. Oxidation
2. Removal of protective groups "^ and cyclization
1. Aromatic electrophilic substitution
2. Transformation
3. Removal of protective (Prot) group

Arom
The above scheme 3 shows, by way of example, the enantioselective synthesis of a 7(J8-diol (R4a or ' R4b and R5a or R5b are in each case hydroxyl), which, if desired, can then additionally be alkylated or its hydroxy groups can additionally be derivatized in a suitable manner (e.g. etherified or converted into the groups R41/R51 or R42/R52).
The group Y in scheme 3 is a suitable leaving group, for example a halogen atom, preferably chlorine,
"*' II
or a 1-4C alkoxy group, preferably methoxy. The acylation is carried out in the manner customary to
the person skilled in the art, preferably using bis(trimethylsilyl)sodamide or potassamide if the leaving
group is a chlorine atom.

The oxidation following the acylation is likewise carried out under conditions which are! customary per
se, using chloranil, atmospheric oxygen, 2,3-dichloro-5,6-dicyano-p-benzoquinone or manganese

-



i; ■ - ■ 11 :
dioxide as an oxidant. For the subsequent removal of protective groups and cyclization, certain
conditions are to be fulfilled with respect to the auxiliary acid to be used. Formic acid is advantageous);
employed as an auxiliary acid. .

The reduction to the diol is likewise carried out - as already in the case of the reduction according to scheme 2 - under standard conditions (see, for example, W098/54188), sodium borohydride, for example, being employed as a reductant, with the use of which the specified 7,8-trans diol can be '.
obtained in over 90% diastereomeric purity. The etherification which follows, if desired! ancj js likewise;
I :'
carried out in a manner customary per se, leads to the compounds of the formula 1* according to the
' '

invention in which R4a and R5b are hydrogen. ||
■• .. i
For the preparation of compounds of the formula 1 in which R5a and R5b are hydrogen, instead of-the dioxolane in scheme 3, starting materials to be used are 3-hydroxypropionic acid derivatives (correspondingly protected on the hydroxy group) in which Y (analogously to the above scheme) is'a , suitable leaving group.!
The introduction of the "prodrug" radical R' subsequently, to the synthesis for the formation of the '
substituents R41 or R51 carried out according to schemes 1 to 3 is carried out in the sense of an *
acylation reaction starting from compounds of the formula 1 in which at least one of the radicals R4a,;';
R4b, R5a and R5b is a hydroxy group, by reaction with compounds of the formula R'-Z in which Z is a
suitable leaving group, for example a halogen atom. The reaction is carried out in a manner known per
se, preferably in the presence of a suitable auxiliary base. For the preparation of the compounds of the
formula 1 in which R4a or R4b is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy and R5a or R5b is the
radical R5', compounds of the formula 1 in which R4a or R4b is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-
alkoxy and R5a or R5b is hydroxyl are reacted with compounds R'-Z. For the preparation of the
compounds of the formula 1 in which R4a or R4b is hydroxyl and R5a or R5b is the radical R5',
compounds of the formula 1 in which R4a and R4b together are 0 (oxygen) and R5a or R5b is J
li >
hydroxyl are reacted with compounds R'-Z. The keto group is then reduced to the hydroxy group. In a
similar manner, compounds of the formula 1 are obtained in which the "prodrug" radical is in the
7-position and the hydroxy group or the 1-4C-alkoxy ori'1-4C-alkoxy-1-4C-alkoxy radical is in the
8-position.
The alkylation of the compounds obtained according to schemes 1 to 3 to give the compounds of the ! formula 1 in which R4a, R4b, R5a or R5b has the meaning 1-7C-alkyl, 2-7C-alkenyl, phenyl or pheh-1-4C-alkyl can generally be carried out according to schemes 4 and 5 below.


Scheme 4:
Scheme 4 generally outlines the preparation of compounds 1 in which R4a or R4b haslthe meaning
i; 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alkyl.



M-R4

Arom

Arom

The introduction of the radical R4a or R4b (called R4 for short) in the 7-position is carried out by
II
reaction with a suitable organometallic (M = metal) compound (e.g. methyllithium, phenyllithium,
II "
2,2-dimethylvinylmagnesium bromide etc.) in a manner known per se. The 8-OH group is optionallyto •
be protected, for example using a suitable silyl radical. The alkylated product obtained can then be'1
reacted further, if desired, as described or in a manner known per se (etherification, introduction bfjja','
"prodrug" radical etc.).
Schema 5:
Scheme 5 generally outlines the preparation of compounds in which R5a or R5b has tjjie meaning 1-7C-alkyl, 2-7C-alkenyl, phenyl or phen-1-4C-alkyl.



R5-Hal

Arom

Arom

The introduction of the radical R5a or R5b (abbreviated to R5) in the 8-position is carried out, for '.
example, by reaction with a suitable halide (Hal = halogen), such as, for example, methyl iodide," benzyl
bromide etc., under suitable, preferably basic conditions in a manner known per se. Advantageously, .»,
the reaction can also be carried out under phase-transfer conditions. The alkylated product'obtained*-!'.
can then be reacted further, if desired, as described or in a manner known per se (reduction of the
7-oxo group, etherification, introduction of a "prodrug" radical etc.). With regard to the specific preparation and isolation of the pure enantiomers, reference is made, for
example, to the corresponding details in WOOO/17200. j;


The starting compounds shown in schemes 1 to 3 are known (see, for example, EP-A--299470,
Kaminski et al., J. Med. Chem. 1985, 28, 876-892, 1989, 32, 1686-1700 and 1991, 34!'533-541 and
Angew. Chem. 1996, 108, 589-591) or they can be prepared in a manner analogous to the known
compounds, for example according to reaction scheme 6 below.
Scheme 6: i ' '
Exemplary preparation of starting compounds needed according to scheme 3 where Rjl, R2 = methyl ,
and various substituents R3b. '



3-Brombutan-2-one


Br,

The reactions to give the 8-benzyloxy-6-bromoimidazopyridines are carried out in a manner such as is
known to the person skilled in the art. The conversion of the bromine atom into an ethyl ester radical
can be carried out in various ways, for example using the Heck reaction (using Pd(ll), carbon monoxic
and ethanol) or by metallation in the 6-position (using lithium or magnesium) and subsequent Grignarc

reaction. The metallation also offers the possibility of introducing other desired groups

R3b in position

6, for example fluorine, chlorine or the carboxy group. Starting from the ester group, further desired'

groups R3b can be introduced into position 6, for example hydroxy-1-4C-aikyl radicals hydroxymethyl radical), by reduction of the ester radical with lithium aluminum hydride
(in particularity
or 1 -4C-alkoxy: 1-4C-alkyl radicals (in particular 1-4C-alkoxymethyl radicals) by subsequent etherificatjpn as outlined i scheme 6.
The debenzylation/reduction is likewise carried out in a manner known per se, for example using , hydrogen/Pd(0). If compounds where R3b = -CO-NR31R32 are desired, an appropriate derivatization can be performed in a manner known per se (conversion of an ester into an amide) atithe stage of the 8-benzyloxy-6-ethoxycarbonyl compound or after the debenzylation/reduction, or alternatively also at i later point in time, e.g. at the stage of the acyloin (see schemes 2 and 3).
Starting compounds having various substituents R1 and R2 are known, or they can be prepared - for

example based on scheme 6 - in a known manner in analogy to known compounds. Alternatively, '•*
derivatizations can also be carried out at the stage of the compounds 1. It is thus possible, for example
starting from compounds where R2 = H, to prepare compounds where R2 = CH2OH (by Vilsmeier .,
reaction and subsequent reduction), where R2 = CI or Br (by chlorination or bromination), where R2 =
propynyl (from the corresponding bromo compound using the Sonogashira reaction) or where R2 ='•
alkoxycarbonyl (from the corresponding bromo compound by Heck carbonylation).
The following examples serve to illustrate the invention in greater detail without restricting it. Likewise, further compounds of the formula 1 whose preparation is not described explicitly can be prepared in a analogous manner or in a manner familiar per se to the person skilled in the art using customary process techniques. The abbreviation min stands for minute(s), h for hour(s) and ee for "enantiomeric excess".


Examples
Final Products
1. 7R,8R,9R)-2,3-Dlmethyl-7(2-methoxyethoxy)-9-phenyl-8-(5-nitrooxy-valetyloxy)-7,8,9,10-'! tetrahydro-imidazo[1,2-h][1,7]naphthyridlne
4.00 g (7.54 mmol) of (7R,8R,9R)-2,3-dimethyl-7(2-methoxyethoxy)-9-phenyl-8-(5-bromo-valeryloxy)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine are added to a solution of 5.13 g (30.20 mmol) ol silver nitrate in acetonitrile (100 ml) and the reaction is stirred in the darkness for 20 h at 25°C.
Afterwards the mixture is concentrated in vacuo and purified by chromatography (diisopropyl ether
|l ;
triethyl amine: 9 /1) to give the title compound (1.80 g / 3.51 mmol / 47 %) as a colourless solid with i

melting point of 87.1 °C (pentane /diisopropyl ether).

2. 7R,8R,9R)-2,3-Dimethyl-7(2-methoxyethoxy)-9-phenyl-8- tetrahydro-imidazo[1,2-h][1,7]naphthyridine
1.80 g (3.48 mmol) of (7R,8R,9R)-2,3-dimethyl-7(2-methoxyethoxy)-9-phenyl-8-(4-bromo-butyryloxy)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine are added to a solution of 2.40 g (14.1 mmol) of silver nitrate in acetonitrile (16 ml) and the reaction is stirred in the darkness for 72 h at 25°C.
Afterwards the mixture is concentrated in vacuo and pdrified by chromatography (diisopropyl ether/' •
|l .•-*■-
triethyl amine: 9 /1) to give the title compound (0.60 g /1.20 mmol / 35 %) as a colourless solid with i

3. (7R,8R,9R)-2,3-Dlmethyl-7-(2-methoxyethoxy)-9-phenyl-8-(5-nitro-oxy-valeryloxy)-7H-8,9i:
dihydro-pyrano[2,3-c]imdazo[1,2-a]pyridine
To a solution of 2.80 g (16.55 mmol) silver nitrate in acetonitrile (20 ml) is added 2.00 g (3.76 mmol) (7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-8-(5-bromo-valeryloxy)-7/-/-8,9J-dihydro- pyrano[2,3-c]imdazo[1,2-a]pyridine and the reaction is stirred in the darkness for 16 h at 25°C. Afterwards the mixture is concentrated in vacuo and purified by chromatography (diisopropyl ether / triethyl amine: 9 /1) to give the title compound (1.37 g / 2.67 mmol / 71 %) as a colourless solid with melting point of 124°C (diethylether).
4. (7R,8R,9R)-2,3-Dimethyl-7-(2-metrioxyethoxy)-9-phenyl-8-(6-nitro-oxy-2-oxa-capryloxy)-7,8,9,10-tetrahydro-imldazo[1,2-h][1,7]naphthyridine

To a solution of 3.00 g (17.7 mmol) silver nitrate in acetonitrile (25 ml) is added 1.90 g

(3.20 mmol)"'

(7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phehyl-8-(6-iodo-2-oxa-capryloxy)-7,8,9,10- tetrahydro-imidazo[1,2-h][1,7]naphthyridine and the reaction is stirred in the darkness for 2 h at 25°C.
Afterwards the mixture is concentrated in vacuo and purified by chromatography (diisopropyl ether /
I'



triethyl amine: 9 /1) to give the title compound (1.25 g / 2,36 mmol / 74 %) as a colourless solid tyitR.a*
melting point of 116°C (diethylether).
5. (7R>8R,9R)-2,3-Dimethyl-7-(2-methoxyethoxy)-9-phenyt-8-(4-nitro-oxymethyl-benzoyloxy)-
7,8,9,10-tetrahydro-imldazo[1,2-h][1,7]naphthyrldine
To a solution of 2.25 g (13.3 mmol) silver nitrate in acetonitrile (15 ml) is added 1.50 g (2.66 mmol);
(7R,8R,9R)-2,3-dimethyl-7-(2-methoxyethoxy)-9-phenyl-8-(4-bromo-methyl-benzoyloxy)-7,8,9,10- :
tetrahydro[1,2-h][1,7]naphthyridine and the reaction is stirred in the darkness for 16 h at 25°C.
Afterwards the mixture is concentrated in vacuo and purified by chromatography (diisopropyl ether / -.)
|l ■ ' ■■>
triethyl amine: 9 /1) to give the title compound (0.15 g / 0.27 mmol /10 %) as a colourless solid.
i . .
\t i ; ,
1H-NMR (200MHz, CDCI3): 8 = 2.40 (s, 6H), 3.25 (s, 3 H), 3.48-3.55 (m,1 H), 3.67-3.73 (m, 1 H), 4!'90J
(dd, 2 H), 5.45 (s,2 H), 5.90 (t, 1 H), 6.90 (d, 1 H), 7.23-7.50 (m, 8 H), 7.93 (d, 2 H). ! ' !, ;
Intermediates and starting compounds

.
100/3),70mg
A. 8-Hydroxy-2,3 one !
1.1 g of 8-amino-7-[2,3-epoxy-1-oxo-3-(3-thienyl)propyl]-2,3-dimethylimidazo[1,2-a]pyridine are dissolved in 20 ml of hexafluoroisopropanol at room temperature, the solvent is stripped off after
19 hours and the residue is purified on silica gel (eluent: methylene chloride/methanol of the title compound of m.p. 222-25°C (diethyl ether) are obtained.

i

B. 7,8-Dihydroxy-2,3-dimethyl-9-(3-thlenyl)-7,8,9I10-tetrahydro-lmidazo[1,2-h][1,7]naphthyridine
50mgof 8-hydroxy-2,3-dimethyl-9-(3-thienyl)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7
one are suspended in 5 ml of methanol and treated with 100 mg of sodium borohydride at room ',
temperature with vigorous stirring. After stirring at room temperature for 1 hour, the solvent is stripped.
off in vacuo, the residue is covered with a layer of 5 ml'of water, the mixture is adjusted to pH 1 with a
few drops of semisaturated aqueous hydrochloric acid and then adjusted to pH 8 using saturated
II
aqueous sodium hydrogen carbonate solution, extracted three times with 20 ml of methylene chloride
each time, the combined organic phases are concentrated to dryness in vacuo and the remaining solid
residue is purified on silica gel (eluent: methylene chlbrjde/methanol = 13/1). 45 mg of the title
compound of m.p. 134-38°C are obtained. ; . .
C. 2,3-Dimethyl-9-(3-thienyl)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7-one
2.6 g of 8-amino-2,3-dimethyl-7-[3-(3-thienyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine are treated at room temperature with 20 ml of aqueous 70% strength sulfuric acid, poured onto ice water (100 ml) after 90 minutes, neutralized with aqueous 6 N sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. The combined organic phases are washed with water,
53

dried over sodium sulfate, the solvent is stripped off in vacuo and the remaining yellowjoil is stirred with • 15 ml of diethyl ether. The yellowish solid obtained here is filtered off and dried in vacuo. 1.8 g of the title compound of m.p. 176-77°C (diethyl ether) are obtained.
D. 9^3-Fuiyl)-^-hydroxy-2,3-dimethyl-7,8,9l10-tetrahydro-irnidazo[1,2-h][1,7]naphthyridln-7H6ne
Analogously to Example A, 70 mg of the title compound are obtained by warming 460 mg of 8-amino-7-[2,3-epoxy-1-oxo-3-(3-furyl)propyl]-2,3-dimethyl-7,8,9,10-tetrahydroimidazo[1,2-a]pyridine in hexa-fluoroisopropanol. 1H-NMR (200 MHz, DMSO): 6= 2.31(s, 3H), 2.36 (s, 3H), 4.09-4.15; (m, 1H), 4.62-
J1H), 7.55-7.63
4.67 (m, 1H), 5.77-5.80 (d, 1 OH), 6.53-6.54 (m, 1H), 6.95-6.98 (d, 1H), 7.44-7.48 (d, (m, 4Hincl.1NH).

E. 9-(3-Furyl)-2,3-dimethyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridln-7-one
. &■ I

Analogously to Example C, 550 mg of the title compound are obtained by treatment of 1.5 g of
8-amino-2,3-dimethyl-7-[3-(3-furyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine with 70% strength sulfuric
acid. 1H-NMR (200 MHz, DMSO): 6 = 2.31 (s, 3H), 2.35 (s, 3H), 2.72-3.04 (m, 2H), 4.85-4.92 (m, 1H),
6.54-6.56 (m, 1H), 6.94-6.98 (d, 1H), 7.39-7.43 (d, 1H), 7.50 (s, 1H), 7.55-7.57 (m, 1H), 7.79-7.80 (d,
1NH).

F. (7R,8R,9R)-8-Hydroxy-7-[2- tetrahydro-imldazo[1,2-h][1,7]naphthyridlne I
onto ice, 100 ml 'N sodium
5gof (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]-naphthyridine are dissolved in 40 ml of 2-(2-methoxyethoxy)ethanol, 3.2 g of sulfuric acid (98%
strength) are added and the mixture is warmed at 50°C for 16 hours. It is then poured of methylene chloride are added and the mixture is adjusted to pH 7 using aqueous 8
hydroxide solution. After separation of the organic phase, the aqueous phase is extracted a further two times using 50 ml of methylene chloride each time, the combined organic phases are washed with

100 ml of water, dried over sodium sulfate and the solvent is stripped off in vacuo. The residue is
II purified on silica gel (eluent: diethyl ether/2-propanol = 10/1). 105 mg of the title compound are
obtained. 1H-NMR (200 MHz, DMSO): 5 = 2.25 (s, 3H),g2.33 (s, 3H), 3.23 (s, 3H), 3.32-3.47 (m.',6f(),
3.59-3.69 (m, 2H), 3.97-4.07 (q, 1H), 4.44-4.47 (m, 2H), 5.18-5.21 (d, 1 OH), 5.85-5.86 (d, 1 NH), 6.74-
6.78 (d, 1H), 7.19-7.45 (m,6H). ;

G. (7S,8R,9R)-8-Hydroxy-7-[2- silica gel (eluent:
350 mg of the title compound are obtained by column chromatographic purification orili
diethyl ether/2-propanol = 10/1) of the crude product from the above reaction of (7R,8R,9R)-7,8-
dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with 2-(2-meth|-
oxyethoxy)ethanol. 1H-NMR (200 MHz, DMSO): 6 = 2.26 (s, 3H), 2.33 (s, 3H), 3.23 (J, 3H), 3.39-4.;01
(m, 8H), 3.59-3.69 (m, 2H), 4.25-4.26 (d, 1H), 4.45-4.50 (m, 1H), 4.64-4.68 (d, 1 OH)| 5.94-5.95 (d; 1
I1 NH), 6.76-6.79 (d, 1H), 7.24-7.44 (m, 6H).


H. (8R,9R)-8-Hydroxy-2-mothyl-9-phonyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyrldln-7-one
course of
30 ml of concentrated hydrochloric acid are added dropwise at room temperature in the i 20 minutes to 29.8 g (73.1 mmol) of (8R,9R)-8-(tert-bulyldimethylsilanyloxy)-2-methyl-9 phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridin-7-one, dissolved in 30 ml of methanol. The mixture is stirred for a further 30 minutes at room temperature. The methanol is stripped off and the pH of the remaining solution is adjusted to 10 using 2M sodium hydroxide solution. The mixture is extracted three times with 30 ml of dichloromethane each time, the combined dichloromethane phases are washed once with 30 ml of water and the organic phase is dried over magnesium sulfate. The drying agent is filtered off, the filtrate is concentrated and the residue is brought to crystallization using diethyl ether. The crystallizate is filtered off with suction and dried in vacuo at 50°C. 12.2 g (57% of theory) of the title compound are obtained.
I. (7R,8R,9R)-7,8-Dlhydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydro-lmldazo[l,z-n][l,7]napn-thyridine
6 g (20.5 mmol) of (8R,9R)-8-hydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[l!2-h][1,7]naph-
thyridin-7-one are suspended in 30 ml of 2-propanol and 2 ml of 0.3% strength methanolic sodium
methoxide solution. 0.4 g (10.2 mmol) of sodium borohydride, dissolved in 5 ml of 0.3% methanolic.
sodium methoxide solution, is added dropwise at 10°C in the course of 10 minutes. The reaction
mixture (suspension) is stirred overnight at room temperature (a solution forms in the course of this). .
The reaction solution is added to 90 ml of water and ex'tracted three times with 30 ml of ethyl acetate
each time. The combined ethyl acetate phases are washed once with water and concentrated. The
residue is chromatographed on silica gel (ethyl acetate/2-propanol 95:5). The product fractions are ;
concentrated and crystallized using diethyl ether. The crystals are filtered off with suction and dried at.
50°C in a high vacuum. 4.3 g (71 % of theory) of the titlej compound of m.p. 119°C (decomposition) are
obtained.
J. (7S,8R,9R)- and (7R,8R,9R)-8-Hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7I8I9,10-tetrahydro-lmidazo[1,2-h][1,7]naphthyridlne
6 g (20.3 mmol) of (7R,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]-naphthyridine are introduced into 75 ml of ethylene glycol monomethyl ether at 65°C, treated
with 4.9 g (50.8 mmol) of methanesulfonic acid and the mixture is stirred at 65°C for 1.5 h. The reaction
II solution is concentrated in a rotary evaporator and residue is treated with 50 ml of dichloromethane
and 50 ml of water. The aqueous phase is adjusted to pH 8 by means of saturated sodium hydrogen .
carbonate solution, the organic phase is separated off and the aqueous phase is extracted twice using
20 ml of dichloromethane each time. The combined dichloromethane phases are concentrated and the
II residue is separated by chromatography on silica gel (ethyl acetate/2-propanol/conc. ammonia water
at 50°C in a
98:2:0.1). The individual product fractions are concentrated and the products are dried
high vacuum. 1.7 g (23% of theory) of (7S,8R,9R)-8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl


7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine of m.p. 149 - 152°C and 0.9 g (13% of theory) of (7R,8R,9R)-8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]-naphthyridine (12b) of m.p. 108-110°C are obtained.
K. (7R,8R,9R)-3-Bromo-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7.8.9.i0-tetrahydro-imldazo[1.2-h][1.7]naphthyridine
■i '
A suspension of 3.30 g (5.90 mmol) (7R,8R,9R)-10-acetyl-3-bromo-7-(2-methoxyethoxy)-2-methyl-9-
l| '
phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine, 1.00 ml (6.00 mmol)
aqueous potassium hydroxide (6 N) and 2.00 ml (51.40 mmol) hydrazine hydrate in methanol is stirred,
at 60°C for 4 h. The methanol is removed in vacuo andithe reaction mixture is diluted with water. ": ,
Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are
washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified .
by column chromatography (toluene / dioxane / acetic acid: 8/1 /1) to give 1.50 g (3.47 mmol / 59 %)
of the title compound as a light yellow solid with a melting point of 153-154°C (acetone)!
L. (7R,8R,9R)-3-Chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7.8.9.10-tetrahydro-,
lmldazo[1.2-h][1.7]naphthyridine
A suspension of 0.27 g (0.53 mmol) (7R,8R,9R)-10-acetyl-3-chloro-7-(2-methoxyethoxy)-2-methyl-9-
II phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine, 0.10 ml (0.60 mmol)
aqueous potassium hydroxide (6 N) and 0.20 ml (5.14 mmol) hydrazine hydrate in methanol is stirred
at 60°C for 4 h. The methanol is removed in vacuo and the reaction mixture is diluted with water.
Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are
washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified,
by column chromatography (toluene / dioxane / acetic acid: 8 /1 /1) to provide 0.34 g (0.88 mmol /.51i
%) of the title compound as a colourless solid with a melting point of 123-126°C (acetone). . ..".»
M. (7R,8R,9R)-3-Chloro-8-hydroxy-7-(2-methoxyethoxy)-2-methyl-9-phenyl-7H-8 9-dihydro-' • pyrano[2,3-c]imidazo[1,2-a]pyridine
A suspension of 0.70 g (1.48 mmol) (7R,8R,9R)-3-chloro-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8f ..
pivaloyloxy-7H-8,9-dihydro-pyrano[2,3-c]imidazo[1,2-a]pyridine and 0.10 g (0.72 mmol) potassium ,.
carbonate in methanol is stirred at 25°C for 18 h. The reaction is quenched by adding of saturated ,i .. '
aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with i t
dichloromethane . The combined organic layers are washed with brine, dried over sodium sulphateand evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate) to give 0.45 g (1.16 mmol / 78 %) of the title compound as a colourless solid with a melting point of 146°C (acetone).
N. (7R,8R,9R)-8-Hydroxy-7-

A suspension of 1.00 g (2.28 mmol) of (7R,8R,9R)-7-(2-Methoxyethoxy)-2-methyl-9-phenyl-8-
pivaloyloxy-7/-/-8,9-dihydro-pyrano[2,3-c]imidazo[1,2-a]pyridine and 0.10 g (1.30 mmol) potassium.
carbonate in methanol is stirred at 25°C for 18 h. The reaction is quenched by adding of saturated
aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with
dichloromethane . The combined organic layers are washed with brine, dried over sodium sulphate'and evaporated in vacuo. The crude product is purified by column chromatography (ethyl acetate) to give ' 0.55 g (1.55 mmol / 68 %) of the title compound as an amorphous solid. 1H-NMR (200MHz,[D6] DMSO): 5 = 2.26 (s, 3 H), 3.28 (s, 3 H), 3.48-3.53 (m, 2 H), 3.80-3.96 (m, 2 H), 3.98-4.18 (m, 1 H), 4.63.. (d, 1 H), 5.04 (d, 1 H), 6.79 (d, 1 H), 7.32-7.53 (m, 5 H), 7.61 (d, 1 H), 8.05 (d, 1 H).
O. (7R,8R,9R)-7,8-Dihydroxy-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imldazo[1l2-ajpyrtdine
To a suspension of 0.46 g (1.43 mmol) (8R,9R)-8-formyloxy-2-methyl-9-phenyl-7H-8,9-dihydro-pyrah-1 7-one[2,3-c]imidazo[1,2-a]pyridine in methanol is added 60 mg (1.50 mmol) sodium borohydride and ', '.[ the mixture is stirred at 25°C for 1 h. The reaction is quenched by adding of saturated aqueous . ,; , ,.'. ammonium chloride solution. Subsequently the mixture is extracted twice with dichloromethane . The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (dichloromethane / methanol: 13 /1) to give -0.31 g (1.05 mmol / 73 %) of the title compound as a colourless solid with a melting point of 252-254°C (acetone).
P. (7S,8R,9R)-7,8-Dlhydroxy-2-fnethyl-9-phonyl-7.8.9.10-tetrahydro-Jmldazo[1.2-h][1.7]naph- ! thyridine
To a of 0°C cooled and stirred solution of hydrobromic acid is added 1.00 g (3.39 mmol) (7R,8R,9RJ- ' 7,8-dihydroxy-2-methyl 9-phenyl-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine. After 0.5 h the * ', reaction is quenched by adding ice and aqueous ammonia solution until the reaction mixture is

transferred to pH 9.8. The precipitated solid is separated, washed with water and dried

in vacuo at

60°C to provide the title compound as an amorphous solid. 'H-NMR (200MHz,[D6] DMSO): 8 = 2.30 (s

3 H), 3.84 (m, 1 H), 4.34 (t, 1 H), 4.48 (dd, 1 H), 6.72 (d, 1 H), 7.25-7.45 (m, 5 H), 7.56 1H).

(d, 1 H), 7.73 (d,

Q. (7R,8R,9R)-8-Hydroxy-7-methoxy-2-methyl-9-phenyl-7.8.9.10-tetrahydro-imldazo[1.2-h][1.7]-; naphthyridine
To a suspension of 0.62 g (2.10 mmol) (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7'8.9.10-
tetrahydro-imidazo[1.2-h][1.7]naphthyridine in dimethoxypropane is added 0.51 g (26.2 mmol) p-
toluenesulphonic acid and acetone (4.0 ml). The mixture is stirred for 6 h at 60°C and 96 h at 25°C
. The reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution.
.;. , . •
Subsequently the mixture is extracted twice with dichloromethane . The combined organic layers are
washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified
by column chromatography (dichloromethane / methanol: 100/3) to give 0.12 g (0.34 ijnmol /16 %) of


the title compound as an amorphous solid. 1H-NMR (200MHz,[D6] DMSO): 5 = 2.29 (s, 3 H), 3.25 (s, i H), 4.05 (q, 1 H), 4.32 (d, 1 H), 4.47 (dd, 1 H), 6.61 (d, 1 H), 7.19-7.46 (m, 5 H), 7.54 (sj 1 H), 7.72 (d, i H).
t ■ »•
R. (7S,8R,9R)-8-Hydroxy-7-methoxy-2-methyl-9-phenyl-7.8.9.10-tetrahydro-lmidazo[1.2-h][1.7]-; naphthyridtne
To a suspension of 0.62 g (2.10 mmol) (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7.8.9:10-

tetrahydro-imidazo[1.2-h][1.7]naphthyridine in dimethbxypropane is added 0.51 g (26.2

mmol) p-.



toluenesulphonic acid and acetone (4.0 ml). The mixture is stirred for 6 h at 60°C and 96 h at 25°C
The reaction is quenched by adding of saturated aqueous'sodium hydrogen carbonate solution. .
|| ■••■■■ . * ■'(■
Subsequently the mixture is extracted twice with dichloromethane . The combined organic layers are
washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified;
by column chromatography (dichloromethane / methanol: 100/3) to give 0.18 g (0.52 mmol / 25 %) of
the title compound as an amorphous solid. 1H-NMR (200MHz,[D6] DMSO): 5 = 2.28 (s, 3 H), 3.30 (s, 1, ,
H), 3.09-4.03 (m, 1 H), 4.06 (d, 1 H), 4.49 (dd, 1 H), 6.67 (d, 1 H), 7.22-7.44 (m, 5 H), fl.54 (d, 1 H)|'
7.69 (d, 1 H).
S. (7R,8R,9R)-3-Hydroxymethyl-8-hydroxy-7- A suspension of 0.60 g (1.10 mmol) of (7R,8R,9R)-10-acetyl-3-hydroxymethyl-7-(2-methoxyethoxy)72-"

methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine and

0.30 g (2.10

mmol) potassium carbonate in aminoethanol is stirred at 90°C for 2 h. The reaction is quenched by

adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is

extracted twice

with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate;-; and evaporated in vacuo. The crude product is purifiednby column chromatography (dichlorometharieV. methanol: 13 /1) to give 0.20 g (0.52 mmol / 47 %) of the title compound as a colourless solid with^a melting point of 180-183°C (diethyl ether).

T. (7R,8R,9R)-3-Hydroxymethyl-8-hydroxy-7- A suspension of 0.17 g (0.30 mmol) (7R,8R,9R)-10-acetyl-3-hydroxymethyl-7-(2-hydroxyethoxy)-2-:
methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine and 0.30 g (2.10
mmol) potassium carbonate in aminoethanol is stirred at 90°C for 2 h. The reaction is quenched by'
II
adding the mixture directly of silica gel for purification by column chromatography (dichloromethane./
II '
methanol: 13 /1) to give 0.02 g (0.06 mmol /19 %) of the title compound as a amorphous solid. H- ,
NMR (200MHz,[D6] DMSO): 8 = 2.29 (s, 1 H), 3.30-3.44 (m, 2 H), 3.46-3.65 (m, 2 H), 4.01 (q; 1 H),'
4.47 (t, 2 H), 4.70 (d, 2 H), 6.79 (d, 1 H), 7.20-7.43' (m.%5 H), 7.63 (d, 1 H).
U. (7R,8R,9R)-2,3-Dimethyl-8-hydroxy-7-(2-hydroxyethoxy)-9-phenyl-7.8.9.10-tetr^hydro-imidazo[1.2-h][1.7]naphthyridine


To a suspension of 2.00 g (6.40 mmol) (7R,8R,9R)-7,8-Dihydroxy-2,3-dimethyl-9-phenyl-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine in 2-methoxyethanol (100 ml) is added 1.26,g (12.8 mmol). sulfuric acid and the mixture is stirred for 3 h at 55°C. Subsequently the reaction is poured out into a oi 0°C cooled aqueous solution of sodium hydroxide (2N). The mixture is extracted with dichloromethane two times. The combined organic layer are washed with water four times, dried over sodium sulfate; and concentrated in vacuo. The crude product is purified by column chromatography (diethyl ether/i 2-; propanol: 10 /1) to give 0.35 g (0.99 mmol /16 %) of the title compound as a colourless solid with a melting point of 107-109°C (diethyl ether).
V. (7R,8R,9R)-3,9-Dlphenyl-8-hydroxy-7-(2-niethoxyethoxy)-2-methyl-7.8.9.10-tetrahydro-imldazo[1.2-h][1.7]naphthyridine
A suspension of 1.14 g (2.05 mmol) of (7R,8R,9R)-10-acetyl-3,9-diphenyl-7-(2-methoxy!ethoxy)-2-
methyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine and 2.28 g (16.5 mmol)
II
potassium carbonate in aminoethanol is stirred at 60°C for 4 h. The reaction is quenched by adding o
., II
saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice with ethyl
acetate. The combined organic layers are washed with brine, dried over sodium sulphate and
evaporated in vacuo. The crude product is purified by column chromatography (diethyl ether / petrol
ether: 7 / 3) to give 0.52 g (1.21 mmol / 60 %) of the title compound as a colourless sohd with a meltinc
point of 190-192°C (diethyl ether).
W. (8R,9R)-8-Hydroxy-2-methoxymethyl-3-methyl-9-phenyl-7,8I9I10-tetrahydro-imidazo[1,2-h][1,7]naphthyridln-7-one
7.1 g of 7-[(2R,3S)-2,3-0-isopropylidene-3-phenylpropan-1-on-1-yl]-2-methoxymethyl-3j-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine are added to 95 ml of 70% sulfuric acid with ice cooling. After addition is complete, the ice bath is removed and stirring is continued for 3 d at ambient temperature..., The reaction mixture is poured onto 200 g of crushed ice and the pH adjusted to ca. 9 by adding 10. %.'
'
sodium hydroxide solution. The aqueous phase is extracted with dichloromethane, the organic phase
washed with water and li-
the residue left crystallized from aceton / diethyletherto give 3.2 g (65 %) of a solid of m.p. 168-173°C

TjJ
'f
X. (7R,8R,9R)-7,8-Dihydroxy-2-methoxymethyl-3-methyl-9-phenyl-7l8,9,10-tetrahydro imldazo[1,2-h][1,7]naphthyridine
6.0 gof (8R,9R)-8-hydroxy-2-methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h]-. [1,7]naphthyridin-7-one are suspended in 40 ml methanol and 0.6 g sodium borohydride are added in * small portions over a period of 30 min. After 1 h at ambient temperature the reaction mixture is poured onto of 60 ml ice water and 2 g ammonium chloride. The organic layer is separated and the aqueous \ phase extracted three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and the solvent removed in vacuo. The residue is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100:1). Crystallization from diethyl .. ether yields 4.7 g (78 %) of the title compound as a light brown solid of m.p. 102-104°G.

Y. (7S.8R.9R)- and (7R,8R,9R)-8-Hydroxy-7-(2-methoxyethoxy)-2-fnethoxymethy|i3-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine
2.0 g of (7R,8R,9R)-7,8-dihydroxy-2-methoxymethyl-3-[pethyl-9-phenyl-7,8,9,10-tetrahyjdro-
imidazo[1,2-h][1,7]naphthyridine are dissolved in 50 ml 2-methoxyethanol and 1 ml of methane sulfonic
acid is slowly added. The reaction is heated at 55 °C for 3 h and subsequently poured onto 80 ml iqe.
water and 100 ml dichloromethane. The organic layer is separated and the aqueous phase extracted
II -
three times with dichloromethane. The combined organic phases are dried over anhydrous sodium^. '
sulfate and the solvent removed in vacuo. The two diastereomers are separated by column
chromatography on silica gel (eluenb.diethyl ether) to)afford 850 mg (36 %) of (7S,8R,9R)":8-hydroxy
(2-methoxyethoxy)-2-methoxymethyl-3-methyl-9-phenyl-7,8,9l10-tetrahydroimidazo[1,2Jh][1,7]naph;
thyridine (28a, m.p. 63-65 °C) and 400 mg (17 %) of (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-
(m.p. 50-53-u;,
methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine

Z. (7S,8R,9R)- and (7R,8R,9R)-7-Ethoxy-8-hydroxy-2-methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydro-Imidazo[1,2-h][1,7]naphthyridlne
The title compound 7S,8R,9R of melting point 145-47° C (diethylether/acetone), and the title compouna 7R,8R,9R of melting point 188-90° C (acetone) are prepared analogously to examDle Yi!
AA.(8R,9R)-8-Hydroxy-2-methyl-9-phenyl-7H-8,9-dihydro-pyran-7-one[2,3-c]imldazo[1,2-a]-pyridine

To a of 0°C cooled suspension of 2.08 g (6.50 mmol) (8R,9R)-8-formyloxy-2-methyl-9-pnenyl-7/-/-8,9' dihydro-pyran-7-one[2,3-c]imidazo[1,2-a]pyridine in methanol (40 ml) is added 0.20 g (1..44 mmol)
potassium carbonate and is stirred for 2 h at this temperature. The reaction is quenched by adding ]pf saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted itwice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by crystallisation from acetone to provide T'50 gV (5.10 mmol / 78 %) of the title compound as a colourless solid with a melting point of 1vf3-175°C (acetone).
BB 7-Acetyl-2,3-dimethyl-8-pivaloylaminolmidazo[1,2-a]pyridine
A vigorously stirred solution of 65.4 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 1:4 I of ' diethyl ether is treated dropwise at -78°C under argon protective gas with 500 ml of a commercially available, 1.5 molar solution of t-butyllithium in n-pentane such that the temperature does not rise

above -70°C. The mixture is then cooled to -90°C in the course of 15 min and 54 ml of

acetyl chloride:

are added dropwise to the dark-red suspension. The mixture is then allowed to warm to -40°C (30 min),
treated with 60 ml of methanol, the contents of the flask are poured onto 1 I of ice water and the"

aqueous phase is extracted three times with 150 ml of methylene chloride each time. The combined
organic phases are washed three times with 100 ml of water each time, dried over sodium sulfate and
the solvent is stripped off in vacuo. The residue is purified on silica gel (eluent: ethyl acetate/petrole'urri
ether = 3/7). 23.2 g of the title compound are obtained.

CC 7-Acetyl-8-amino-2,3-dimethylimldazo[1,2-a]pyridine
A cooled solution of 80.4 g of 7-acetyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridirie in 720 mliof methanol is treated with 496 ml of concentrated sulfuric acid and heated at reflux for 2.5 hours. It isj then poured onto 1 I of ice water, 400 ml of methylene chloride are added and the mixture is adjusted to pH 7 with 10 N sodium hydroxide solution with cooling. After phase separation, the aqueous phase is again extracted twice with 300 ml of methylene chloride each time, the organic phases are collectively washed with 1 I of water, dried over sodium sulfate and the solvent is stripped off in vacuo: The solid residue is purified on silica gel (eluent: ethyl acetate). 22.5 g of the title compound of m.p.= 195-97°C (diethyl ether) are obtained.


DD 8-Amino-2,3-dimethyl-7-[3-(3-thlenyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridinej
A mixture of 5 g of 7-acetyl-8-amino-2,3-dimethylimidazo[1,2-a]pyridine, 2.9 g of thiophene-3-carbox aldehyde, 1.6 g of sodium hydroxide and .100 ml of ethanol is stirred at room temperature for 3 days':,')!:
is then concentrated in vacuo to half the volume, poured'onto 100 ml of saturated aqueous ammonium'
II '
chloride solution and extracted three times with 100 ml of methylene chloride each time. The combined
organic phases are washed with a little water, the solvent is stripped off in vacuo and the residue is
stirred in ethyl ether. After filtering off and drying in vacuo, 4.6 g of the title compound are obtained.i
EE S-Amlno-T-p.S-epoxy-l-oxo-S^S-thienyOpropyll^.S-dimethylimidazoII^-alpyridine
A suspension of 2.6 g of 8-amino-2,3-dimethyl-7-[3-(3-thienyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyrid|ne' in 80 ml of ethanol is treated successively with 5.2 ml of 6 N aqueous sodium hydroxide solution and \[
i
for 48 hours
5 ml of 30% strength aqueous hydrogen peroxide solution, stirred at room temperature
poured onto 200 ml of ice water and adjusted to pH 7-8 with semi saturated aqueous hydrochloric acid. The mixture is then extracted three times with 100 ml of dichloromethane each time, the combined

organic phases are washed once with saturated sodium thiosulfate solution and once with 100 ml of

distilled water, the solvent is stripped off in vacuo and the residue is purified on silica gel (eluent:. methylene chloride/methanol = 100/3). 1.2 g of the title compound of m.p. 186-89°C (diethyl ether) are,,


obtained.
FF 8-Amino-2,3-dimethyl-7-[3-(3-furyl)-1-oxo-2-propenyl]imldazo[1,2-a]pyrldlne
4.6 g of the title compound are obtained by reaction of 5 g of 7-acetyl-8-amino-2,3-dimethyl-imidazo[1,2-a]pyridine with 2.9 g of furan-3-carbaldehyde analogously to Example DD
GG 8-Amino-7-[2,3-epoxy-1 -oxo-3-(3-furyl)propyl]-2,3-dimethyl-7,8,9,10-tetrahydroimidazo-
[1,2-a]pyridine
Analogously to Example EE, 0.7 g of the title compound is obtained by reaction of 2.4 g of 8-amino-
I 2,3-dimethyl-7-[3-(3-furyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine with hydrogen peroxide (30%
strength aqueous).



HH 2-Methyl-6,7-dihydro-5H-imldazo[1,2-a]pyridln-8-one .
60 g (251.8 mmol) of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine (Kaminski et al, J. Med. Chem.'1985, •
' ;:•', ■.'■.■.■.«;, !
28, 876-892) are hydrogenated on Pd-carbon in 400 ml of methanol at a hydrogen pressure of:55'b;ar/||*M
and 70°C. After completion of the hydrogenation, the catalyst is filtered off and the filtrate is :
concentrated. The residue (38 g) is taken up in dichloromethane and the solution is treated in portions! ,
at room temperature with manganese dioxide (109.5 g). The reaction mixture is stirred at room „
temperature for 22 h and then filtered through silica gel. The filtrate is concentrated to a residue and 1
the crystallizate is dried in vacuo at 60°C. 25.13 g (66% of theory) of the title compound are obtained.,
II (8R,9R)-8-(tert-Butyldlmethylsllanyloxy)-2-methyl-9-phenyl-5,6,7,8,9,10-hexahydro-imidazo-
[1,2-h][1,7]naphthyrldin-7-one
19.4 g (128.3 mmol) of 2-methyl-6,7-dihydro-5H-imidazo[1,2-a]pyridin-8-one, 42.07 g (1:30.2 mmol)^|.,v
ethyl (2R,3R)-3-amino-2-(t-butyldimethylsilanyloxy)-3-phenylpropionate and 0.65 g of p-pluenesulfo'nic
acid monohydrate are boiled under reflux in a water separator for 1.5 h in 100 ml of absolute toluene. -
j|
The solution is cooled to room temperature and treated with 100 ml of absolute tetrahydrofuran. 154 ml
of 2M LDA (lithium diisopropylamide) solution (THF) are then added drop wise to the reaction solution; -
which is cooled to -25°C. After the LDA addition, the temperature is allowed to rise to OfC and'the ,
mixture is stirred further at 0°C for 1 h. The reaction solution is washed once at room temperature with' '
200 ml of saturated ammonium chloride solution, once with 50 ml of saturated ammonium chloride!,,
I |l .i\..■,•'..,'-;
solution and once with water. The organic phase is concentrated and chromatographed on silica "gel.i
II ■ -■ ■•.. . r
(petroleum ether/ethyl acetate 2:1). The concentrated product fractions are dried in a high vacuum.!
50.8 g (97% of theory) of the title compound are obtained.
JJ (8R,9R)-8-{tert-Butyldimethylsllar»yloxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydro-lmldazo-
[1,2-h][1,7]naphthyrldln-7-one
50.7 g (123.8 mmol) of (8R,9R)-8-(tert-butyldimethylsilanyloxy)-2-memyl-9-phenyl-5,6,7J,8,9,10- hexahydro-imidazo[1,2-h][1,7]naphthyridin-7-one are treated in portions at 5°C - 10°C with 35.6 g (153.5 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone. After the end of the addition] the reaction mixture is stirred at room temperature for 2 days. The reaction mixture is extracted with 150 mlof
sodium hydroxide solution and the sodium hydroxide solution phase separated off is extracted with!' '"
v II I
150 ml of toluene and the combined toluene phases are washed with 150 ml of water. The organic!; '
phase is concentrated and the residue is dried overnight in a high vacuum. The solid crystallised in'this
way is stirred in diisopropyl ether, filtered off with suction and dried in vacuo at 50°C. 10.1 g (20% of ..
theory) of the title compound are obtained.
KK (7R,8Rf9R)-10-Acetyl-3,9-diphenyl-7-(2-methoxyethoxy)-2-methyl-8-plvaloyloxy-7.8.9.10-
.-
tetrahydro-Jmidazo[1.2-h][1.7]naphthyridlne
2.61 g (4.67 mmol) (7R,8R,9R)-10-acetyl-3-bromo-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7] naphthyridine, 0.63 g (5.14 mmol) phenylboronic , '. acid, 0.89 g (15.4 mmol) KF (spray-dried), 0.14 g (0.15 mmol) Pd2(dba)3, 0.07 g (0.36 mmol /10 wt.%,!


solution in hexane)P(f-Bu)3 and THF (30 ml) are added to a Schlenk tube under argon. 'Afterwards the[ Schlenk tube is evacuated and refilled with argon in a freeze-pump-thaw cycles technique three times'.'

The reaction mixture is stirred under argon for 2 d at 25°C. Subsequently the reaction is diluted by ,s . (
|| • ■ ■ i: »■
/70%)of.the» ;;• 20-(s19.-H):[-'S-7
adding of ethyl acetate and then filtrated through silica gel. The concentrated crude product is purified i
by column chromatography (diethyl ether / petrol ether: 6 / 4) to give 1.80 g (3.24 mmol
title compound as an amorphous colourless solid. 1H-NMR (200MHz,[D6] DMSO): 5 = 1
^
2.20 (s, 3 H), 2.43 (s, 3 H), 3.30 (s, 3 H), 3.40-3.57 (rpflH), 3.88 (t, 2 H), 4.64 (d, 1 H), 5.35 (t,'1 '
5.83 (d, 1 H), 7.00 (d, 1 H), 7.10-7.30 (m, 5 H), 7.41-7.68 (m, 5 H),'8.24 (d, 1 H).


LL (7R,8R,9R)-10-Acetyl-3-bromo-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-plvaloyloxy-7.8.9.10-tetrahydro-imldazo[1.2-h][1.7]naphthyridine
To a of 0°C cooled solution of 2.20 g (4.60 mmol) (7R,8R,9R)-10-acetyl-7-(2-methoxyethoxy)-2-methyl-j
9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine in ethanol (20 ml) is added
ll
0.84 g (4.60 mmol) NBS and the mixture is stirred for 1 h. Afterwards the reaction is quenched by ,
adding of saturated aqueous sodium hydrogen carbonate solution and it is extracted twice with ",'
dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and
l| • K ■'
evaporated in vacuo. The crude product is purified by crystallisation (cyclohexane) to give 1.60 g (2.86
mmol / 62 %) of the title compound as a colourless solid with a melting point of 166-167°C
(cyclohexane). '
MM(7R,8R,9R)-10-Acetyl-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-
tetrahydro-imidazo[1.2-h][1.7]naphthyridlne ,', ■
To a of-30°C cooled solution of 7.40 g (17.6 mmol) (7R,8R,9R)-10-acetyl-7-hydroxy-2 methyl-9-
i > m ■ I
phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine in dichloromethane (25ml)
.-..'■• ., . , ||
and N-methyl-pyrrolidinone (25 ml) is.added 4.00 g (19.3 mmol) methoxyethyl triflate and 1.40:g"(35.2
mmol) sodium hydride and it is stirred for further 2 h at this temperature. The reaction is quenched by * ^
adding of saturated aqueous ammonium chloride solution. Subsequently the mixture is extracted twice J
with dichloromethane . The combined organic layers are washed with brine, dried over sodium , .,"
sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ethyl , '.i ..
acetate / cyclohexane / triethylamine: 5 / 4 /1) to give 7.50 g (15.63 mmol / 89 %) of the title compound
as a yellow amorphous solid. 1H-NMR (200MHz,[D6] DMSO): 6 = 1.19 (s, 9 H), 2.15 (sj 3 H), 2.38 (s, 3 .,
I -i ■> •■
H), 3.27 (s, 3 H), 3.45-3.57 (m, 2 H), 3.83-3.93 (m, 2 H), 4.60 (d, 1 H), 5.31 (t, 1 H), 5.79 (d, 1 H), 6.94

(s, 1 H), 7.20 (s, 5 H), 7.74 (s, 1 H), 8.43 (d, 1 H).


NN (7R,8R,9R)-10-Acetyl-3-chloro-7- To a of 0°C cooled solution of 1.00 g (2.10 mmol) (7R,8R,9R)-10-acetyl-7-(2-methoxy 9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine in ethanol 0.28 g (2.10 mmol) NCS and the mixture is stirred for 2 h. Afterwards the reaction is c adding of saturated aqueous sodium hydrogen carbonate solution and is extracted tw dichloromethane . The combined organic layers are washed with brine, dried over soc evaporated in vacuo. The crude product is purified by column chromatography (ethyl






OO(7R,8R,9R)-10-Acetyl-3-bromo-8-{2-methoxyethQxy)-2-methyl-9-phenyl-7-pivi 7.8.9.10-tetrahydro-lmidazo[1.2-h][1.7]naphthyridine
To a of 0°C cooled solution of 0.40 g'(0.83 mmol) (7R,'8R,9R)-10-acetyl-8-(2-methoxy 9-phenyl-7-pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridine in ethanol 0.15 g (0.83 mmol) NBS and the mixture is stirred for 1 h. Afterwards the reaction is q adding of saturated aqueous sodium hydrogen carbonate solution and it is extracted t dichloromethane . The combined organic layers are washed with brine, dried over soc evaporated in vacuo. The crude product is purified by column chromatography (ether
/ 5) to provide 0.30 g (0.53 mmol / 65 %) of the title compound as an amorphous solid (200MHz,[D6] DMSO): 8 = 0.96 (s, 9 H), 2.09 (s, 3 H), 2.42 (s, 3 H), 3.23 (s, 3 H), 3.4





3.69-3.98 (m, 2 H), 4.23 (t, 1 H), 5.75 (d, 1 H), 6.02 (s, 1 H), 6.80 (d, 1 H), 7.16 (s, 5 I
PP (7R,8R,9R)-10-Acetyl-7-hydroxy-2-methyl-8-pivaloyloxy-9-phenyl-7.8.9.10-tet lmidazo[1.2-h][1.7]naphthyridlne
To a of 0°C cooled suspension of 5.00 g (11.9 mmol) (8R,9R)-10-acetyl-2-methyl-9-pr pivaloyloxy-7.8.9.10-tetrahydro-imidazo[1.2-h][1.7]naphthyridin-7-one in 2-propanol is (23:80 mmol) sodium cyanoborohydride, methylorange (0.5 ml / ethanolic solution) an hydrochloric acid until the solution colour is lasting red.This mixture is stirred for furthi Subsequently the reaction is quenched by adding of saturated aqueous sodium hydroi solution and is extracted twice with dichloromethane. The combined organic layers an brine, dried over sodium sulphate and evaporated in vacuo to provide 4.90 g (11.6 mn title compound as an amorphous solid. 1H-NMR (200MHz,[D6] DMSO): 8 = 1.21 (s, 9 I 2.37 (s, 1 H), 4.72 (t, 1.H), 5.04-5.10 (m, 1 H), 5.66 (d, 1 H), 7.00 (d, 1 H), 7.17 (s, 5 \ 8.45 (d, 1 H).
QQ(8R,9R)-10-Acetyl-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydro-imlda; naphthyridin-7-one
To a of 0°C cooled solution of 7.00 g (18.5 mmol) (8R,9R)-2-methyl-9-phenyl-8-pivalo; tetrahydro-imidazo[1.2-h][1.7]naphthyridin-7-one in toluene (70 ml) is added 4.10 ml (J


chloride and 7.70 ml (55.5 mmol) triethylamine and the^eaction mixture is stirred for 1
Afterwards further 4.10 ml (55.5 mmol) acetyl chloride and 7.70 ml (55.5 mmol) triethy
• ■•••: ' . . ■*••■ ■•!'■ •■■ -"'
to the reaction mixture and it is warmed up to 25°C and stirred at this temperature for Subsequently the reaction is quenched by adding of saturated aqueous ammonium ch This mixture is extracted twice with dichloromethane. The combined organic layers an brine, dried over sodium sulphate and evaporated in vacuo. The crude product is crys
diethyl ether to provide 5.4 g (12.7 mmol / 70 %) of the title compound as a colourles; melting point of 168-169°C (diethyl ether).







RR 2-Methyl-7-[(2R,3S)-2,3-0,0-lsopropylidene-3-phenylpropan-1-on-1-yl]-6>7-di lmldazo-8-imidazo[1,2-a]pyr1dln-8-one
To a suspension of 5.00 g (33.3 mmol) 2-methyl-6,7-dihydro-5/-/-imidazo[1,2-a]pyridin-(100 ml) is added dropwise at 10°C 35.0 ml MM in THF / 35.0 mmol) NaHDMS and 4. mmol) triethylamine. The reaction mixture is stirred for 1 h. Subsequently the mixture i -78°C and 8.42 g (35.0 mmol) (2R,3S)-2,3-0,0-isoprpylidene-3-phenyl-propionyl chloi slowly. The reaction is stirred for 2 h between -70 to - 60°C and warmed up to 25°C ai again. The reaction is quenched by adding of saturated aqueous ammonium chloride.
-si
extracted twice with ethyl acetate. The combined organic layers are washed with brine sodium sulphate and evaporated in vacuo. The crude product is filtrated over silica ge fractions are concentrated in vacuo and crystallised from diethyl ether to provide 6.10 51 %) of the title compound as a colourless solid with a melting point of 126°C (diethyl



SS 2-Methyl-7-[(2R,3S)-2,3-0,0-lsopropylidene-3-phenylpropan-1-on-1-yl]lmida2 a]pyrldin-8-ol
A mixture of 20.5 g (57.8 mmol) 2-methyl-7-[(2R,3S)-2,3-0,0-isopropylidene-3-phenyl yl]-6,7-dihydro-5/-/-imidazo-8-imidazo[1,2-a]pyridin-8-one and 14.2 g (57.8 mmol) chlor 200 ml) is stirred for 40 h at 50°C. Afterwards the solvent is evaporated in vacuo and I is purified by column chromatography (toluene / dioxane / acetic acid: 8/1/1). The pi are concentrated in vacuo and crystallised from 2-propanol to give the provided comp TT 2-Methoxycarbonyl-3-methyl-8-pIvaloylamlnolmidazo[1,2-a]pyridine
To a stirred solution of 30 g of 2-amino-3-pivaloylaminopyridine in 300 ml of dry tetrafy added dropwise under argon 40 g of 3-bromo-2-oxobutanoic acid methylester. The brc stirred at ambient temperature for 3 d. The resulting suspension is poured onto a mixti and ethyl acetate and the mixture is neutralised by adding 10'M sodium hydroxide soli organic phase is separated and the aqueous layer extracted two times with ethyl aceti combined organic phases are washed with water and dried over anhydrous sodium su solvent is removed in vacuo and the blue coloured residue purified by column chromat gel to yield 35 g (78 %) of a light brown solid (m.p. 132 °C).


UU 2-Hydroxymethyl-3-methyl-8-pivaloylamlnolmldazo[1,2-a]pyridlne
To a solution of 36.6 g of 2-methoxycarbonyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]p of dry tetrahydrofuran are added 5.5 g of lithium aluminium hydride at ambient tempei period of 1 h. The reaction mixture is then carefully hydrolysed with 15 ml water and 1 sodium hydroxide solution. The precipitate is removed, by filtration and washed thorou tetrahydrofuran. The filtrate is washed with 100 ml saturated ammonium chloride solu
concentrated in vacuo. The residue is dissolved in 400 ml tetrahydrofuran / toluene 1: solvent distilled off at 80 "C. The precipitate is filtered off. and dried in vacuo to yield 2 the title compound (m.p. 186-187 °C).



W 2-Chloromethyl-3-methyl-8-pivaloylaminolmidazo[1,2-a]pyridlne
To a stirred suspension of 13 g of 2-hydroxymethyl-3-methyl-8-pivaloylaminoimidazo[' 500 ml of dry dichloromethane is added dropwise a solution of 6.5 g thionyl chloride ir dichloromethane at 0-5 °C to give a clear yellow solution. After 2 h the reaction mixtur by adding 200 ml saturated sodium bicarbonate solution under cooling. The resulting transferred to a separatory funnel and shaken vigorously. The organic layer is separa water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo to g of the title compound (m.p. 168 °C).
WW 2-Methoxymethyl-3-methyl-8-pivaloylaminbimidazo[1,2-a]pyridlne
A solution of 12.8 g 2-chloromethyl-3-methyl-8-pivaloylam"inoimidazo[1,2-a]pyridine in methanol is refluxed for 5 h. The reaction mixture is concentrated in vacuo to half the
addition of 200 ml of saturated sodium bicarbonate solution, the mixture is extracted v The organic phase is washed with water and 'dried over anhydrous sodium sulfate. R« solvent in vacuo yields 12.5 g (99 %) of the title compound (m.p. 104 °C).
XX 7-[(2R,3S)-2,3-0-lsopropylidene-3-phenylpropan-1-on-1-yl]-2-methoxymethy pivaloylaminoimidazo[1,2-a]pyridine
60 ml of fe/f-butyllithium solution (1.5 M in r?-pentane) are added dropwise to 50 ml of diethyl ether at -90 °C with exclusion of moisture and under an argon atmosphere. A s of 2-methoxymethyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 220 ml of anhy

residue is coevaporated twice with acetonitrile and dichloromethane and dried in vacut (45 %) of the title compound as a yellow solid (m.p. 50-52 °C).





YY (7R,8R,9R)-2,3-Dimethyl-7-(2-methoxyethoxy)-9-prienyl-8-(5-bromo-valerylox^ tetrahydro-imldazo[1,2-h][1>7]naphthyridine :




10.0 g (55.8 mmol) of 5-bromovaleric acid and 9.13 g (56.3 mmol) of N,N'-carbonyldiirr
stirred in THF for 3h at 40°C. Subsequently 10.0 g (27.'2 mmol) of (7R,8R,9R)-2,3-dim ZZ (7R,8R,9R)-2,3-Dimethyl-7-(2-methoxyethoxy)-9-phenyl-8-(4-bromo-butyrylo)c tetrahydro-Jmldazo[1,2-h][1,7]naphthyridlne
10.0 g (56.0 mmol) of 4-bromobutyric acid and 9.70 g (56.0 mmol) of N,N'-carbonyldiirt stirred in THF for 3h at 40°C. Subsequently 10.0 g (27.2 mmol) of (7R,8R,9R)-2,3-dimi 7-(2-methoxyethoxy)-9-phenyl -7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine an (56.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are added at 25°C and the mixture further 2 h. The reaction is quenched by adding of saturated aqueous hydrogen carbor The mixture is extracted with dichloromethane three times and the combined organic I; concentrated in vacuo. The crude product is purified by chromatography (dichlorometh 100 / 3 to 13 /1) to provide the title compound as a colourless solid (2.15 g / 4.16 mm
melting point of 114.4°C (diisopropyl ether).



AAA. (7R,8R,9R)-2,3-Dlmethyl-7-(2-methoxyethoxy)-9-phenyl-8-(5-bromo-valerylc
dihydro-pyrano[2,3-c]imdazo[1,2-a]pyridine i 3.33 g (18.2 mmol) 5-bromovaleric acid and 3.04 g (18.2 mmol) N,N'-carbonyldiimidaz


AAB. (7R,8R,9R)-2,3-Dlmethyl-7-(2-mothoxyethoxy)-9-phenyl-8-(6-iodo-2-oxa-cap 7,8,9,10-tetrahydro-lmldcizo[1l2-h][1I7]naphthyridine
To a solution of 2.00 g (4.00 mmol) (7R,8R,9R)-2,3-dimethyl-7-(2-memoxyethox chloro-2-oxa-capryloxy)-7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine in aceton g (37.90 mmol) sodium iodide and the mixture is stirred for 56 d at 25°C. Afterwarc
concentrated in vacuo and purified by chromatography (dichloromethane / methanol: the title compound (1.95 g / 3.28 mmol / 82 %) as a hygroscopic foam.
MS (MeOH / H20 / HCOOH : 80/20/0.1 ,+,ESI): m/z (%) = 594 (55) [M+H].
AAC. (7R,8R,9R)-2,3-Dimethyl-7-(2-methoxyethoxy)-9-phenyl-8-(6-chloro-2-oxa-c; 7,8,9,10-tetrahydro-imldazo[1,2-h][1,7]naphthyrldine
To a solution of 5.00 g (13.6 mmol) (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxye' 7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine, 5.8 ml (42.00 mmol) triethylarr (1.40 mmol) dimethylpyridine in dichloromethane (50 ml) is added 3.82 ml (27.2 mmc chloroformate and the reaction is stirred for 18 h at,25°C. Subsequently the mixture and extracted with dichloromethane twice. The combined organic layers are concentra
compound (3.30 g / 6.57 mmol / 48 %) as a colourless solid with a melting point c
the crude product is purified by chromatography (ethyl acetate / petrol ether: 1/1) compound (3.30 g / i acetate / petrol ether)







AAD. (7R,8R,9R)-2,3-Dimethyl-7-(2-methoxyethoxy)-9-phenyl-8-(4-bromomethyl-b 7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine
To a solution of 5.00 g (13.6 mmol) (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxye1 7,8,9,10-tetrahydro-imidazo[1,2-h][1,7]naphthyridine, 4.46 ml (32.00 mmol) triethylan





(1.40 mmol) dimethylpyridine in dichloromethane (50 ml) is added at -10°C 4.60 g



bromomethylbenzoyl bromide and the reaction is stirred for 1 h at -5°C. Subsequent

poured on ice and extracted with dichloromethane twice. The combined organic layers



saturated NaHC03 solution, are concentrated in vacuo and the crude producl chromatography (dichloromethane / methanol: 100/3) to give the title compound (3.0( 39 %) as a colourless solid.
'H-NMR (200MHz, [D6] DMSO): 5 = 2.34 (d, 6H), 3.07-3.30 (m, 5 H), 3.36-3.46 (m,1 Hj H), 4.92 (m, 1 H), 5.68 (t, 1 H), 6.49 (d, 1 H), 7.19-7.29 (m; 3 H), 7.80-7.87 (m, 2 H).


Commercial utility

The compounds of the formula 1 and their salts have,valuable pharmacological propei them commercially utilisable. In particular, they can be characterised on one hand as i antagonists (APAs) with less side effects than knownj APAs with comparable structure hand, they can be characterised as compounds with marked activity against Helicoba* less side effects than known compounds with such activity- Additionally, the compoun can be characterised - on account of their NO (nitric oxide) releasing activity - as comi antibacterial activity, in which the effect against Helicobacter bacteria is synergistically account of the gastric acid inhibiting activity of these compounds.
The compounds of formula 1 exhibit a marked inhibition of gastric secretion and an ex and intestinal protective action in warm-blooded animals, in particular humans. The cc according to the invention are distinguished here by a high selectivity of action, an adv duration of action, a particularly good enteral activity, the absence of significant side e therapeutic breadth. In addition, the excellent activity of compounds of the formula 1ai
against Helicobacter bacteria allows their use in human medicine as active compound treatment of illnesses which are based on Helicobacter«-bacteria.
"Gastric and intestinal protection" in this connection is understood as meaning the pre treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory dis lesions (such as, for example, gastric ulcer, peptic ulcerj, including peptic ulcer bleedin ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be example, by microorganisms (e.g. Helicobacter pylori),' bacterial toxins, medicaments i antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemica gastric acid or stress situations. "Gastric and intestinal protection" is understood to inc to general knowledge, gastroesophageal reflux disease (GERD), the symptoms of whi are not limited to, heartburn and/or acid regurgitation.
In their excellent properties, the compounds according to the invention surprisingly pre superior to the compounds known from the prior art in various models in which the ant the antisecretory properties are determined. On account of these properties, the comp formula 1 and their pharmacologically tolerable salts are outstandingly suitable for use veterinary medicine, where they are used, in particular, for the treatment and/or proph disorders of the stomach and/or intestine.





The invention therefore further relates to a process for the treatment of mammals, in p who are suffering from illnesses which are based on hyperacidity of the stomach and/c of Helicobacter bacteria. The process comprises administering to the sick individual a


efficacious and pharmacologically tolerable amount of one or more compounds of the I their pharmacologically tolerable salts.

The invention moreover relates to the compounds of the formula 1 and their pharmaco tolerable salts for use in the treatment of illnesses which are based on hyperacidity of 1 and/or the presence of Helicobacter bacteria.
The invention also comprises the use of compounds of the formula 1 and their pharma tolerable salts in the production of medicaments which are employed for the control of





which are based on hyperacidity of the stomach and/or the presence of Helicobacter b
The invention further relates to medicaments for the control of Helicobacter bacteria, w or more compounds of the general formula 1 and/or theirpharmacologically tolerable s





Of the Helicobacter strains against which the compounds of the formula 1 prove active Helicobacter pylori may be mentioned in particular.



A further subject of the invention are therefore the compounds according to the invent! treatment and/or prophylaxis of the abovementioned illnesses.
The invention likewise comprises the use of the compounds according to the invention production of medicaments which are employed for the treatment and/or prophylaxis 01
abovementioned illnesses.
'V
The invention furthermore comprises the use of the compounds according to the inven : treatment and/or prophylaxis of the abovementioned illnesses.
A further subject of the invention are medicaments which contain one or more compou
formula 1 and/or their pharmacologically tolerable salts.

The medicaments are prepared by processes which are known per se and familiar to in the art. As medicaments, the pharmacologically active compounds (= active compo to the invention are employed either as such, or preferably in combination with suitabh excipients or vehicles in the form of tablets, coated tablets, capsules, suppositories, p TTS), emulsions, suspensions or solutions, the active compound content advantages between 0.1 and 95% and it being possible by the appropriate choice of the excipients obtain a pharmaceutical administration form exactly suited to the active compound am



desired onset of action and/or to the duration of action (e.g. a delayed-release form or


The person skilled in the art is familiar on the basis .'of, his/her expert knowledge with e vehicles which are suitable for the desired pharmaceutical formulations. In addition to formers, suppository bases, tablet excipients and other active compound carriers, it is for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, presei solubilizers, colorants or in particular permeation promoters and complexing agents (e cyclodextrins).
The active compounds can be administered orally, parenterally or percutaneously.
In general, it has proven advantageous in human medicine to administer the active coi case of oral administration in a daily dose of approximately 0.01 to approximately 20, p 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of a number to 4, individual doses to achieve the desired result. In the case of parenteral treatment particular in the case of intravenous administration of the active compounds) as a rule be used. Any person skilled in the art can easily fix the optimum dose and manner of i the active compounds necessary in each case on the basis of his/her expert knowledc
If the compounds according to the invention and/or their Walts are to be employed for t the abovementioned illnesses, the pharmaceutical preparations can also contain one c pharmacologically active constituents of other pharmaceutical groups. Examples whicl mentioned are: tranquillizers (for example from the group consisting of the benzodiaze diazepam), spasmolytics (e.g. bietamiverine or camylofin), anticholinergics (e.g. oxyph phencarbamide), local anesthetics (e.g. tetracaine orprocaine), and optionally also en; or amino acids.

In particular to be emphasized in this connection is the combination of the compounds invention with pharmaceuticals which inhibit acid secretion, such as, for example, H2 b cimetidine, ranitidine) or H+/K+ ATPase inhibitors (e.g. omeprazole, lansoprazole, rab example, mezlocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxime, imipenem amikacin, erythromycin, ciprofloxacin, metronidazole,.clarithromycin, azithromycin and thereof (e.g. clarithromycin + metronidazole).



In view of their excellent gastric and intestinal protection action, the compounds of forr

for a free or fixed combination with those medicaments (e.g. certain antiinflammatories





antirheumatics, such as NSAIDs), which are known to Have a certain ulcerogenic potency. In addition the compounds of formula 1 are suited for a free or fixed combination with motility-modifying drugs.".

Pharmacology

been provi
The excellent gastric protective action and the gastric secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models.' compounds according to the invention investigated in* the model mentioned below have with numbers which correspond to the numbers of these compounds in the examples.

Testing of the secretion-Inhibiting action on the perfused rat stomach




In Table A below, the influence of the compounds according to the invention after intravenous ;'-; administration is shown on the acid secre'tionjstimulated by pentagastrin of the perfused rat.storna vivo.
Table A


No. Dose
(umol/kg)
l.d. Inhibition of acid secretion (%)
1 1 100
2 1 100
3 1 100
4 1 100






The abdomen of anesthetized rats (CD rats, female,' 200-250 g; 1.5 g/kg i.m. uretl after tracheotomy by means of a median upper abdominal incision and a PVC catl transorally in the esophagus and a further catheter via the pylorus such that the ei projected into the gastric lumen. The catheter leading from the pylorus led outwarc opening in the right abdominal wall.
After thorough rinsing (about 50-100 ml), warm physiological NaCI solution at 37°( passed through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glass >• electrode EA 147; = 5 mm, Metrohm), and, by titration with a freshly prepared 0.01 N.NaOH solution} to pH 7 (Dosimat 665 Metrohm), the secreted HCI were determined in the effluent in each case collected at an interval of 15 minutes.

The gastric secretion was stimulated by continuous perfusion of 1 ug/kg (= 1.65 mUh) pentagastrin (left femoral vein) about 30 min after the e~nd of the operation (i.e. after The body temperature of the animals was kept at a constant 37.8-38°C by infrared irr pads (automatic, stepless control by means of rectal temperature sensors).
&l

We Claim:
1. Compounds of the formula 1

K3a pi
(1*) Arom
in which
Rl is methyl
R2 is hydrogen, methyl, or chloro,
R3a is hydrogen,
R3b is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, methoxy,
ethoxy, hydroxyethoxy, methoxyethoxy or methoxyethoxyethoxy,
R5a is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-0-N02, -0-C(0)-0-(CH2)x-0-N02, -0-C(0)-C6H4-CH2-0-
N02 or -0-C2H4-(CH2)x-0-N02,
in which
x is an integer from 2 to 4,
R5b is hydrogen,
Arom is a phenyl radical and
X is O (oxygen) or NH,
and their salts.
2. Compounds according to claim 1, in which R53 is -0-C(0)-CH2-(CH2)x-0!:N02, -O-C(0)0-(CH2)x-0-N02 or -0-C(0)-C6H4-CH2-0-NC>2.
3. Compounds according to claim 1, in which Rl is methyl,
R2 is hydrogen, methyl, or chloro, R3a is hydrogen, R3b is hydrogen,
55

one of the substituents R4a and R4b is hydrogen and the other is methoxyethbxy, R5a
is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-0-N02 or -0-C(0)-0-(CH2)JrO-N02,
in which
x is an integer from 2 to 4,
R5b is hydrogen,
Arom is a phenyl radical and
X is O (oxygen) or NH,
and their salts.
4. Compounds according to claim 1, in which
Rl is l-4C-alkyl,
R2 is l-4C-alkyl,
R3a is hydrogen,
R3b is hydrogen,
one of the substituents R4a and R4b is hydrogen and the other is l^C-alkqxy-l^C-
alkoxy,
R5a is the radical R53,
where
R53 is -0-C(0)-CH2-(CH2)x-0-N02, -0-C(0)-C6H4-CH2-0-N02 or -0-C(0)-0-(CH2)x-
O-NO2,
in which
x is an integer from 2 to 4, ,
R5b is hydrogen,
Arom is a phenyl radical and
X is O (oxygen) or NH,
and their salts.
5. Compounds according to claim 1, in which
Rl is l-4C-alkyl,
R2 is l-4C-alkyl, R3a is hydrogen, R3b is hydrogen,
56

one of the substituents R4a and R4b is hydrogen and the other is l-4C-alkoxy-l-4C-
alkoxy, R5a is the radical R53, ,
where
R53 is -0-C(0)-CH2-(CH2)x-0-N02 or -0-C(0)-0-(CH2)x-0-N02/
in which
x is an integer from 2 to 4,
R5b is hydrogen,
Arom is a phenyl radical and
X is O (oxygen) or NH,
and their salts.
6. A medicament comprising a compound as claimed in claim 1 and/ or a pharmacologically tolerable salt thereof together with customary pharmaceutical excipients and/or vehicles, whereby the active compound content is between 0.1 and
95%.

Documents:

511-mumnp-2004-abstract(27-8-2007).pdf

511-mumnp-2004-cancelled pages(27-8-2007).pdf

511-mumnp-2004-claims(granted)-(27-8-2007).pdf

511-mumnp-2004-claims(granted)-(27-8-2007).pdf.doc

511-mumnp-2004-correspondence(27-8-2007).pdf

511-mumnp-2004-correspondence(ipo)-(28-12-2006).pdf

511-mumnp-2004-form 18(3-2-2006).pdf

511-mumnp-2004-form 1a(15-9-2007).pdf

511-mumnp-2004-form 2(granted)-(27-8-2007).pdf

511-mumnp-2004-form 3(15-9-2004).pdf

511-mumnp-2004-form 5(15-9-2004).pdf

511-mumnp-2004-form-pct-ipea-416(27-8-2007).pdf

511-mumnp-2004-form-pct-isa-210(15-9-2004).pdf

511-mumnp-2004-form2(granted)-(27-8-2007).doc

511-mumnp-2004-power of attorney(15-9-2004).pdf


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Patent Number 211395
Indian Patent Application Number 511/MUMNP/2004
PG Journal Number 43/2008
Publication Date 24-Oct-2008
Grant Date 26-Oct-2007
Date of Filing 15-Sep-2004
Name of Patentee ALTANA PHARMA AG
Applicant Address BYK-GULDEN-STRASSE 2, D-78467 KONSTANZ, DEUTSCHLAND, GERMANY.
Inventors:
# Inventor's Name Inventor's Address
1 DR. PETER JAN ZIMMERMANN ZUM LERCHENTAL 43/1, 78315 RADOLFZELL, GERMANY.
2 DR. WOLFGANG-ALEXANDER SIMON SCHUBERTSTRASSE 17, 78464 KONSTANZ, GERMANY.
3 DR. JORG SENN-BILFINGER SANTISSTRASSE 7, 78464 KONSTANZ, GERMANY.
4 DR. STEFAN POSTIUS AUSTRASSE 4B, 78467 KONSTANZ, GERMANY.
5 DR. GUIDO HANAUER SANTISBLICK 18, 78465 KONSTANZ, GERMANY.
6 DR. WOLFGANG KROMER HINTERHAUSERSTR 5, 78464 KONSTANZ, GERMANY.
7 DR. WILM BUHR ZUM KIRCHENWALD 7, 78465 KONSTANZ, GERMANY.
PCT International Classification Number C07D 471/14
PCT International Application Number PCT/EP03/04134
PCT International Filing date 2003-04-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 02009104.7 2002-04-24 EPO