N-[4-(heteroarylmethyl)phenyl]-heteroarylamines

Details N-[4-(heteroarylmethyl)phenyl]-heteroarylamines N-[4-(heteroarylmethyl)phenyl]-heteroarylamines

2000-07-25

2002-11-26

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S377000, C514S383000, C514S398000, C514S399000, C514S426000, C548S264800, C548S222000, C548S234000, C548S311100, C548S525000

Reexamination Certificate

active

06486187

ABSTRACT:

The present invention concerns N-[4-(heteroaryl-methyl)phenyl]-heteroarylamines, their N-oxides and addition salts; it further relates to processes for their preparation, and compositions comprising them. The compounds of the present invention are potent inhibitors of the retinoic acid-metabolism, and hence, their use as a medicine is also described.
EP-A-0,260,744, published on Mar. 23, 1988, discloses (1H-imidazol-1-ylmethyl) substituted benzimidazoles as inhibitors of the androgen formation from C
21
-steroids, as inhibitors of the biosynthesis of thromboxane A
2
, and also having the capability to increase the excretion of ureic acid. EP-A-0,371,559, published on Jun. 6, 1990, discloses said benzimidazoles and analogous benzotriazoles as potent suppressers of the plasma elimination of endogenously or exogenously administered retinoic acid.
Retinoic acid (RA) is a key molecule in the regulation of growth and differentiation of epithelial tissues. However, RA is very rapidly metabolized by a series of enzymatic reactions, which results in its deactivation. Inhibition of RA-metabolism leads to enhanced RA levels in plasma and tissue. Therefore, compounds with such an inhibitory action, also called retinoic mimetic activity, have therapeutic and/or preventive potential in the field of dermatology and oncology.
The novel compounds of the present invention have retinoic mimetic activity and, moreover, show little or no endocrinological side-effects.
The present invention is concerned with compounds of formula
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
R
1
represents hydrogen, hydroxy, C
1-6
alkyl or aryl;
R
2
represents hydrogen; C
1-12
alkyl; C
3-7
cycloalkyl; C
2-8
alkenyl; aryl; pyrrolidinyl optionally substituted with C
1-12
alkyl or C
1-4
alkyloxycarbonyl; or C
1-12
alkyl substituted with one or two substituents selected from C
3-7
cycloalkyl, hydroxy, C
1-4
alkyloxy, cyano, amino, mono- and di(C
1-4
alkyl)amino, mono- and di(aryl-amino, arylC
1-4
alkylamino, (C
1-4
alkyl)(arylC
1-4
alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl optionally substituted with C
1-4
alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C
1-4
alkyloxycarbonyl, aminocarbonyl, mono- and di(C
1-4
alkyl)aminocarbonyl, aryl, aryloxy and arylthio;
R
3
represents hydrogen, C
1-6
alkyl, aryl or C
1-6
alkyl substituted with aryl;
Het represents an unsaturated heterocycle selected from imidazolyl, triazolyl, tetrazolyl and pyridinyl; each of said unsaturated heterocycles may optionally be substituted with amino, mercapto, C
1-6
alkyl, C
1-6
alkylthio or aryl;
 represents an unsaturated mono- or bicyclic heterocycle selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, purinyl, phtalazinyl, cinnolinyl, quinazolinyl and quinoxalinyl; each of said unsaturated mono- or bicyclic heterocycles may optionally be substituted with one, two or three substituents selected from hydroxy, halo, nitro, amino, C
1-6
alkyl, hdroxyC
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylthio formyl, carboxyl, mono- or di(C
1-6
alkyl)amino, C
1-6
alkyloxycarbonyl or aryl; or
 represents a radical of formula
wherein:
each X independently represents NR
8
, O, S, S(═O) or (═O)
2
; wherein R
8
is hydrogen, C
1-6
alkyl, aryl or arylC
1-6
alkyl;
R
4
and R
5
each independently represent hydrogen, hydroxy, halo cyano, nitro, amino, C
1-6
alkyl, hydroxyC
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkyloxy, formyl, carboxyl, mono- or di(C
1-6
alkyl)amino, C
1-6
alkyloxycarbonyl or aryl;
—R
6
R
7
— represents a bivalent radical of formula:
—CR
9
═CR
9
—CR
9
═CR
9
—  (b-1);
—N═CR
9
—CR
9
═CR
9
—  (b-2);
—CR
9
═N—CR
9
═CR
9
—  (b-3);
—CR
9
═CR
9
—N═CR
9
—  (b-4);
—CR
9
═CR
9
—CR
9
═N—  (b-5);
—CR
9
═N—N═CR
9
—  (b-6);
—CR
9
═N—CR
9
═N—  (b-7);
 —CR
9
═CR
9
—N═N—  (b-8);
—N═N—CR
9
═CR
9
—  (b-9);
—N═CR
9
—N═CR
9
—  (b-10);
—N═CR
9
—CR
9
═N—  (b-11);
—CR
9
═N—N═N—  (b-12);
—N═CR
9
—N═N—  (b-13);
—N═N—CR
9
═N—  (b-14) or
—N═N—N═CR
9
—  (b-15);
wherein each R
9
independently represents hydrogen, hydroxy, halo, nitro, amino, C
1-6
alkyl, hydroxyC
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkyloxy, formyl, carboxyl, mono- or di(C
1-6
alkyl)amino, C
1-6
alkyloxy-carbonyl or aryl; and
aryl represents phenyl or phenyl substituted with one, two or three substituents selected from hydroxy, halo, cyano, amino, mono- or di(C
1-6
alkyl)amino, C
1-6
alkyl, haloC
1-6
alkyl, hydroxyC
1-6
alkyl, C
1-6
alkyloxy, formyl, carboxyl and C
1-6
alkylcarbonyl; or two adjacent carbon atoms on said phenyl may be substituted by a single bivalent radical having the formula C
1-12
alkanediyl or haloC
1-12
alkanediyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
3-7
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C
2-8
alkenyl defines straight and branch chained hydro-carbon radicals containing one double bond and having from 2 to 8 carbon atoms such as, for example, ethyl, 1-pro;enyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 2-hexenyl, 2-heptenyl, 2-octenyl and the like; C
1-4
defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methybutyl, hexyl, 2-methylpentyl and the like; C
1-12
alkyl is meant to include C
1-6
alkyl and the higher homologues thereof having from 7 to 12 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2-methylhexyl, 3-ethyloctyl and the like; C
1-12
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 12 carbon atoms such as, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl, 1,1,4,4-tetramethylbutane-1,4-diyl and the like; haloC
1-6
alkyl is defined as polyhalosubstituted C
1-6
alkyl, in particular C
1-6
alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; haloC
1-12
alkanediyl is defined as polyhalo-substituted C
1-12
alkanediyl substituted with 1 to 12 halogen atoms; triazolyl is meant to include 1,2,4-triazolyl and 1,3,4-triazolyl; tetrazolyl is meant to include 1H-tetrazolyl and 2H-tetrazolyl.
The unsaturated heteroaryl group represented by Het may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heteroaryl group is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4triazol-2-yl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic,

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