Diphenylmethane derivatives

Details Diphenylmethane derivatives Diphenylmethane derivatives

2003-03-11

2004-10-12

Killos, Paul J. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S058000, C560S015000, C560S016000, C562S426000, C562S468000, C514S534000, C514S557000, C568S054000

Reexamination Certificate

active

06803480

ABSTRACT:

The invention relates to novel diphenylmethane derivatives, processes for their preparation and their use in medicaments, in particular for the indications of arteriosclerosis and hypercholesterolaemia.
European application 580 550 A describes oxamic acid derivatives having cholesterol-lowering properties in mammals. This application describes an in vitro test based on the binding of thyroid hormone cell receptors (called T
3
nuclear receptors). Some of the compounds described therein are stated to have IC-50 values of 0.2 nM and 0.1 nM in the L-triiodothyronine (LT
3
) nuclear receptor test. The pharmacological property which is emphasized is the reduction in plasma cholesterol, in particular LDL-cholesterol. Cholesterol-lowering effects are also described in the European application EP-A-188 351 for certain diphenyl ethers with thyroid hormone-like effects.
Tripp et al. in J. Med. Chem. 1973, 16(1), 60-64 describe the synthesis of methylene- and carbonyl-bridged analogs of iodothyronine. They found that their thyromimetic activity was less than that of the corresponding O- or S-bridged compounds.
Psychoyos et al. in Endocrinology 1973, 92(1), 243-250 also investigated the thyromimetic activity of methylene-bridged thyroid hormone analogs. They likewise concluded that the methylene-bridged compounds were less potent than the O-bridged compounds.
WO 98/57919 discloses selective thyroid hormone agonists with a diphenylmethane basic structure and their use in medicaments.
WO 99/26966 describes novel methods for designing ligands which bind to certain receptors (called “nuclear receptors”). It is reported in particular that molecules suitable for modulating the thyroid receptor must comply with certain three-dimensional requirements.
The invention relates to diphenylmethane derivatives of the general formula (I)
in which
X is CH
2
, CHF or CF
2
,
R
1
is a group of the formula
—A—(CH
2
)
n
—[C(O)]
m
—R
7
 in which
A is CH
2
, S, C(O) or NR
8
,
n is the number 0, 1, 2 or 3,
m is the number 1 or 2,
where m is the number 2 in the case where R
2
and R
3
are halogen,
R
7
is (C
1
-C
6
)-alkyl or a radical of the formula —NR
9
R
10
or —OR
11
,
in which
R
8
, R
9
, R
10
and R
11
are identical or different and are, independently of one another, hydrogen, (C
1
-C
6
)-alkyl or (C
1
-C
8
)-cycloalkyl,
R
2
and R
3
are identical or different and are halogen, (C
1
-C
6
)-alkyl, (C
3
-C
7
)-cycloalkyl, vinyl, CF
3
, CHF
2
or CH
2
F,
R
4
is hydrogen, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-acyl,
R
5
is hydrogen, halogen, hydroxyl, cyano, CF
3
, (C
1
-C
6
)-alkyl or (C
1
-C
6
)-alkoxy,
R
6
is a radical of the formula
—(D)
p
—R
12
 in which
D is a group of the formula
 in which
R
13
and R
14
together are an oxo group or are identical or different and are hydrogen, halogen, hydroxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or a radical of the formula —NR
15
R
16
,
in which
R
15
and R
16
are identical or different and are hydrogen, benzyl, (C
1
-C
6
)-alkyl or (C
3
-C
8
)-cycloalkyl,
p is the number 0 or 1,
and
R
12
is hydrogen, OR
17
, NR
18
R
19
, (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 with up to three identical or different heteroatoms from the series of S, O and/or N,
where
the aforementioned hydrocarbon radicals and heterocycles may optionally be substituted once to three times, identically or differently, by substituents from the group of halogen, hydroxyl, oxo, cyano, nitro, amino, CF
3
, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, (C
3
-C
8
)-cycloalkyl, —O—C(O)—R
20
, —C(O)—O—R
21
, —C(O)—NR
22
R
23
or —NH—C(O)—O—R
24
,
and
in which
R
17
, R
18
, R
19
, R
20
, R
21
, R
22
, R
23
and R
24
are identical or different and are each, independently of one another, hydrogen, (C
1
-C
6
)-alkyl or (C
3
-C
8
)-cycloalkyl, each of which in turn may be substituted by hydroxyl, amino, mono- or di-(C
1
-C
6
)-alkylamino, phenyl, a saturated, unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series of S, O and/or N,
and the salts thereof.
Heterocycles which may be preferably mentioned in the definition of R
12
and R
17
to R
24
are:
A 5- to 8-membered saturated, partly unsaturated or aromatic, optionally benzo-fused heterocycle with up to 4 heteroatoms from the series of S, N and/or O, i.e. a heterocycle which may 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.
Preference is given to the following from this list: pyridyl, pyrimidyl, pyridazinyl, pyrimidinonyl, pyridazinonyl.
(C
1
-C
8
)-Alkyl, (C
1
-C
6
)-alkyl, (C
1
-C
4
)-alkyl and (C
1
-C
3
)-alkyl are for the purposes of the invention a straight-chain or branched alkyl radical respectively with 1 to 8, 1 to 6, 1 to 4 and 1 to 3 carbon atoms. A straight-chain or branched alkyl radical with 1 to 3 carbon atoms is preferred. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.
(C
6
-C
10
)-Aryl is for the purposes of the invention an aromatic radical with 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
(C
3
-C
8
)-Cycloalkyl, (C
3
-C
7
)-cycloalkyl and (C
3
-C
6
)-cycloalkyl are for the purposes of the invention a cycloalkyl group respectively with 3 to 8, 3 to 7 and 3 to 6 carbon atoms. Those which may be mentioned as preferred are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
(C
1
-C
6
)-Alkoxy is for the purposes of the invention a straight-chain or branched alkoxy radical with 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical with 1 to 3 carbon atoms is preferred. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
(C
1
-C
6
)-Acyl is for the purposes of the invention particularly a straight-chain or branched alkyl radical with 1 to 6 carbon atoms which has a doubly bonded oxygen atom in the 1 position and is linked via the 1 position. Examples which may be mentioned are: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl.
Halogen includes for the purposes of the invention fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.
The compounds according to the invention may, depending on the substitution pattern, exist in stereoisomeric forms which either are related as image and mirror image (enantiomers) or are not related as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and to respective mixtures thereof. The racemic forms can, just like the diastereomers, be separated into the stereoisomerically pure constituents in a known manner.
Certain compounds may furthermore exist in tautomeric forms. This is known to the skilled person, and such compounds are likewise encompassed by the scope of the invention.
The compounds according to the invention may also be in the form of salts. Physiologically acceptable salts are preferred for the purposes of the invention.
Physiologically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with, organic carboxylic or sulphonic acids such as, for example, acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethane-sulphonic acid, benzenesulp

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