Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-14
2001-07-24
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S238000
Reexamination Certificate
active
06265407
ABSTRACT:
This invention concerns novel 3-(3-substituted-1,2,4-thiadiazol-5-yl)pyridazine derivatives acting as angiogenesis inhibitors, and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
Angiogenesis, i.e. the formation of new vessels by endothelial cells, plays an important role in a variety of physiologic and pathophysiologic processes. The development of a vascular supply is essential for the growth, maturation and maintenance of normal tissues. It is also required for wound healing. Angiogenesis is critical for solid tumor growth and metastasis and is involved in a variety of other pathological conditions such as neovascular glaucoma, diabetic retinopathy, psoriasis and rheumatoid arthritis. These pathological states are characterized by augmented angiogenesis during which normally quiescent endothelial cells become activated, degrade extracellular matrix barriers, proliferate, and migrate to form new vessels. To control these angiogenesis dependent disorders, compounds with angiogenesis inhibitory properties would be very useful.
Several compounds inhibiting angiogenesis, also called angiostatics, angio-inhibitors or angiogenic antagonists, are disclosed in the art. For instance hydrocortisone is a well known angiogenesis inhibitor (Folkman et al., Science 230:1375, 1985' “A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment”; Folkman et al., Science 221:719, 1983, “Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone”).
EP-0,398,427, publised on Nov. 22, 1990, discloses antirhinoviral pyridazinames, and in EP-0,435,381, published on Jul. 3, 1991, pyridazinamines are described having antipicornaviral activity. EP-0,429,344, published on May 29, 1991, discloses aminopyridazine derivatives as cholinergic agonists.
The compounds of the present invention differ from the prior art compounds by the fact that they are invariably substituted with a thiadiazolyl moiety and particularly by the fact that unexpectedly these compounds have angiogenesis inhibiting properties.
This invention concerns compounds of formula
the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein
R
1
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxy, C
1-6
alkylthio, amino, mono- or di(C
1-6
alkyl)amino, Ar
1
, Ar
1
—NH—, C
3-6
cycloalkyl, hydroxymethyl or benzyloxymethyl;
R
2
and R
3
are hydrogen, or taken together may form a bivalent radical of formula —CH═CH—CH═CH—;
R
4
, R
5
and R
6
are each independently selected from hydrogen, halo, C
1-6
alkyl, C
1-6
alkyloxy, trifluoromethyl, nitro, amino, cyano, azido, C
1-6
alkyloxyC
1-6
alkyl, C
1-6
alkylthio, C
1-6
alkyloxycarbonyl or Het
1
;
or when R
4
and R
5
are adjacent to each other they may be taken together to form a radical of formula —CH═CH—CH═CH—;
wherein X is a direct bond, —O—, —S—, C═O, —NR
8
— or Het
2
;
R
7
is hydrogen, C
1-6
alkyl or Ar
2
methyl;
R
8
is hydrogen, C
1-6
alkyl or Ar
2
methyl;
Alk
1
is C
1-6
alkanediyl;
Alk
2
is C
1-6
alkanediyl;
Ar
1
is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, trihalomethyl, amino or nitro;
Ar2 is phenyl; phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, C
1-6
alkyl, C
1-6
alkyloxy, trihalomethyl, amino or nitro;
Het
1
is a monocyclic heterocycle selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl or oxazolinyl; and each monocyclic heterocycle may optionally be substituted on a carbon atom with C
1-4
alkyl; and
Het
2
is tetrahydrofuran; a tetrahydrofuran substituted with C
1-6
alkyl; a dioxane; a dioxane substituted with C
1-6
alkyl; a dioxolane; or a dioxolane substituted with C
1-6
alkyl.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl 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 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-methylbutyl, hexyl, 2-methylpentyl and the like; C
2-4
alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C
1-4
alkanediyl is meant to include C
2-4
alkanediyl and methylene; and C
1-6
alkanediyl is meant to include C
1-4
alkanediyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term “C═O” refers to a carbonyl group.
Wherever in the compounds of the present invention the bivalent radical A is (a-2) or (a-3), the nitrogen of the —NR
7
-moiety is preferably linked to the pyridazinyl moiety of said compound. Analogously, wherever the bivalent radical A is (a-4), (a-5) or (a-6) the oxygen or sulfur atom is preferably linked to the pyridazinyl moiety. Examples of the bivalent radical A are for instance,
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; hitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one of the pyridazinyl nitrogens is N-oxidized.
Whenever used hereinafter, the term “compounds of formula (I)” is meant to include also the pharmaceutically acceptable acid addition salts and all stereoisomeric forms.
A group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
a) R
1
is hydrogen, C
1-6
alkyl, amino or di(C
1-6
alkyl)amino;
b) R
2
and R
3
are hydrogen;
c) R
4
, R
5
a
Ceusters Marc André
Luyckx Marcel Gerebernus Maria
Stokbroekx Raymond Antoine
Tuman Robert W.
Van der Aa Marcel Jozef Maria
Bernhardt Emily
Janssen Pharmaceutica N.V.
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