Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-18
2003-08-19
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C548S304400, C548S306400
Reexamination Certificate
active
06608049
ABSTRACT:
The invention relates to new indazole derivatives, processes for their preparation, and their use in medicaments.
EP-A-580 550 describes oxamic acid derivatives which have cholesterol-lowering properties in mammals. The pharmacological characteristic emphasized is the reduction of plasma cholesterol, in particular of LDL cholesterol. Cholesterol-lowering actions are also described in EP-A-188 351 for certain diphenyl ethers having thyroid hormone-like actions, which differ clearly in their chemical structure from the compounds according to the invention.
Indazoles which are connected to a substituted phenyl ring in the 5 position via a bridge member have been disclosed (JP-A-08022109, JP-A-59098060). No thyroid hormone-like properties are described for these 5-substituted indazoles.
An object of the invention is the provision of novel compounds having improved actions, in particular pharmaceutical actions.
It has now been found that compounds of the general formula (I),
in which
Z represents O, S, CH
2
, CHF or CF
2
,
R
1
and R
2
are identical or different and represent hydrogen, halogen, (C
1
-C
6
)-alkyl, CF
3
, CHF
2
, CH
2
, CH
2
F, vinyl or (C
3
-C
7
)-cycloalkyl, where at least one of the two substituents is not equal to hydrogen and is in the ortho position relative to the bridge bond,
R
3
represents a head group having an optionally derivatized carboxyl radical, preferably a group of the formula
A-(CH
2
)
n
—(CO)
m
—R
8
,
in which
A represents CH
2
, O, S, CO or NR
9
, in which R
9
denotes hydrogen, (C
1
-C
6
)-alkyl or (C
3
-C
8
)-cycloalkyl or represents the group —(CH
2
)
n
—(CO)
m
—O—(C
1
-C
4
)-alkyl,
n represents the numbers 0 to 3,
m represents the number 0, 1 or 2,
R
8
represents hydrogen, hydroxyl, OR
10
, NR
11
R
12
, (C
1
-C
8
)-alkyl, (C
3
-C
8
)-cycloalkyl, (C
6
-C
10
)-aryl, or a saturated, unsaturated or aromatic 5- to 10-membered heterocycle having up to four identical or different heteroatoms from the series S, O and/or N, where the abovementioned radicals are optionally substituted by one, two or three, identical or different substituents from the group halogen, hydroxyl, cyano, nitro, amino, CF
3
, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
3
-C
8
)-cycloalkyl, —OCO—R
13
, —CO—O—R
14
, —CO—NR
15
R
16
, —NHCOR
17
or NHCOOR
17
, where R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
and R
17
are identical or different and in each case represent hydrogen, phenyl, benzyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or (C
3
-C
8
)-cycloalkyl, which for their part are optionally mono- or polysubstituted by halogen, hydroxyl, amino, (C
1
-C
4
)-alkoxy, —CO—O(C
1
-C
4
)-alkyl, —NH—CO—O(C
1
-C
4
)-alkyl, —O—CO—(C
1
-C
4
)-alkyl, a heterocycle or optionally halogen- or hydroxyl-substituted phenyl,
R
4
and R
5
are identical or different and in each case represent hydrogen, hydroxyl, halogen, cyano, nitro, (C
1
-C
4
)-alkyl, or the radical of the formula NR
18
R
19
, where R
18
and R
19
have the meaning indicated for R
10
and can be identical to or different from this substituent,
R
6
represents halogen or has the meaning indicated for R
8
and is identical to or different from this substituent or represents the radical
in which
R
20
and R
21
together represent oxygen, or are each identical or different and represent hydrogen, halogen, hydroxy, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or the radical —NR
15
R
16
and
R
22
has the meaning of R
8
and is identical to or different from this,
R
7
represents hydrogen or an acyl group which can be cleaved under physiological conditions with formation of an NH function, preferably hydrogen or acetyl,
and their salts,
preferably the compounds which are mono- or di-ortho-substituted in the phenyl moiety and have a substituent in the 3 position in the indazole ring,
show a pharmacological action and can be used as medicaments or for the production of pharmaceutical formulations.
Heterocycles which may preferably be mentioned in the definition of R
8
or of R
6
are:
a 5- to 8-membered saturated, partly unsaturated or aromatic optionally benzo-fused heterocycle having up to 4 heteroatoms from the series S, N and/or O, i.e. a heterocycle which can contain one or more double bonds and which is linked via a ring carbon atom or a ring nitrogen atom. Examples which may be mentioned are: tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl, piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl, piperazin-1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl, furan-2-yl, furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrimidinonyl, pyridazinonyl.
Those preferred from this list are: pyridyl, pyrimidyl, pyridazinyl, pyrimidinonyl, pyridazinonyl and thiophenyl.
Derivatized carboxyl radicals in the definition of the substituent R
3
preferably denote groups which can be broken down in the sense of a prodrug to the carboxylic acid or its salts, such as halides, anhydrides, esters or amides.
Alkyl in the context of the invention represents a straight-train or branched alkyl radical preferably having 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-, i-, s- or t-butyl, n-pentyl and n-hexyl.
Aryl in the context of the invention represents an aromatic radical preferably having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
Cycloalkyl in the context of the invention represents a cycloalkyl group preferably having 3 to 8, 3 to 7 or 3 to 6 carbon atoms. The following may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Alkoxy in the context of the invention preferably represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred. The following may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine is preferred.
Depending on the substitution pattern, the compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be converted into the stereoisomerically uniform constituents in a known manner.
Certain compounds can furthermore be present in tautomeric forms. This is known to the person skilled in the art, and compounds of this type are likewise encompassed by the scope of the invention.
The compounds according to the invention can also be present as salts. Physiologically acceptable salts are preferred in the context of the invention.
Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preferred salts are those with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts can likewise be salts of the compounds according to the invention with bases, such as metal or ammonium salts. Preferred examples are alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), and also ammonium salts which are derived from a
Bischoff Hilmar
Faeste Christiane
Haning Helmut
Kretschmer Axel
Pernerstorfer Josef
Anderson Rebecca
Bayer Aktiengesellschaft
McKane Joseph K.
Pellegrino Susan M.
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