Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-06
2002-02-12
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S401000, C514S436000, C514S460000
Reexamination Certificate
active
06346626
ABSTRACT:
The invention relates to chromanone and thiochromanone derivatives. It concerns the compounds of formula I
wherein
R
1
and R
2
independently are hydrogen, acyl, alkoxycarbonyl or alkyl;
either the sulfamoyloxy side chain is bound to the 6 position;
R
3
is alkyl; alkenyl; alkinyl; a cycloalkyl moiety optionally substituted by alkyl, alkoxy or halogen; arylalkenyl; arylalkinyl; acyl; cycloalkylalkyl; 3-oxo-2-oxacamphanyl; or is 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl; and
R
4
is hydrogen; alkyl; hydroxy; or alkoxy;
or the sulfamoyloxy side chain is bound to the 7 position;
R
3
has the significance indicated above for R
4
; and
R
4
has the significance indicated above for R
3
;
X is O or S; and the symbol
- - -
is a single or a double bond;
in free form or salt form; hereinafter briefly named “the compounds of the invention”.
A compound of formula I may be present in free, i.e. neutral or base, form or, where such forms exist, in salt, particularly acid addition salt form. A compound of formula I in free form may be converted into a salt form in conventional manner and vice-versa.
The sulfamoyloxy side chain is bound preferably to the 6 position.
Acyl preferably is the residue of a carboxylic acid, in particular of an alkyl, arylalkyl or aryl carboxylic acid. It preferably is alkylcarbonyl of altogether 2 to 5 carbon atoms, it especially is acetyl. Alkoxycarbonyl preferably is of altogether 2 to 5 carbon atoms, it especially is methoxycarbonyl. Alkyl as a moiety R
1
or R
2
or as part of a substituent preferably is of 1 to 5 carbon atoms, it especially is methyl. Alkyl as a moiety R
3
or R
4
preferably is of 1 to 12 carbon atoms, it especially is methyl, ethyl or t-butyl, particularly t-butyl. Alkenyl preferably is of 2 to 5 carbon atoms, it conveniently is ethenyl. Alkinyl preferably is of 2 to 5 carbon atoms, it conveniently is ethinyl.
A cycloalkyl moiety may be monocyclic or polycyclic. When it is monocyclic, it preferably is of 3 to 12 carbon atoms, it especially is cyclopropyl, cyclopentyl or cyclohexyl; when it is polycyclic, it preferably is adamantyl, especially 1-adamantyl; nor-adamantyl; or bicyclo[2.2.2]oct-1-yl. When cycloalkyl is substituted, it preferably is substituted by alkyl.
Arylalkenyl preferably is of 2 to 4 carbon atoms in the alkenylene part thereof. It preferably is 2-phenylethenyl, preferably in the trans configuration. Arylalkinyl preferably is of 2 to 4 carbon atoms in the alkinylene part thereof.
Cycloalkylalkyl preferably is of 1 to 4, especially 1 carbon atom in the alkylene part thereof. The cycloalkyl part thereof may be monocyclic or polycyclic; when it is monocyclic, it preferably is of 3 to 12 carbon atoms, it especially is cyclopentyl or cyclohexyl; when it is polycyclic, it preferably is bicyclo[2.2.1]hept-2-yl.
Alkoxy preferably is of 1 to 4 carbon atoms, it especially is methoxy. Halogen is fluorine, chlorine or bromine, preferably chlorine.
R
1
and R
2
preferably are hydrogen or alkyl, especially hydrogen. They preferably are identical. R
3
preferably is alkyl or cycloalkyl. R
4
preferably is hydrogen. X conveniently is O. The symbol
- - -
preferably is a double bond.
In a preferred subgroup of compounds of the invention R
1
and R
2
are identical and are hydrogen or methyl, and R
3
is t-butyl; cyclopentyl; cyclohexyl; adamantyl; bicyclo[2.2.1]hept-2-ylmethyl; nor-adamantyl; 4-pentylbicyclo[2.2.2]oct-1-yl; 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl; camphanyl; styryl; 2,2,3,3-tetramethylcyclopropyl; or alkyl of 1 to 4 carbon atoms.
In a further preferred subgroup R
1
, R
2
and R
4
are hydrogen; the sulfamoyloxy side chain is bound to the 6 position; R
3
is a bulky moiety selected from the significances indicated above for R
3
, preferably branched alkyl of 4 to 12 carbon atoms, such as tert-butyl; a monocyclic cycloalkyl moiety of 5 to 12 carbon atoms or a bi- or tricyclic cycloalkyl moiety of 6 to 10 carbon atoms, each optionally mono- or independently di- or independently trisubstituted by alkyl of 1 to 5 carbon atoms; 3-oxo-2-oxacamphanyl; or 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl; and X and the symbol
- - -
are as defined above.
A further preferred subgroup of compounds of the invention is the compounds of formula Ip
wherein
R
1p
and R
2p
independently are hydrogen or alkyl;
either the sulfamoyloxy side chain is bound to the 6 position,
R
3p
with the exception of 3-oxo-2-oxacamphanyl has the significance indicated above for R
3
, and
R
4p
is hydrogen;
or the sulfamoyloxy side chain is bound to the 7 position,
R
3p
is hydrogen, and
R
4p
with the exception of 3-oxo-2-oxacamphanyl has the significance indicated above for R
3
; and
X and the the symbol
- - -
are as defined above;
in free form or salt form.
A further preferred subgroup of compounds of the invention is the compounds of formula Is
wherein
R
1s
is hydrogen, methyl, acetyl or methoxycarbonyl;
R
2s
is hydrogen or methyl;
either the sulfamoyloxy side chain is bound to the 6 position,
R
3s
is alkyl of 1 to 12 carbon atoms; a monocyclic cycloalkyl moiety of 3 to 12 carbon atoms optionally substituted by methyl; 1-adamantyl; nor-adamantyl; 4-pentylbicyclo[2.2.2]oct-1-yl; 2-phenylethenyl; bicyclo[2.2.1]hept-2-ylmethyl; 3-oxo-2-oxacamphanyl; or 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl, and
R
4s
is hydrogen;
or the sulfamoyloxy side chain is bound to the 7 position,
R
3s
is hydrogen, and
R
4s
is cycloalkyl of 5 to 7 carbon atoms; and
X and the symbol
- - -
are as defined above;
in free form or salt form.
The invention also provides a process for the preparation of the compounds of the invention comprising
a) sulfamoylating the compounds of formula II
wherein R
3
, R
4
, X and the symbol
- - -
are as defined above; or
b) for the preparation of the compounds of formula Ia
wherein
X, R
1
, R
2
and the symbol
- - -
are as defined above and
R
3
′ and R
4
′ with the exception of alkenyl, alkinyl, arylalkenyl, arylalkinyl and 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl have the significance indicated above for, respectively, R
3
and R
4
,
reducing the corresponding compounds of formula Ib
wherein the substituents are as defined above; or
c) for the preparation of the compounds of formula I wherein at least one of R
1
and R
2
is alkyl, acyl or alkoxycarbonyl,
N-substituting the compounds of formula I wherein at least one of the substituents R
1
and R
2
is hydrogen;
and recovering the resultant compounds of formula I in free form or salt form.
The process of the invention is carried out in conventional manner.
Process variant a) is performed using standard conditions for sulfamoylation, e.g. by reacting a compound of formula II with:
&agr;) sulfuryl chloride and sodium- or potassium azide to generate corresponding intermediates wherein the hydrogen atom of tho hydroxy group is replaced with a group —SO
2
N
3
, which after reduction of the azide group give compounds of formula I wherein R
1
and R
2
are hydrogen, or
&bgr;) CISO
2
—NCO, followed by aqueous hydrolysis of the resultant intermediates to yield compounds of formula I wherein R
1
and R
2
are hydrogen, or
&ggr;) a compound of formula III
wherein R
1
and R
2
are as defined above and Y is a leaving group, e.g. halogen, preferably chlorine, in an inert solvent, e.g. dimethylformamide, where convenient with addition of an organic base, such as an organic tertiary amine, or an inorganic base, e.g. an alkali(hydrogen)carbonate or alkali hydride, preferably sodium hydride.
Process variant b) may be performed following standard procedures for hydrogenation of double bonds, e.g. catalytically, preferably using hydrogen in combination with a hydrogenation catalyst such as Pd, Pt or Rh, most preferably Pd on charcoal. Starting from compounds of formula I wherein R
3
is alkenyl alkinyl, arylalkenyl or arylalkynyl, in a first step of the reaction these groups are reduced. The reaction may be stopped at this stage and the double bond in the chromenone
Billich Andreas
Nussbaumer Peter
Schreiner Erwin
Schuster Ingeborg
Higel Floyd D.
Loeschorn Carol A.
Novartis AG
Saeed Kamal
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