Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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HoechstAktiengesellschaft HOE 96/F 119 K Dr. v. F./St
Description
5 Sulfonamide-substituted chromans, processes for their preparation, their use as a
medicament or diagnostic, and medicament comprising them
The invention relates to chromans of the formula I
R~) ~~
R(5) N~S\R(3)
R(6) l l
~'~ I
~ R(2)
R(7) ¦ R(1)
1 5 R(8)
in which:
R(1 ) and R(2)
independently of one another are hydrogen, CpF2p+1, alkyl having 1, 2~ 3, 4, 5
or 6 carbon atoms or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents selected
from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy,
sulfamoyl, methylsulfonylamino and methylsulfonyl;
p is 1, 2 or3;
or
R(1 ) and R(2)
together are an alkylene chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon
atoms;
R(3) is R(9)-CnH2n[NR(11)]m-;
R(9) is hydrogen or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms;
n is zero,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
m iszeroor1;
R(11 ) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
or
R(11), together with R(9), is an alkylene group having from 1, 2, 3, 4, 5, 6, 7
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or 8 carbon atoms;
where one CH2 group of the group CnH2n can be replaced by -O-, ~SOq or
-NR(10);
q is zero,1 or 2;
R(10) is hydrogen, methyl or ethyl;
R(4) is R(12)~CrH2r;
R(12)
is hydrogen, cycloalkyl having 3,4,5,6,7 or 8 carbon atoms,
piperidyl,1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CpF2p+1,
pyridyl, thienyl, imidazolyl or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents
selected from the group consisting of F, Cl, Br, l, CF3, methyl,
methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino;
r is 1, 2, 3,4,5,6,7,8,9,10,11,1 2, 1 3,14,15,16,17,18,19 or 20;
where one CH2 group of the group CrH2r can be replaced by -O-, -C=C-,
-C--C-, -CO-, -CO-O-, ~SOq~ or -NR(10)-;
q is zero,1 or 2;
R(10) is hydrogen, methyl or ethyl;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, l, alkyl having 1, 2, 3 or4 carbon atoms, cycloalkyl having 3,4,5,6,7 or 8 carbon atoms,-CN, -CF3,
-C2F5, -C3F7, -N3, -NO2, -CONR(13)R(14), -COOR(15), R(16)-CsH2s-Y- or
phenyl,
which is unsubstituted or substituted by 1 or 2 substituents selected
from the group consisting of F, Cl, Br, l, CF3, methyl, methoxy,
sulfamoyl and methylsulfonyl;
R(13) and R(14)
independently of one another are hydrogen or alkyl having 1, 2 or 3
carbon atoms;
R(15) is hydrogen, methyl, ethyl, phenyl or-CuH2u-NR(13)R(14);
u is 2 or 3;
R(16) is hydrogen, cycloalkyl having 3,4,5,6,7 or 8 carbon atoms, -
COOR(15), thienyl, imidazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl,
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1-pyrrolidinyl, N-morpholino, N-methylpiperazino, CtF2t+1 or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents
selected from the group consisting of F, Cl, Br, I, CF3, methyl,
methoxy, sulfamoyl or methylsulfonyl;
s iszero, 1,2,3,4,5cr6;
t is 1, 2 or3;
Y is SOql -CO-, -SO2-NR(10)-, -O-, -NR(10)- or -CO-NR(10);
but where R(6) cannot be -OCF3 or -OC2F5;
and their physiologically tolerable salts.
Preferred compounds of the formula I are those in which:
R(1) and R(2)
independently of one another are hydrogen,CF3, alkyl having 1, 2 or 3 carbon
atoms, jointly an alkylene chain having 4 or 5 carbon atoms or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents selected
from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy,
sulfamoyl and methylsulfonyl;
R(3) is R(9)-cnH2n[NR(11)]m-;
R(9) is hydrogen;
n iszero, 1, 2, 3, 4, 5 or6;
m iszeroor1;
R(11 ) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(4) is R(1 2)~CrH2r;
R(1 2)
is hydrogen, cycloalkyl having 5, 6, 7 or 8 carbon atoms, CF3, pyridyl
or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents
selected from the group consisting of F, Cl, CF3, sulfamoyl or
methylsulfonyl;
r is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
where one CH2 group of the group CrH2r can be replaced by -O-, -CO-,
-CO-O- or -SOq-;
q is zero, 1 or 2;
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R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, l, alkyl having 1 or 2
carbon atoms, -CN, -CF3, -NO2, -CONR(13)R(14), -COOR(15),
R(16)-CsH2s-Y- or phenyl,
which is unsubstituted or substituted by a substituent selected from the
group consisting of F, Cl and CF3;
R(13) and R(14)
independently of one another are hydrogen or alkyl having 1,2 or 3
carbon atoms;
R(15) is methyl, ethyl, phenyl or-CuH2u-NR(13)R(14);
u is20r3;
R(16) is hydrogen, cycloalkyl having 5 or 6 carbon atoms, CtF2t+, or phenyl,
which is unsubstituted or substituted by a substituent selected
from the group consisting of F, Cl, Br, CF3, methyl, methoxy,
1~ sulfamoyl or methylsulfonyl;
t is1,20r3;
s is zero,1,2,3 or 4;
Y is SOql -CO-, -SO2-NR(10)-, -O-, -NR(10)- or -CO-NR(10);
q is zero,1 or 2;
R(10) ishydrogenormethyl;
but where R(6) cannot be -OCF3 or -OC2F5;
and their physiologically tolerable salts.
Particularly preferred compounds of the formula I are those in which:
2~ R(1) and R(2)
independently of one another are CF3, methyl or phenyl,
which is unsubstituted or substituted by 1 or 2 substituents selected
from the group consisting of F, Cl, Br, l, CF3, methyl, methoxy,
sulfamoyl and methylsulfonyl;
R(3) is alkyl having 1,2,3 or 4 carbon atoms, dimethylamino or diethylamino;
R(4) is R(12)~CrH2r;
R(12)
is hydrogen, cycloalkyl having 5 or 6 carbon atoms or CF3;
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r is1,2,3,4,5,6,70r8;
where one CH2 group of the group CrH2r can be replaced by -O-, -CO-,
-CO-O- or -SOq-;
q is zero,1 or 2;
R(5), R(6), R(7) and R(8)
independently of one another are hydrogen, F, Cl, Br, l, alkyl having 1 or 2
carbon atoms, -CN, -NO2, -COOR(15), R(16)-CsH2S-Y- or phenyl,
which is unsubstituted or substituted by a substituent selected from the
group consisting of F or Cl;
13 R(15) is methyl, ethyl, phenyl or -CUH2u-NR(13)R(14);
u is 2 or 3;
R(13) and R(14)
independently of one another are hydrogen or alkyl having 1,2
or 3 carbon atoms;
R(16) is hydrogen, CF3 or phenyl,
s is zero,1,2,3 or 4;
Y is SOq, -CO-, -SO2-NR(10)-, -O-, -NR(10)- or -CO-NR(10);
q is zero,1 or 2;
R(10) ishydrogenormethyl;
but where R(6) cannot be -OCF3;
and their physiologically tolerable salts.
Very particularly preferred compounds of the formula I are the following:
4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman,
2~ 6-cyano4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman,
4-(N-ethylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethyl-chroman,
6-cyano4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethyl-chroman,
4-(N-butyl-N-ethylsulfonyl)amino-6-cyano-2,2-dimethylchroman,
4-(N-ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman,
7-chloro4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethylchroman,
6,7-dichloro4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman,
4-(N-butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethylchroman,
4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylenechroman,
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4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-dimethyl-chroman,4-(N-ethylsulfonyl-N-hexyl)amino-6-fluoro-2,2-dimethylchroman,
6-ethyl-4-~N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-dimethyl-chroman.
If the compounds I contain an acidic or basic group or a basic heterocycle, the
corresponding, pharmacologically and toxicologically tolerable salts are also a
subject of the invention. Thus the compounds I which carry one or more -COOH
groups, for example as alkali metal salts, can preferably be used as sodium or
potassium salts. Compounds I which carry a basic, protonatable group or a basic
1D heterocyclic radical can also be used in the form of their organic or inorganic,
pharmacologically and toxicologically tolerable acid addition salts, for example as
hydrochlorides, methanesulfonates, acetates, lactates, maleates, fumarates,
malates, gluconates etc. If the compounds I contain an acidic and basic group in the
same molecule, the invention also includes, beside the salt forms described internal
15 salts, so-called betaines.
lf the substituents of the compounds of the formula I or alternatively of the formula la
contain groups with different stereochemical possibilities, the invention also includes
the individual possible stereoisomers. Thus the compounds I and la contain a chiral
2~ center in position 4 of the chroman system, so the individual pure optical antipodes
and any desired mixtures of the optical isomers are part of the invention.
The compounds of the formula I can be prepared by different chemical processes,
which are likewise part of the invention.
2~
Thus a compound of the formula I is obtained by
a) reacting a compound of the formula ll
R(5) L
R(6) l l
,~R(2)
R(7) R(1)
~ (8)
in which R(1), R(2), R(5), R(6), R(7) and R(8) have the meaning indicated and L is
3~ the nucleofugic leaving group customary for an alkylation, in particular Cl, Br, I,
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MeS02-0-, a p-toluenesulfonyloxy radical,
with a sulfonamide or its salt of the formula lll
O O
R(4) \\// lll
~ 'S~R( )
M
in a manner known per se, in which R(3) and R(4) have the meaning indicated, but r
in the substituent R(4) also has the meaning zero, and M is hydrogen or preferably a
metal atom, particularly preferably lithium, sodium or potassium;
orby
b) reacting a compound of the formula IV
R~)
R(5) NH
R(6) l l
R(7~RR((12)) IV
R(8)
in which R(1), R(2), R(4), R(5), R(6), R(7) and R(8) have the meaning indicated, but
r in the substituent R(4) also has the meaning zero,
with a sulfonic acid derivative of the formula V
R(3)- S ~2- W V
2~ in which R(3) has the meaning indicated and W is a nucleofugic leaving group, such
as fluorine, bromine, 1-imidazolyl, but in particular chlorine;
or by
30 c) reacting a compound of the formula Vl
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O O
M \\ //
R(5) \N~S\R(3)
R(6 1~ Vl
,J~ J~R(2)
R(7) R(1)
~(8)
in which R(1), R(2), R(5), R(6), R(7), R(8) and M have the meaning indicated, in a
manner known per se with an alkylating agent of the formula Vll
R(4)-L Vl I
in the sense of an alkylation reaction, in which R(4), with the exception of hydrogen,
and L have the meaning indicated;
or by carrying out,
d) in a compound of the formula I
R~) ~\\ /p
2~ Rl (5) N ~ \R(3)
~,~ J~R(2)
R(7) R(1 )
2~i ~<(8)
in which R(1 ) to R(4) have the meaning indicated, an electrophilic substitutionreaction in at least one position R(5) to R(8), if this position is hydrogen and the
remaining substituents R(5) to R(8) have the meaning indicated.
Procedure a)
describes the alkylation, which is known per se, of a sulfonamide or of one of its
salts of the formula lll by a chroman derivative of the formula ll having alkylating
action. As the alkylation of a sulfonamide is carried out from the salt form, when
3~ using a free sulfonamide (formula lll, M = H) a sulfonamide salt (formula lll, M =
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cation), which is distinguished by higher nucleophilicity and thus by higher reactivity,
must be produced by action of a base. If free sulfonamide (M = H) is employed, the
deprotonation of the sulfonamide to the salt is carried out in situ with preferred use
of those bases which are themselves not alkylated or only slightly alkylated, such as
5 sodium carbonate, potassium carbonate, a sterically strongly hindered amine, e.g.
dicyclohexylamine, N,N,N-dicyclohexylethylamine or other strong nitrogen bases of
low nucleophilicity, for example DBU, N,N',N"'-triisopropylguanidine etc. However,
other bases customarily used for the reaction can also be employed, such as
potassium tert-butoxide, sodium methoxide, alkali metal hydrogen carbonates, alkali
10 metal hydroxides, such as, for example, LiOH, NaOH or KOH, or alkali metal
hydroxides, for example Ca(OH)2.
In this case, the reaction is preferably carried out in aprotic polar solvents such as
dimethylformamide, dimethylacetamide, tetramethylurea,
1~ hexamethylphosphoramide, tetrahydrofuran etc. In principle, however, the reaction
can also be carried out in polar protic solvents, such as water, methanol, ethanol,
isopropanol, ethylene glycol or its oligomers and their corresponding semiethersand ethers. The reaction is carried out in a preferred temperature range from 20 to
140~C, particularly preferably from 40 to 1 00~C. Conveniently, procedure a) can20 also be carried out under the conditions of a two-phase catalysis. The compounds of
the formula ll are obtained by methods known from the literature, for example from
the corresponding alcohols (formula lll, L = -OH ) by action of hydrogen halide HL (L
= Cl, Br, I) or by action of an inorganic acid halide (POCI3, PCI3, PCI5, SOCI2,SOBr2) or by free-radical halogenation of the corresponding chroman derivatives
25 (formula ll, L = H) with elemental chlorine or bromine, or with free radical-activatable
halogenating agents such as N-bromo-succinimide (NBS) or SO2CI2 (sulfuryl
chloride) in the presence of a free radical chain initiator such as energy-rich light of
the visible or ultraviolet wave range or by use of a chemical free-radical initiator
such as azobisisobutyronitrile.
Procedure b)
describes the reaction, which is known per se and frequently used, of an activated
sulfonyl compound of the formula V, in particular of a chlorosulfonyl compound (W =
Cl), with an amine of the formula IV to give the corresponding sulfonamide
35 derivative of the formula 1. In principle, the reaction can be carried out without a
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solvent, but reactions of this type are in most cases carried out using a solvent.
The reaction procedure is preferably carried out using a polar solvent, preferably in
the presence of a base which itself can be used as a solvent, e.g. when using
triethylamine, pyridine and its homologs. Solvents preferably used are, for example,
water, aliphatic alcohols, e.g. methanol, ethanol, isopropanol, sec-butanol, ethylene
glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers,
tetrahydrofuran, dioxane, dialkylated amides such as DMF, DMA, and also TMU and
HMPT. The reaction is in this case carried out at a temperature from 0 to 1 60~C,
preferably from 20 to 1 00~C.
The amines of the formula IV are obtained in a manner known per se from the
literature, preferably from the corresponding carbonyl compounds of the formula X
R(5) A
R(6) l ll
R(7~R(1)
(8)
in which R(1), R(2), R(5), R(6), R(7) and R(8) have the meaning indicated and A is
oxygen, either using ammonia or an amine of the formula Xl
R(4)-NH2 Xl
with R(4) having the meaning indicated, but in which r in the substituent R(4) also
has the meaning zero, under reductive catalytic conditions, preferably at relatively
high temperature in an autoclave. In this case, the Schiff bases of the formula X
where A is equal to R(4)-N= are formed primarily by condensation reaction of theketones X (where A = oxygen) and amines (Xl) in situ and immediately converted
reductively without isolation thereof into the amine of the formula IV.
Correspondingly, the Schiff bases intermediately resulting from X and Xl in this3D reaction (formula X, A: R(4)-N=) can be prepared and isolated in order to convert
them subsequently in a separate step with a suitable reductant such as NaBH4,
LiAlH4, NaBH3CN or by catalytic hydrogenation into the compounds of the formula
lV
The compounds IV where R(4) is equal to hydrogen can advantageously be
3~ obtained in a manner known from the literature by reduction of oximes or oxime
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ethers (formula X, A is equal to RO-N=), hydrazones (formula X, A: R(1 8)R(1 9)N-
N=) by use of a complex metal hydride or by catalytic hydrogenation. The necessary
oximes and hydrazones are preferably prepared conveniently and in a manner
known per se from the ketones of the formula X (A is equal to oxygen) using
hydrazine or one of its derivatives or, for example, using hydroxylamine
hydrochloride under dehydrating conditions.
Procedure c)
describes, like procedure a), the alkylation reaction of a sulfonamide, which is10 known per se, or of one of its salts Vl with an alkylating agent of the formula Vll.
Corresponding to this reaction analogy, the reaction conditions already described in
detail under procedure a) apply for procedure c).
The preparation of the sulfonamide derivatives Vl and their precursors have already
been described in procedure b). The preparation of the alkylating agents Vll is
15 carried out according to analogous procedures of the literature or as described
under procedure a), preferably from the corresponding hydroxyl compounds
(formula Vll where L is equal to -OH).
Procedure d)
20 describes the further chemical conversion of compounds of the formula I according
to the invention into other compounds of the formula I by electrophilic substitution
reactions in one or in more of the positions designated by R(5) to R(8), which in
each case are hydrogen.
2~ Preferred substitution reactions are
1. aromatic nitration to introduce one or more nitro groups, and their subsequent
reduction to NH2-,
2. aromatic halogenation, in particular to introduce chlorine, bromine or iodine,
3. chlorosulfonation to introduce a chlorosulfonyl group by action of chlorosulfonic
30 acid,
4. the Friedel-Crafts acylation reaction to introduce an acyl radical R(1 6)-CsH2s-CO-
or a sulfonyl radical R(16)-CsH2s-SO2- by action of the corresponding acid chlorides
R(16)-CsH2s-CO-CI or R(16)-CsH2s-SO2-Cl in the presence of a Lewis acid as a
Friedel-Crafts catalyst, preferably of anhydrous aluminum chloride.
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The compounds I and la are related to the class of 4-acylaminochroman derivatives,
in particular of 2,2-dialkyl-4-acylamino-3-chromanols, worked on intensively in
pharmaceutical chemistry in the last decade. The most prominent representative of
4-acylaminochromans of this type is cromakalim of the formula Xll
N ~
NC~,~ OH Xll
~0 ~0~
and numerous secondary preparations derived from this preparation (e.g. Edwards
and Weston, TIPS 1 1, 417-422 (1990), "Structure Activity Relationships of K+
channel openers"
1~ Cromakalim and other related 4-acylaminochroman derivatives are compounds
having a relaxant action on smooth muscular organs, so that they are used for
lowering increased blood pressure as a result of vascular muscle relaxation and in
the treatment of asthma as a result of the relaxation of the smooth musculature of
the airways. It is common to all these preparations that they act at the cellular level,
for example, of smooth muscle cells and lead there to an opening of specific ATP-
sensitive K+ channels. The increase in negative charge in the cell
("hyperpolarization") induced by the efflux of K+ ions counteracts by means of
secondary mechanisms the increase of intracellular Ca2+ and thus cell activation,
e.g. muscle contraction.
2~
ln contrast to these 4-acylaminochroman derivatives which, as mentioned, were
identified as openers of the ATP-sensitive K+ channel, the compounds of the
formula land the compounds of the formula la according to the invention
R~) ~ \ ~
N S_R(3)
¦ ~R(B)
R(C) [~R(2)
R(1 )
3~
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where
R(A) is hydrogen, OH, -O(CO)alkyl having 1, 2, 3 or 4 carbon atoms or
-O-SO2-alkyl having 1, 2, 3 or 4 carbon atoms;
R(B) is hydrogen;
or
R(A) and R(B)
together are a bond;
R(1) to R(4) are as indicated above;
R(C) is CN, acyl having 1, 2, 3, 4, 5 or 6 carbon atoms, F, Cl, Br, I, NO2 or alkyl
0 having 1, 2, 3, 4, 5 or 6 carbon atoms;
with the 4-sulfonylamino structure surprisingly show a strong and specific blocking
(closing) action on a K+ channel which is opened by cyclic adenosine
monophosphate (cAMP) and differs fundamentally from the K+(ATP) channel
mentioned. More recent investigations on the contrary show that this K+(cAMP)
channel identified in the large intestine appears to be very similar, perhaps even
identical, to the ISK channel identified in cardiac muscle. As a result of this blocking
of the K~(cAMP) channel (= ISK channel), the compounds develop in the living body
pharmacological actions of high therapeutic utility.
The preparation of compounds of the formula la from suitable 3,4-epoxychromans
and sulfonamides of the formula lll is described in Lohrmann et al., Pflugers Arch. -
Eur. J. Physiol. (1995) 429: 517 - 530.
Thus the compounds I and la are distinguished as a novel active compound class of
potent inhibitors of stimulated gastric acid secretion. The compounds of the formula
I or la are thus useful medicaments for the treatment of ulcers of the stomach and of
the intestinal region, for example of the duodenum. On account of their strong
gastric secretion-inhibiting action, they are also suitable as excellent therapeutics
for the treatment of reflux esophagitis.
The compounds I and la are furthermore distinguished by an antidiarrheal action
and are therefore suitable as pharmaceuticals for the treatment of diarrheal
illnesses.
The compounds I and la can furthermore be used as pharmaceuticals for the
CA 0220~477 1997-0~
14
treatment and prevention of all types of arrhythmias including atrial, ventricular and
supraventricular arrhythmias. They can be used in particular for the control of
reentry arrhythmias and for the prevention of sudden heart death as a result of
ventricular fibrillation.
Meanwhile, publications exist from which a correlation between ISK channel-
inhibitory action and the suppression of life-threatening cardiac arrhythmias isdescribed, such as are caused, for example, by 13-adren-ergic hyperstimulation (e.g.
T. J. Colatsky, C. H. Follmer and C .F. Starmer: "Channel Specificity in
Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role insuppressing and aggravating cardiac arrhythmias", Circulation (1990) 82: 2235 -
2242; A. E. Busch, K. Malloy, W. J. Groh, M. D. Varnum, J. P. Adelman and J.
Maylie; "The novel class lll antiarrhythmics NE-10064 and NE-10133 inhibit ISK
channels in xenopus oocytes and IKS in guinea pig cardiac myocytes", Biochem.
Biophys. Res. Commun. (1994) 202: 265 - 270).
Beside the abovementioned cromakalim and acylaminochroman derivatives, in the
course of the last years compounds of 4-sulfonyl-aminochroman structure have also
been described in the literature, which either differ markedly in structure or in
20 biological action from the compounds of the formula land the compounds of theformula la according to the invention. Thus, European Offenlegungsschrift 315 009
describes chroman derivatives of 4-phenylsulfonylamino structure, which are
distinguished by antithrombotic and antiallergic properties.
2~ European Offenlegungsschrift 370 901 describes 3-hydroxychroman derivatives
having a 4-phenylsulfonylamino group, in which the remaining valency of the
nitrogen atom carries a hydrogen atom. These compounds are thus substituted
differently in essential groups of the formula I or la. Accordingly, actions on the
central nervous system are found for these compounds of European
Offenlegungsschrift 370 901, so that they also differ in a pharmacological respect.
European Offenlegungsschrift 389 861 describes 3-hydroxychroman derivatives
having a 4-sulfonylamino group. In this case, the benzopyran derivatives described
in the EP Offenlegungsschrift are activators or openers of the so-called adenosine
35 triphosphate-sensitive K+ channel [K+(ATP) channel]. Now, as is known, the
CA 0220~477 1997-0~
pharmacological actions of K+(ATP) channel openers are completely different fromthe blockers of the ISK channel described here. Thus for the K+(ATP) channel
openers, typical vasodilating and hypotensive properties were demonstrated for this
mechanism. As expected, the described K+(ATP) channel openers synthesized by
the authors show typical, specific antiarrhythmic properties for this mechanism of K+
channel opening. In a basic study, Lucchesi et al. (J.Cardiovasc. Pharmacol.15,
452 - 464 [1990]) were impressively able to show that K+(ATP) channel openers donot have an antiarrhythmic action on the diseased heart which is undersupplied with
oxygen or in sudden ischemias, but in contrast even cause life-threatening
profibrillatory effects. These dangerous conditions are caused as a consequence of
the reductions in the repolarization period resulting from the activation of theK+(ATP) channel. Unlike these life-threatening profibrillatory effects on the
diseased, defectively supplied heart due to the action of K+(ATP) channel openers,
blockers of the K+(cAMP) channel should show antifibrillatory action under theseconditions. As a prominent representative of the compounds of the formula la
synthesized by us, in the meantime 6-cyano-4-(n-ethylsulfonyl-N-methyl)amino-2,2-
dimethyl-3-chromanol found its way into the most recent literature under the name
293B as an example of a highly specific IKS Or ISK channel blocker having a
corresponding lengthening of the action potential on the heart (Sul3brich et al,Naunyn Schiedebergs Arch.Pharm. [1996] 353 (4,Suppl.), R72; Pflugers Arch.-Eur.
J. Physiol. 431 (6) [Suppl], R 22 [1996], A. Busch et al., Pflugers Arch.-Eur. J.
Physiol. 432 (6) [Suppl],1094-1096 [1996]).
On the basis of specific structural knowledge, a few compounds were synthesized
and investigated by us which admittedly are already disclosed in the
Offenlegungsschrift mentioned (EP Offenlegungsschrift 389 861), but were not
described, synthesized or recognized in their therapeutic action by the authors. For
these specific 3-hydroxy-substituted chromans prepared and investigated by us, apotent blockade of the K+(cAMP) channel (Pflugers Arch. - Eur. J. Physiol. [1995]
429: 517 - 530 A new class of inhibitors of cAMP-mediated Cl- secretion in rabbit
colon, acting by the reduction of cAMP-activated K+ conductance) has now
surprisingly been found and the inhibition of the IKS channel on the heart. The ISK
channel-blocking action of the 3-hydroxy-substituted chromans, however, is
markedly less pronounced than that of the corresponding hydroxyl group-free
chromans of the formula 1.
The invention therefore also relates to the use of compounds of the formula la for
CA 0220~477 1997-0
16
the treatment of sudden cardiac death, ventricular fibrillations and generally of
arrhythmias of the diseased heart which are to be attributed to the IKS channel
The publication "N-Sulfonamides of benzopyran-related potassium channel5 openers: conversion of glyburyde insensitive smooth muscle relaxants to potentsmooth muscle contractorsD in Bioorg. Med. Chem. Lett. (1994) 4: 769 - 773
describes specific trifluoromethyl-substituted 4-sulfonyl-aminochroman derivatives
which, however, in contrast to the structurally different K+(cAMP) channel blockers
described here have biologically different pharmacological actions and thus other
10 therapeutic application areas.
Most recently, spiro[2H-1-benzopyran-2,4'-piperidines] having an essential basicside group have additionally been described in the literature, e.g. MK-499 "Cardiac
electrophysiology and antiarrhythmic actions of two long-acting spirobenzopyran
piperidine class lll agents, L-702,958 and L-706,000 (MK499)" J. Pharmakol. Exp.Ther. (1994) 269: 541 - 554; T. J. Colatsky und T. M. Argentieri, "Potassium channel
blockers as antiarrhythmic drugs"; Drug Develp. Res. (1994) 33: 235 - 249.
These "spirobenzopyran piperidine class lll agents" are, however, very clearly
20 characterized in the literature with respect to their mode of action [P. S. Spector, M.
E. Curran, M. T. Keating, M. C. Sanguinetti, Circulation Res. (1996) 78: 499 - 503;
J.J. Lynch et al., J. Pharmacol. Exp. Ther. (1994) 269: 541 - 554]. In this case, it is
clearly described and shown in the literature cited that the antiarrhythmic action of
these compounds is caused by the inhibition of the HERG channel and of the rapidly
25 activating component of the delayed rectifier K+ channel, of the IKr channel. Thus
the spirobenzopyran piperidines are characterized as substances having a
proarrhythmic component and having the danger of an increased mortality
compared to placebo, as has been shown for this active compound class in the
Sword study. This is in clear contrast to the compounds according to the invention,
30 whose advantage consists in the blocking of the slow-activating component of the
delayed rectifier K+ channel, of the IKS channel, which compounds do not have this
proarrhythmic component.
The compounds of the formula I or la can also be combined with other active
CA 0220~477 1997-0~
compounds to achieve an advantageous therapeutic action. But in the treatment ofcardiovascular disorders, advantageous combinations with cardiovascular
substances are conceivable. Possible advantageous combination components of
this type for cardiovascular disorders can be, for example, other antiarrhythmics, i.e.
class 1, ll or lll antiarrhythmics, such as, for example, so-called IKr channel blockers~
e.g. dofetilide, furthermore hypotensive substances such as ACE inhibitors (for
example enalapril, captopril, ramipril), angiotensin antagonists, K+ channel
activators, and also alpha- and R-receptor blockers, but also sympathomimetic
compounds and compounds having an adrenergic action, as well as Na+/H+
10 exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and
other substances having positive inotropic action such as digitalis glycosides and
diuretics.
A combination with substances having antibiotic action and with antiulcer agents, for
1~ example with H2 antagonists (ranitidine, cimetidine, famotidine etc.) can furthermore
be advantageous, such as, in particular, in the application for the treatment ofgastrointestinal illnesses.
Pharmaceuticals which contain a compound I or a compound of the formula la
20 according to the invention can be administered orally, parenterally, intravenously,
rectally or by inhalation, the preferred administration being dependent on the
particular clinical picture of the illness. The compounds I and la can in this case be
used on their own or together with pharmaceutical auxiliaries, namely both in
veterinary and in human medicine.
2~
The auxiliaries which are suitable for the desired pharmaceutical formulation are
familiar to the person skilled in the art on the basis of his expert knowledge. Beside
solvents, gel-forming agents, suppository bases, tableting auxiliaries and otheractive compound excipients, it is possible to use, for example, antioxidants,
30 dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or
colorants.
For a form for oral use, the active compounds I and la are mixed with the additives
CA 0220~477 1997-0~
18
suitable for this purpose, such as excipients, stabilizers or inert diluents, and are
brought by means of the customary methods into the suitable administration forms,
such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily
solutions. Inert excipients which can be used are, for example, gum arabic,
5 magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch,
in particular corn starch. In this case, preparation can be carried out both as dry and
as moist granules. Suitable oily excipients or solvents are, for example, vegetable or
animal oils, such as sunflower oil or cod-liver oil.
10 For subcutaneous or intravenous administration, the active compounds of the
formula I or of the formula la are brought into solution, suspension or emulsion, if
desired with the substances customary for this purpose such as solubilizers,
emulsifiers or other auxiliaries. Possible solvents are, for example: water,
physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, and in
15 addition also sugar solutions such as glucose or mannitol solutions, or alternatively
a mixture of the various solvents mentioned. As solubilizers, for example,
oligosaccharides such as cyclodextrins are also used.
Suitable pharmaceutical formulations for administration in the form of aerosols or
20 sprays are, for example, solutions, suspensions or emulsions of the active
compound of the formula I or of the formula la in a pharmaceutically acceptable
solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If
required, the formulation can also contain other pharmaceutical auxiliaries such as
surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation
25 customarily contains the active compound in a concentration of approximately 0.1 to
10, in particular of approximately 0.3 to 3% by weight.
The dose of the active compound of the formula I or of the formula la to be
administered and the frequency of administration depend on the potency and
30 duration of action of the compounds used; but also on the nature and severity of the
illness to be treated as well as on the sex, age, weight and individual
responsiveness of the mammal to be treated.
CA 0220~477 1997-0~
19
On average, the daily dose of a compound of the formula I in the case of a patient of
weight approximately 75 kg is at least 0.1 mg, preferably 10 mg to at most 100 mg,
preferably at most 1 9; or for compounds of the formula la at least 1 mg, preferably
~0 mg, up to at most 300 mg, preferably 1 9.
Explanation of the abbreviations used in the text
DMA Dimethylacetamide
HMPT Hexamethylphosphoramide
TMU Tetramethylurea
hr Hour(s)
mol Mole
mmol Millimole
min Minutes
1~ TEA Triethylamine
THF Tetrahydrofuran
Examples:
Example 1: 4-(N-Ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman
o.;~
N~
a) 2,2-Dimethyl4-chromanone oxime
A reaction mixture prepared from 10 mmol of 2,2-dimethyl4-chromanone, 12 mmol
3D of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine is heated
with stirring over the course of 2 hours to 80 - 85~C, the solvent is distilled off on a
rotary evaporator and the oily residue is crystallized under water.
Crystalline substance, melting point 115 - 118 ~C.
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b) 4-Amino-2,2-dimethylchroman hydrochloride
A solution of 10 mmol of 2,2-dimethyl-4-chromanone oxime and 75 ml of methanol
is hydrogenated, after addition of Raney nickel as a catalyst, in an autoclave with
hydrogen at 60~C, 100 atm. pressure for a period of 6 hours. After filtration and the
removal of the solvent by distillation, the amorphous residue is dissolved in ethyl
acetate and the solution is treated with diethyl ether saturated with HCI gas until it
has a strongly acidic reaction. The crystalline precipitate of 2,2-dimethyl-4-
aminochroman hydrochloride is filtered off, washed several times with ethyl acetate
and dried.
10 Colorless crystals, melting point 268~C.
c) 4-N-Ethylsulfonylamino-2,2-dimethylchroman
Variant 1: a solution of 4.5 mmol of ethanesulfonyl chloride in 5 ml of THF is added
at 0~C in portions to a stirred solution prepared from 4.3 mmol of 4-amino-2,2-
dimethylchroman hydrochloride, 15 ml of THF and 1.25 ml of TEA. The mixture is
stirred for about 2 hours at 0~C and for 1 hour further at room temperature, theprecipitate is filtered and the solvent is distilled off on a rotary evaporator. The
residual oil crystallizes under petroleum ether.
Colorless crystals, melting point 106 -108~C.
Variant 2: 0.83 9 (0.0065 mol) of ethanesulfonyl chloride is added in portions
between 0 and 5~C to a suspension of 1.06 g (0.005 mol) of 4-amino-2,2-
dimethylchroman hydrochloride and 2.0 g (0.02 mol) of TEA in 25 ml of DMA and
the mixture is stirred at room temperature for 2 days. After removal of the solvent by
distillation on a rotary evaporator, the residue is treated with water, whereupon the
oil which separates solidifies in crystalline form after a short time.
Melting point 106 - 1 09~C.
d) 4-N-Ethylsulfonyl-N-methylamino-2,2-dimethylchroman:
A solution of 0.0111 mol of 4-N-ethylsulfonylamino-2,2-dimethylchroman in 15 ml of
anhydrous methanol is slowly added to a sodium methoxide solution, prepared from0.0166 gram atom of sodium in 20 ml of anhydrous methanol. A solution of
0.014 mol of methyl iodide in 5 ml of anhydrous methanol is then added in portions
CA 0220~477 1997-0~
to this mixture and it is heated for 6 hours at 50~C under a reflux condenser. The
solvent is distilled off on a rotary evaporator, and the residue is treated with ethyl
acetate and extracted with 2 N NaOH. The organic phase is dried over anhydrous
sodium sulfate and 4-N-ethylsulfonyl-N-methylamino-2,2-dimethylchroman is
obtained by again removing the solvent by distillation.
Colorless crystalline substance, melting point: 90 - 92~C.
Example 2: 4-(N-Ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman:
0~ //
/~N~
1!~
0.0111 mol of 4-N-ethylsulfonylamino-2,2-dimethylchroman is added with stirring in
portions to a suspension of 0.0122 mol of sodium hydride in 30 ml of anhydrous
dimethylacetamide under an argon atmosphere and the mixture is stirred at room
temperature for a further hour. After subsequent addition of 0.0122 mol of ethyl2D bromide, the mixture is stirred at room temperature for a further 24 hours. The
solvent is distilled off under reduced pressure, the residue is then treated with ethyl
acetate and extracted with water and the organic phase is distilled off in a rotary
evaporator after separation and drying over anhydrous sodium sulfate. 4-(N-Ethyl-N-
ethylsulfonylamino-2,2-dimethylchroman is obtained by crystallization under
25 petroleum ether as a colorless crystalline substance,
melting point 85~C.
CA 0220~477 1997-0~
Example 3: 4-(N-Benzyl-N-ethylsulfonyl)amino-2,2-dimethylchroman
o
T o~ll
~N~S
is obtained analogously to the procedure indicated in Example 2 from 4-N-
10 ethylsulfonylamino-2,2-dimethylchroman and benzyl bromide.
Colorless crystals, melting point 95 - 97~C.
Example 4: 4-lN-Ethylsulfonyl-N-(2-dimethylaminoethyl)]amino-2,2-dimethylchroman
N ~ ~S
~0~
2D is o~tained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-2,2-dimethylchroman and 2-chloroethyldimethylamine
hydrochloride using double the amount of sodium hydride.
Colorless crystals, melting point 90 - 93~C.
Example 5: 4-N-Ethylsulfonylamino-2,2-dimethyl-6,8-dinitrochroman
o~
O HN
3D .~,
N+
3.71 mmol of 4-N-ethylsulfonylamino-2,2-dimethylchroman are added in portions
CA 0220~477 1997-0~
with stirring to 4.3 ml of 100% strength nitric acid cooled to -15 to -20~C and the
mixture is stirred for a further 20 minutes while maintaining the cooling. The reaction
mixture is poured into 50 ml of ice water and filtered, and the yellow crystals are
washed several times with water. The compound is purified by chromatography on
silica gel using a mixture of 3 parts of ethanol and 7 parts of ethyl acetate and
subsequently crystallized using petroleum ether.
Yellow crystalline compound, melting point 140 -142~C.
Example 6: 4-N-Ethylsulfonylamino-2,2-dimethyl-6-nitrochroman
1D O
0~//
o- HN
1~ ZN~
0.~4 ml of 100% strength nitric acid is added in portions at -20~C to a mixture of
3.71 mmol of 4-N-ethylsulfonylamino-2,2-dimethylchroman in 2.54 ml of acetic acid
and the mixture is stirred at -20~C for a further 5 min. The reaction mixture is poured
into 50 ml of ice water, and the violet-colored precipitate is filtered and washed
20 several times with cold water on the filter. The crystals are dissolved in a little ethyl
acetate and chromatographed on silica gel using a mixture of 3 parts of petroleum
ether and 2 parts of ethyl acetate.
Pale yellow crystals, melting point 198 - 201~C.
2~ Example 7: 4-(N-Ethyl-N-ethylsulfonyl)amino-2,2-dimethyl-6-nitrochroman
0~//
O- /~N~
3D ~_ ~ ~ ~ ~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-2,2-dimethyl-6-nitrochroman and ethyl bromide.
CA 0220~477 1997-0~
24
Pale yellow crystals, melting point 180 - 1 85~C.
Example 8: 4-(N-Ethylsulfonyl-N-methyl)amino-2,2-dimethyl-6-nitrochroman
o
~ ~S
o N
~zN~
~0~
10 is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-2,2-dimethyl-6-nitrochroman and methyl iodide.
Pale yellow crystals, melting point 190 - 1 92~C.
Example 9: 6-Amino-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman
1 5 hydrochloride
o
x HCI
N
H2N ~/\
~
is obtained by catalytic hydrogenation of 7.21 mmol of 4-N-ethylsulfonyl-N-
methylamino-2,2-dimethyl-6-nitrochroman with hydrogen gas in 150 ml of methanol
using Raney nickel as a catalyst until the theoretical amount of hydrogen has been
absorbed over a period of approximately 1.5 hr at 760 torr. After filtration andevaporation of the solvent, the amorphous residue is dissolved in ethyl acetate and
~he product is purified, by addition of a saturated solution of HCI gas in diethyl ether,
by precipitation of the hydrochloride.
Colorless crystals, melting point 75 - 78~C.
CA 0220~477 1997-0~
Example 10: 6-Amino-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethyl-chroman
hydrochloride
x HCI ~ ~S~
H2N
~0~
is obtained analogously to the procedure indicated in Example 9 from 4-N-ethyl-N-
10 ethylsulfonylamino-2,2-dimethyl~-nitrochroman by catalytic hydrogenation with Raney nickel.
Colorless crystals, melting point 95 - 100~C.
Example 11: 4-N-(Dimethylaminosulfonyl)amino-2,2-dimethylchroman
1~ o /~
,S~
~
A solution of 0.03 mmol of TEA in 30 ml of DMA is added to a suspension of
10 mmol of 4-amino-2,2-dimethylchroman hydrochloride in 75 ml of anhydrous THF.
The mixture is stirred at room temperature for approximately 30 min and a solution
of 12 mmol of N,N-dimethylsulfamoyl chloride in 10 ml of anhydrous THF is added
2~ dropwlse to the suspension with cooling at approximately 1 0~C. After removing the
cooling bath, the mixture is stirred at room temperature for a further 24 hr. The
solvent is then distilled off on a rotary evaporator and the residue is stirred under
water, crystallization taking place after some time. After filtering off the crystals and
washing with water, 4-N-(dimethylaminosulfonyl)amino-2,2-dimethylchroman is
obtained as colorless crystals,
melting point 77 - 79~C.
Example 12: 4-N-Methyl-N-(dimethylaminosulfonyl)amino-2,2-dimethyl-chroman
CA 0220~477 1997-0~
26
\\ ~ ~
5 ~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
(dimethylaminosulfonyl)amino-2,2-dimethylchroman and methyl iodide.
Colorless crystals, melting point 146 -148~C.
Example 13: 4-N-Ethylsulfonylamino-6-fluoro-2,2-dimethylchroman
0;~ //
HN
F ~,
~0~
a) 4-Fluorophenyl acetate
is obtained as an oily residue by boiling 4-fluorophenol in acetic anhydride and then
evaporating the solvent.
b) 5-Fluoro-2-hydroxyacetophenone
is obtained from 0.0376 mol of 4-fluorophenyl acetate and 0.083 mol of anhydrousAICI3 (for Friedel-Crafts reactions) at 120~C for 2 to 3 hours and by then
decomposing with ice water after cooling. The mixture is extracted with ethyl acetate
and, after drying over sodium sulfate, the solvent is removed by distillation and the
amorphous viscous residue is crystallized under cyclohexane.
Colorless crystalline substance, melting point 46 - 47~C.
c) 6-Fluoro-2,2-dimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 5-fluoro-2-
hydroxyacetophenone and acetone in the presence of pyrrolidine.
CA 0220~477 1997-0~
Colorless to slightly yellow amorphous residue.
d) 6-Fluoro-2,2-dimethyl4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro-
5 2,2-dimethyl4-chromanone and hydroxylamine hydrochloride, by crystallization of
the product under water and recrystallization from cyclohexane using activated
carbon.
Colorless crystals, melting point 108 - 1 10~C.
e) 4-Amino-6-fluoro-2,2-dimethyl-4-chroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation in an autoclave from 6-fluoro-2,2-dimethyl-4-chromanone oxime,
Raney nickel and hydrogen.
Colorless crystals, melting point 226~C, sublimation from 296~C.
f) 4-N-Ethylsulfonylamino-6-fluoro-2,2-dimethylchroman
5.5 mmol of ethanesulfonyl chloride are added to a suspension of 5 mmol of 4-
amino-6-fluoro-2,2-dimethyl-4-chroman hydrochloride in 20 ml of DMA and 15 mmol
of TEA with stirring and cooling to 1 0~C. The mixture is stirred for a further 24 hours
20 at room temperature, then the solvent is distilled off on a rotary evaporator and the
residue is stirred under 75 ml of water. The oil which separates is extracted with
ethyl acetate, and the organic phase is separated off and dried over anhydrous
sodium sulfate. After distilling off the solvent in a rotary evaporator, 4-
ethylsulfonylamino-6-fluoro-2,2-dimethylchroman is obtained as an amorphous
25 product.
Example 14: 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethyl-chroman
o
0~ //
~N~
F~_,
CA 0220~477 1997-0~
28
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and methyl iodide.
Amorphous oily product.
Example 15: 6-Fluoro-4-N-(dimethylaminosulfonyl)amino-2,2-dimethyl-chroman
0~//
,S~
F~
is obtained analogously to the procedure indicated in Example 11 from 4-amino-6-fluoro-2,2-dimethylchroman and N,N-dimethylsulfamoyl chloride in anhydrous DMA.
Colorless crystals, melting point 86 - 88~C.
Example 16: 6-Fluoro4-[N-methyl-N-(dimethylaminosulfonyl)]amino-
2,2-dimethylchroman
0~//
~ ~S~
F ~,~
L 1~
~ o ~
25 is obtained analogously to the procedure indicated in Example 2 from 6-fluoro4-N-
(dimethylaminosulfonyl)amino-2,2-dimethylchroman and methyl iodide.
Amorphous oily product.
Example 17: 6-Cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman
CA 0220~477 1997-0~
0
~N,S~
NC ~yl~
~0~
a) 6-Cyano-2,2-dimethylchroman
A suspension consisting of 10 mmol of 6-cyano-2,2-dimethyl-3,4-chromene, 50 ml of
methanol and about 500 mg of palladium catalyst on barium sulfate(10% strength) is
shaken in a shaking duck under a hydrogen atmosphere at 1 atm and at 20~C until
the theoretical amount of hydrogen has been absorbed. After filtration of the
catalyst, the solvent is distilled off on a rotary evaporator and 6-cyano-2,2-
dimethylchroman is obtained as a colorless to slightly yellowish oil.
b) 4-Bromo-6-cyano-2,2-dimethylchroman
11 mmol of N-bromosuccinimide and 0.22 9 of azobisisobutyronitrile (Aldrich) areadded to a solution of 10 mmol of 6-cyano-2,2-dimethyl-chroman in 30 ml of carbon
tetrachloride and the suspension thus obtained is heated to boiling under a reflux
condenser for 3 hours. Insoluble succinimide is then filtered off, the solvent is
distilled off and the residue is crystallized under a mixture of n-hexane and
diisopropyl ether.
Slightly yellow crystals, melting point 93 - 94~C.
~) 6-Cyano-4-[N-ethylsulfonyl-N-methyl]amino-2,2-dimethylchroman
A solution of 11 mmol of ethanesulfonic acid N-methylamide is added dropwise
under a protective gas atmosphere of argon to a suspension of 11 mmol of sodium
hydride (as an 80% strength oil suspension) in 5 ml of anhydrous DMA and the
mixture is stirred for about one hour at room temperature. It is then treated with a
solution of 10 mmol of 4-bromo-6-cyano-2,2-dimethylchroman in 7 ml of anhydrous
DMA and stirred for 72 hours at 70~C. The reaction mixture is poured with stirring
into 75 ml of water, the oily amorphous precipitate is extracted with ethyl acetate
CA 0220~477 1997-0~
and the organic phase is dried over anhydrous sodium sulfate. The solvent is
distilled off on a rotary evaporator and the amorphous residue is separated by
column chromatography on the silica gel column using a solvent mixture consisting
of 1 part of toluene and 1 part of ethyl acetate as eluent. After distilling off the
elution liquid in the rotary evaporator, the 6-cyano4-[N-ethylsulfonyl-N-
methyl]amino-2,2-dimethylchroman is obtained as a colorless crystalline product,Melting point 1 66 -1 68~C.
Example 18: 4-N-Ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman
O
0~//
~O HN~
a) 3-Acetyl4-hydroxybenzoic acid
36.6 g (0.274 mol) of AICI3 are suspended in 50 ml of 1,2,4-trichloro-benzene and
treated with 9 9 (50 mmol) of 4-acetoxybenzoic acid. After dropwise addition of
7.84 9 (0.1 mol) of acetyl chloride, the reaction mixture is heated to 130 -140~C, the
evolution of HCI gas occurring from approximately 60~C. The mixture is stirred for
approximately 1 hour at 1 30~C and then allowed to cool to 60 - 70~C, and the
mixture is poured cautiously into stirred ice water. It is extracted several times with
ethyl acetate, then the combined organic phases are extracted with saturated
aqueous sodium bicarbonate solution and the combined aqueous phases are
adjusted carefully to pH ~ 1 using concentrated HCI, the 3-acetyl4-hydroxybenzoic
acid separating as sparingly soluble material.
Colorless crystalline substance, melting point 228 - 233~C.
b) 6-Carboxy-2,2-dimethyl-4-chromanone
13.8 9 of pyrrolidine and 40 ml of acetone are added to a suspension of 14.7 9
(0.0815 mol) of 3-acetyl4-hydroxybenzoic acid in 200 ml of acetonitrile. The slowly
discoloring solution is allowed to stand at room temperature for 2 days, the solvent
CA 0220~477 1997-0~
is distilled off on a rotary evaporator, the residue is treated with water and adjusted
to acidic pH ~ 1 using conc. hydrochloric acid and the crystalline substance is
filtered off.
Colorless crystals, melting point 154 - 160~C.
c) 6-Carboxy-2,2-dimethyl-4-chromanone oxime
14.9 9 of 6-carboxy-2,2-dimethyl-3-chromanone are dissolved in 100 ml of ethanoland 100 ml of pyridine, and after addition of 5.16 9 of hydroxylamine hydrochloride
the mixture is heated at 80~C with stirring for 6 hours. The solvent is distilled off on a
10 rotary evaporator. The residue is treated with water and adjusted to pH < 1 using
conc. hydrochloric acid, and the colorless crystals are filtered off.
Melting point 223 - 225~C.
d) 4-Amino4-carboxy-2,2-dimethylchroman
~5 35.2 9 (0.15 mol) of 6-carboxy-2,2-dimethyl-4-chromanone oxime are dissolved in
300 ml of methanol by addition of 600 ml of concentrated aqueous ammonia and,
after addition of a few grams of Raney nickel catalyst, hydrogenated at 80~C for10 hours under 100 atm hydrogen pressure. After filtering off the catalyst,
approximately 3/4 of the solvent is distilled off in a rotary evaporator. The crystalline
20 precipitate of 4-amino-6-carboxy-2,2-dimethylchroman is filtered off.
Colorless crystals, melting point 307 - 310~C.
e) 4-Amino4-methoxycarbonyl-2,2-dimethylchroman
0.05 mol of 4-amino-6-carboxy-2,2-dimethylchroman is treated with 9.5 ml of conc.
25 sulfuric acid in 200 ml of methanol and the dark solution is heated to reflux for
6 hours. The reaction mixture is adjusted to pH 9 with ice cooling by addition in
portions of saturated aqueous potassium carbonate solution and the precipitated
salt is filtered off. The solvent is distilled off on a rotary evaporator, the oily residue
is treated with water and the mixture is extracted several times with diethyl ether.
30 After removing the solvent by distillation, the oily amorphous residue is crystallized
under n-heptane.
Colorless crystalline substance, melting point 62 - 65~C.
CA 0220~477 1997-0~
f) 4-N-Ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 1 c) from 0.0184 mol
of 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with 0.021 mol of
ethanesulfonyl chloride in THF using excess TEA.
Colorless crystals, melting point 1 11 - 113~C.
Example 19: 4-(N-Ethylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
o
~~
~O N
0~,
is obtained analogously to the procedure indicated in Example 2 from 0.0155 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.0232 mol of
NaH (as an 80% strength suspension in oil) and 0.0217 mol of methyl iodide in
anhydrous DMA.
Colorless crystalline substance, melting point 184 -187~C.
Example 20: 6-Methoxycarbonyl-4-N-(dimethylaminosulfonyl)amino-2,2-
dimethylchroman
o
0~ //
~O H I N--
OJ ~
is obtained analogously to the procedure indicated in Example 11 from 4-amino-6-30 carboxy-2,2-dimethylchroman, dimethylamidosulfonyl chloride and triethylamine in
THF.
Colorless crystals, melting point 127 -129~C.
CA 0220~477 1997-0~
Example 21: 6-Methoxycarbonyl-4-[N-methyl-N-(dimethylaminosulfonyl)]-amino-2,2-
dimethylchroman
0~//
~O ~N~ 'N--
ls obtained analogously to the procedure indicated in Example 2 from
10 6-methoxycarbonyl-4-N-(dimethylaminosulfonyl)amino-2,2-dimethylchroman, NaH
and methyl iodide in DMA.
Colorless crystalline substance, melting point 125 -129~C
Example 22: 4-(N-Butyl-N-ethylsulfonyl)amino-6-methoxycarbonyl-2,2-
1 5 dimethylchroman
o
~ 0~ //
o N
20 o-~r~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, NaH and 1-butyl
iodide in DMA.
2~ Colorless to slightly yellow oily amorphous product.
Example 23: 6-Carboxy-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman
o
0;~ //
HO N~ \
O ~
CA 0220~477 1997-0~
34
A suspension consisting of 1 9 (0.00305 mol) of 4-N-ethylsulfonyl-N-methylamino-6-
methoxycarbonyl-2,2-dimethylchroman, 30 ml of methanol and a solution of 0.36 9
(0.0091 mol) of NaOH in 20 ml of water is stirred under reflux conditions for
approximately 10 hours until the formation of a solution. The solvent is distilled off
on a rotary evaporator, the residue is treated with water, the mixture is adjusted to
pH 0 to 1 using HCI and the colorless crystals are filtered off.
Melting point 235 - 237~C.
Example 24: 6-Aminocarbonyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2-
10 dimethylchroman
o
0~//
H2N ~N~S~--
O '~--''~ ~~
0.38 9 (0.0023 mol) of carbonyldiimidazole is added to a solution of 0.7 9 of 6-carboxy4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman (0.0021 mol) in 25
ml of anhydrous THF, and the mixture is stirred for 3 hours at room temperature and
20 then treated with 10 ml of conc. aqueous ammonia solution (25% strength). After
stirring at room temperature for about 15 hours, the solvent is largely distilled off on
a rotary evaporator, the residue is treated with water and the white crystallinesubstance is filtered off.
Melting point 202 - 204~C.
Example 25: 6-Cyano-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman
0
N
NC~
~0~
CA 0220~477 1997-0~
.~ 9 (0.0015 mol) of 6-aminocarbonyl-4-(N-ethylsulfonyl-N-methyl)amino-2,2-
dimethylchroman is treated, as a mixture with 0.72 g (0.0045 mol) of N-
trimethylsllylpyrrolidone, with 0.0013 9 (0.000075 mol) of sodium
bis(trimethylsilyl)amide under an argon atmosphere and the mixture is heated to
90~C (bath temperature). From the initial solid mixture is formed a solution, which is
sfirred at 90~C for 4 hours and then allowed to stand overnight at room temperature.
After removing the inert gas protection and stirring with water, crystallization of the
oil occurs. The crystals are filtered off with suction and purified from still-present
starting material by chromatography on silica gel using a mixture of 10 parts of10 methylene chloride and 1 part of methanol as elution medium.
Melting point 164 - 167~C.
Example 26: 6-Carboxy-4-N-ethylsulfonylamino-2,2-dimethylchroman
o
1~ 0~//
HO HN ~S~
O~
2û is obtained analogously to the procedure indicated in Example 1 a) from 4-amino-6-
methoxycarbonyl-2,2-dimethylchroman with isopropylsulfonyl chloride in THF usingexcess TEA.
Colorless crystals, melting point 112 - 115~C.
Example 27: 4-lN-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]-6-methoxy-carbonyl-
2,2-dimethylchroman
F~ 0~ /
oS~J~
W~o~
CA 0220~477 1997-0~
36
is obtained analogously to the procedure described in Example 2 from 4-N-
ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and 4,4,4-trifluoro-1-
iodobutane in DMA.
Pale yellow to colorless oily amorphous product.
.5
Example 28: 6-Carboxy-4-~N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]-2,2-
dimethylchroman
~~~/S
HO N~ ~
0
~0
is obtained analogously to the procedure described in Example 23 by alkaline
hydrolysis of 4-N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman.
Colorless crystalline substance, melting point 189 - 1 92~C.
Example 29: 4-(N-Butyl-N-ethylsulfonyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
~ //
~ N~
O ~
is obtained analogously to the procedure described in Example 2 from 4-N-
ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and butyl iodide in
DMA. Colorless crystalline substance, melting point 81 - 84~C.
CA 0220~477 1997-0~
Example 30: 6-Methoxycarbonyl-4-N-methylsulfonylamino-2,2-dimethylchroman
0~ //
~o HN ~
O=
is obtalned analogously to the procedure described in Example 1 c) from 4-amino~-
methoxycarbonyl-2,2-dimethylchroman with methanesulfonyl chloride.
1û Colorless crystalline substance, melting point 159 -163~C.
Example 31: 6-Aminocarbonyl-4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)-amino]-2,2-
dimethylchroman
1~; F~Q o~ll
H2N N~ \
O
2D is obtained analogously to the procedure described in Example 24 from 6-carboxy-
~N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino-2,2-dimethyl-chroman,
carbonyldiimidazole and ammonia.
Colorless crystalline substance, melting point 170 -174~C.
2~ Example 32: 6-Carboxy4-[N-methyl-N-(dimethylaminosulfonyl)amino]-2,2-
dimethylchroman
0~
3D ~ ~S
is obtained analogously to the procedure indicated in Example 23 from
CA 0220~477 1997-0~
38
6-methoxycarbonyl-4-[N-methyl-N-(dimethylaminosulfonyl)amino]-2,2-
dimethylchr~n ~an.
Colorless crystalline compound, melting point 245 - 248~C.
Example 33: 6-Cyano4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino]-2,2-
dimethylchroman
F~
F N~S~
NC~
L 11 ~""'
~o ~
;s obtained analogously to the procedure indicated in Example 25 from
6-aminocarbonyl4-N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)amino-2,2-dimeth-
15 ylchroman and by subsequent purification by column chromatography on silica gel
using a mixture of 10 parts of methylene chloride and 1 part of methanol as eluent.
Colorless to pale yellow crystalline substance, melting point 172 - 176~C.
Example 34: 6-Aminocarbonyl-4-[N-methyl-N-(dimethylamino)-sulfonylamino]-2,2-
20 dimethylchroman
0~//
H2N ~ ,S
O~ i 5 ~
is obtained analogously to the procedure indicated in Example 24 from 6-carboxy4-
~N-methyl-N-(dimethylaminosulfonyl)amino]-2,2-dimethyl-chroman.
Colorless crystalline substance, melting point 215 - 218~C.
3~
Example 35: 6-Cyano~-[N-methyl-N-(dimethylaminosulfonyl)amino]-2,2-
dimethylchroman
-
CA 0220~477 1997-0~
39
0~
~N N--
N ~r~~
is obtained analogously to the procedure indicated in Example 25 from
6-aminocarbonyl-4-[N-methyl-N-(dimethylaminosulfonylamino]-2,2-dimethylchroman.
1D Colorless crystalline substance, melting point 100 -102~C.
Example 36: 4-(N-Butyl-N-ethylsulfonyl)amino-6-carboxy-2,2-dimethylchroman
HO N~ \
oS~
~0
is obtained analogously to the procedure indicated in Example 23 from 4-N-(butyl-N-
2D ethylsulfonyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.
Colorless crystalline compound, melting point 148 -151~C.
Example 37: 6-Aminocarbonyl-4-(N-butyl-N-ethylsulfonyl)amino-2,2-
dimethylchroman
/~ 0~/l
H2N N~
0~
W~o~
is obtained analogously to the procedure indicated in Example 24 from 4-(N-butyl-N-
ethylsulfonyl)amino-6-carboxy-2,2-dimethylchroman.
Colorless crystalline substance, melting point 195 -199~C.
CA 0220~477 1997-0~
Example 38: 4-(N-Butyl-N-ethylsulfonyl)amino-6-cyano-2,2-dimethyl-chroman
/~ N
N~
~0~
is obtained analogously to the procedure indicated in Example 25 from
1 D 6-aminocarbonyl-4-N-butyl-N-ethylsulfonylamino-2,2-dimethylchroman.
Colorless crystalline substance, melting point 96 - 98~C.
Example 39: 4-[N-Ethylsulfonyl-N-(4-picolyl)amino]-6-methoxycarbonyl-2,2-
dimethylchroman
1~ ~N 'i
~o~, //~
O N
~
~0~
is obtained analogously to the procedure indicated in Example 2 from 0.005 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman, 0.015 mol of NaH
2~ and 0 007 mol of 4-picolyl chloride hydrochloride.
Dark-colored, oily amorphous substance.
Example 40: 6-Carboxy4-[N-ethylsulfonyl-N-(4-picolyl)amino]-2,2-dimethylchroman
CA 0220~477 1997-0~
~N ~
~o~ llo
HO N~
0
~0
10 is obtained analogously to the procedure indicated in Example 23 from 4-[N-
ethylsulfonyl-N-(4-picolyl)amino]4-methoxycarbonyl-2,2-dimethyl-chroman.
Colorless crystalline substance, melting point 210 - 212~C.
Example 41: 6-Aminocarbonyl-4-[N-ethylsulfonyl-N-(4-picolyl)amino]-2,2-
1 5 dimethylchroman
~0~//
H2N N ~
O J y~"' ~'~
is obtained analogously to the procedure indicated in Example 24 from 6-carboxy-4-
N-ethylsulfonyl-N-(4-picolyl)amino-2,2-dimethylchroman.
Colorless crystalline compound, melting point 193 - 1 96~C.
Example 42: 6-Piperidinocarbonyl-4-N-ethylsulfonyl-N-methylamino-2,2-
dimethylchroman
CA 0220~477 1997-0~
o
N~ N~
O J
ls obtained analogously to the procedure indicated in Example 24 from 0.003 mol of
6-carboxy-4-[N-ethylsulfonyl-N-methylamino]-2,2-dimeth-ylchroman, 0.0033 mol of
10 N,N-carbonyldiimidazole and 0.012 mol of piperidine.
Colorless crystals from ethanol, melting point 184~C.
Example 43: 4-N-lsopropylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman
O~//
~O HN~
I /
05~
is obtained analogously to the procedure indicated in Example 1 c) from 0.024 mol
of 4-amino-6-methoxycarbonyl-2,2-dimethylchroman with 0.0319 mol of
ethanesulfonyl chloride using excess TEA in THF under reflux conditions in the
course of 12 hours and by additional purification of the product by column
chromatography on silica gel using a mixture of 1 part of ethyl acetate and 3 parts of
2~ toluene as eluent.
Colorless crystals, melting point 111 - 113~C.
Example 44: 4-(N-lsopropylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
CA 0220~477 1997-0~
43
0~//
~O ~N~ ~
O =
is obtained analogously to the procedure described in Example 2 from 4-N-
isopropylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchrorrlan and methyl iodide.
Colorless crystals, melting point 115 -119~C.
Example 45: 6-Carboxy4-(N-isopropylsulfonyl-N-methyl)amino-2,2-
dimethylchroman
o
O~//
o'' I~ 'r ~~
20 is obtained analogously to the procedure described in Example 23 from 4-(N-
isopropylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.
Colorless crystals, melting point 228 - 233~C.
Example 46: 6-Aminocarbonyl-4-(N-isopropylsulfonyl-N-methyl)amino-2,2-
25 dimethylchroman
o
0.~ //
H2N ~N~S~--
o ~r~r~
is obtained analogously to the procedure described in Example 24 from 6-carboxy-4-(N-isopropylsulfonyl-N-methyl)amino-2,2-dimethylchroman.
CA 0220~477 1997-0~
44
Colorless crystalline product, melting point 217 - 220~C.
Example 47: 6-Cyano-4-(N-isopropylsulfonyl-N-methyl)amino-2,2-dimethylchroman
o
~S
~N~
N~, /
~0~
10 is obtained analogously to the procedure described in Example 25 from
6-aminocarbonyl-4-(N-isopropylsulfonyl-N-methyl)amino-2,2-dimethylchroman. Afterisolation of the product by filtration, it is purified by chromatography on silica gel
using a mixture of 10 parts of methylene chloride and 1 part of methanol and thesubstance is crystallized under diisopropyl ether after removing the solvent by
1 5 distillation.
Colorless crystals, melting point 129 -135~C.
Example 48: 4-N-Butylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman
o
0;~
'o HN~ \
0 ~
25 is obtained analogously to the procedure described in Example 1 c) from 4-amino-
2,2-dimethylchroman hydrochloride and 1-butylsulfonyl chloride.
Melting point 1 17 - 1 20~C.
Example 49: 4-(N-Butylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-
30 dimethylchroman
CA 0220~477 1997-0~
0
N~
O~,~
is obtained analogously to the procedure described in Example 2 from 4-N-
butylsulfonylamino-6-methoxycarbonyl-2,2-dimethylchroman and methyl iodide.
10 Colorless to pale yellow amorphous oily product.
Example 50: 4-(N-Butylsulfonyl-N-methyl)amino-6-carboxy-2,2-dimethylchroman
0~//
1~ HO ~N~S~~
O' ~
is obtained analogously to the procedure described in Example 23 from 4-(N-
butylsulfonyl-N-methyl)amino-6-methoxycarbonyl-2,2-dimethyl-chroman.
Colorless crystalline product, melting point 200 - 205~C.
Example 51: 6-Aminocarbonyl-4-(N-butylsulfonyl-N-methyl)amino-2,2-
dimethylchroman
O
~~S//
H2N N
O ~~~
is obtained analogously to the procedure described in Example 24 from 4-(N-
butylsulfonyl-N-methyl)amino-6-carboxy-2,2-dimethylchroman.
Colorless crystalline product, melting point 162 -166~C.
CA 0220~477 1997-0~
46
Example 52: 6-Cyano4-N-butylsulfonyl-N-methylamino-2,2-dimethyl-chroman
0~//
~N ~S~
NC
~0~
is obtalned analogously to the procedure described in Example 25 from
6-aminocarbonyl4-(N-butylsulfonyl-N-methyl)amino-2,2-dimethylchroman. After
10 isolation of the product by filtration, it is purified by chromatography on silica gel
using a mixture of 10 parts of methylene chloride and 1 part of methanol and thesubstance is crystallized under diisopropyl ether after removing the solvent by
distillation.
Colorless crystals, melting point 57 - 62~C.
Example 53: 6-Methoxycarbonyl4-(N-methyl-N-methylsulfonyl)amino-2,2-
dimethylchroman
o
0~ //
O
is obtained analogously to the procedure described in Example 2 from
2~ 6-methoxycarbonyl4-N-methylsulfonylamino-2,2-dimethylchroman and methyl
iodide.
Colorless crystalline substance, melting point 160 -164~C.
CA 0220~477 1997-0~
47
Example 54: 6-Carboxy4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethylchroman
0~, //
HO ~N~ ~
O=
is obtained analogously to the procedure described in Example 23 from
6-methoxycarbonyl-4-N-methyl-N-methylsulfonylamino-2,2-dimethylchroman by
~0 alkaline hydrolysis.
Colorless crystalline compound of melting point 214 - 216~C.
Example 55: 6-Aminocarbonyl-4-(N-methyl-N-methylsulfonyl)amino-2,2-
dimethylchroman
O
0~ //
is obtained analogousiy to the procedure described in Example 24 from 6-carboxy-4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethylchroman.
Colorless crystalline substance, melting point 179 -182~C.
Example 56: 6-Cyano-4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethylchroman
o
0~ //
~N~ ~
NC~ ,
W~
is obtained analogously to the procedure desribed in Example 25 from
CA 0220~477 1997-0~
48
6-aminocarbonyl-4-(N-methyl-N-methylsulfonyl)amino-2,2-dimethyl-chroman. After
isolation of the product by filtration, it is purified by chromatography on silica gel
using a mixture of 10 parts of methylene chloride and 1 part of methanol and thesubstance is crystallized under diisopropyl ether after removing the solvent by
distillation.
Colorless crystals, melting point 196 - 200~C.
Example 57: 4-(N-Ethylsulfonyl-N-ethyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
O
O ~//
~O --N' \
is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.013 mol of NaH
(as an 80% strength suspension in oil) and 0.0126 mol of ethyt iodide in anhydrous
20 DMA.
Colorless crystalline substance,
melting point 114 - 116~C.
CA 0220~477 1997-0~
49
Example 58: 4-(N-Ethylsulfonyl-N-propyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
o
O ~//
~; ~O \/~N '
O=
is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.013 mol of NaH
(as an 80% strength suspension in oil) and 0.0126 mol of 1-propyl iodide in
anhydrous DMA.
Colorless crystalline substance,
melting point 106-108~C.
Example 59: 4-(N-Ethylsulfonyl-N-cyclopropyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
V o
~ O ~ //
O N
2~ ~ ~ [ ~l<
is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.013 mol of NaH
(as an 80% strength suspension in oil) and 0.0126 mol of bromomethylcyclopropanein anhydrous DMA.
3D Colorless crystalline substance,
melting point 108-11 0~C.
CA 0220~477 1997-0~
Example 60: 4-(N-Ethylsulfonyl-N-1-pentyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
~ ~~ 11~
~ O N \~
~
1D is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.013 mol of NaH
las an 80% strength suspension in oil) and 0.0126 mol of pentyl iodide in anhydrous
DMA.
Oily amorphous product.
1~;
Example 61: 4-(N-Ethylsulfonyl-N-1-hexyl)amino-6-methoxycarbonyl-2,2-
dimethylchroman
~ ~ O~ //o
2D o
~--;''I' ~
2~ is obtained analogously to the procedure indicated in Example 2 from 0.0091 mol of
4-N-ethylsulfonylamino-6-methoxycarbonyl-2,2-dimethyl-chroman, 0.013 mol of NaH
(as an 80% strength suspension in oil) and 0.0126 mol of hexyl iodide in anhydrous
DMA.
Oily amorphous product.
CA 0220~477 1997-0~
51
Example 62: 4-(N-Ethylsulfonyl-N-methyl)amino-6,7-dimethoxy-2,2-dimethylchroman
O~
N
~0~
a) 6,7-Dimethoxy-2,2-dimethyl-4-chromanone oxime
is obtained by reaction of 0.0189 mol of 6,7-dimethoxy-2,2-dimethyl-4-chromanonewith 0.02 mol of hydroxylamine hydrochloride in a mixture of 20 ml of methanol and
20 ml of pyridine for 20 hours at 60 - 80~C. After removing the solvent by distillation,
the colorless crystalline product is obtained by treating the residue with water.
melting point 110~C.
b) 4-Amino-6,7-dimethoxy-2,2-dimethyl-4-chroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 6,7-dimethoxy-2,2-dimethyl-4-chromanone oxime and subsequent
work-up in the presence of hydrochloric acid. Colorless crystalline substance ofmelting point 210-215~C.
c) 4-N-Ethylsulfonylamino-6,7-dimethoxy-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 1 c) (variant 1) from
4-amino-6,7-dimethoxy-2,2-dimethyl4-chroman hydrochloride and ethanesulfonyl
2~ chloride in THF in the presence of triethylamine.
Colorless crystalline product,
melting point 132 - 135~C
d) 4-(N-Ethylsulfonyl-N-methyl)amino-6,7-dimethoxy-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 2 from 0.0036 mol of
4-N-ethylsulfonylamino-6,7-dimethoxy-2,2-dimethylchroman, 0.00504 mol of NaH
(as an 80% strength suspension in oil) and 0.0054 mol of methyl iodide in
anhydrous DMA.
Amorphous viscous oil.
CA 0220~477 1997-0~
Example 63: 7-Chloro4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-
dlmethylchroman
O~
N
Cl
10 a) 2-Fluoro-~-acetoxychlorobenzene
is obtained by reaction of 3-chloro-4-fluorophenol in acetic anhydride at 80~C for 6
hours.
Colorless, crystalline product,
melting point 42-46~C.
1~
b) 4-Chloro-5-fluoro-2-hydroxyacetophenone
is obtained by heating a mixture of 0.0705 mol of 2-fluoro-5-acetoxy-chlorobenzene
with 0.148 mol of anhydrous aluminum chloride with mechanical stirring at 120~C for
about 3 hours, decomposition of the reaction mixture with an ice water/ice mixture
20 and filtration of the precipitate. Colorless crystalline substance by treatment with
activated carbon in methanol and, after distillation of the solvent, by subsequent
digestlon with a mixture of n-heptane and diisopropyl ether.
Colorless crystals,
melting point 66 - 71 ~C.
2~
c) 7-Chloro-6-fluoro-2,2-dimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 4-chloro-
~-fluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in
acetonitrile as solvent.
30 Colorless to slightly yellow amorphous residue.
d) 7-Chloro-6-fluoro-2,2-dimethyl4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 7-chloro-6-
fluoro-2,2-dimethyl4-chromanone and hydroxylamine hydrochloride.
3~ Crystalllne product,
CA 0220~477 1997-0~
melting polnt 120 -125~C.
e) 7-Chloro-6-fluoro-2,2-dimethyl4-aminochroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
5 hydrogenation of 7-chloro4-fluoro-2,2-dimethyl4-chromanone oxime and work-up
in the presence of hydrochloric acid.
Two melting points:
1 st melting point: 258 - 260~C with fresh crystallization of the melt,
2nd melting point > 31 0~C.
f) 7-Chloro-6-fluoro-2,2-dimethyl4-ethylsulfonylaminochroman
is obtained analogously to the procedure indicated in Example 1 c) by reaction of 7-
chloro-6-fluoro-2,2-dimethyl-4-aminochroman hydrochloride with ethanesulfonyl
chloride in the presence of TEA in THF
~5
g) 7-Chloro4-(N-ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-dimethyl-chroman
is obtained analogously to the procedure indicated in Example 2 by reaction of 7-
chloro~-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman with sodium hydride and
methyl iodide.
20 Colorless crystalline substance,
melting point 104 - 1 07~C.
Example 64: 4-(N-Ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman
o
O ~ //
N
H3C
a) 2,2,6-Trimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 5-methyl-
2-hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as
solven~
35 Amorphous oily product.
CA 0220~477 1997-0~
54
b) 2,2,6-Trimethyl4-chromanone oxime
;s obtalned analogously to the procedure indicated in Example 1 a) from 2,2,6-
trimethyl4-chromanone and hydroxylamine hydrochloride.
Crystalline product, melting point 120 - 125~C.
c) 4-Am;no-2,2,6-trimethyl4-aminochroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 2,2,6-trimethyl4-chromanone oxime and work-up in the presence
of hyrochloric acid.
10 Two melting points:
1st melting point.: 245 - 248~C with fresh crystallization of the melt,
2nd melting point > 31 0~C.
d) 4-Ethylsulfonylamino -2,2,6-dimethylchroman
1~ is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4-
amino-2,2,6-trimethylchroman hydrochloride with ethanesulfonyl chloride in the
presence of TEA in THF.
Colorless crystalline product,
melting point 114 - 1 17 ~C.
4-(N-Ethylsulfonyl-N-methyl)amino-2,2,6-trimethylchroman
is obtained analogously to the procedure indicated in Example 2 by reaction of 4-
ethylsulfonylamino -2,2,6-dimethylchroman with sodium hydride and methyl iodide.Colorless crystalline substance,
25 melting point 107~C.
Example 65: 6,7-Dichloro4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman
o
O~
N
Cl~
3~
CA 0220~477 1997-0~
a) 4,5-Dichloro-2-hydroxyacetophenone
is obtained analogously to the procedure indicated in Example 63 b) from 3,4-
dichlorphenyl acetate and anhydrous, active aluminum chloride.
Colorless to slightly yellowish-colored crystalline substance,
melting point 100 - 1 03~C.
The 3,4-dichlorphenyl acetate used is obtained as a brown oil from 3,4-
dichlorophenol and acetic anhydride analogously to the procedure described in
Example 63 a).
b) 6,7-Dichloro-2,2-dimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 4,5-
dichloro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in
acetonitrile as solvent.
Amorphous brown oily product.
c) 6,7-Dlchloro-2,2-dimethyl-4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6,7-
dichloro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.
Crystalline product,
melting point 115 -121~C.
d) 4-Amino-6,7-dichloro-2,2-dimethylchroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 6,7-dichloro-2,2-dimethyl4-chromanone oxime and work-up in the
25 presence of hydrochloric acid.
Two melting points:
1 st melting point: 260 - 262~C with fresh crystallization of the melt,
2nd melting point > 310~C.
30 e) 6,7-Dichloro-2,2-dimethyl~-N-ethylsulfonylaminochroman
is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4-
amino-6,7-dichloro-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloridein the presence of TEA in THF.
Colorless crystalline product, melting point 116 - 120~C.
CA 0220~477 1997-0~
56
fl 6,7-Dichloro4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 2 by reaction of 6,7-
dichloro-2,2-dimethyl-4-N-ethylsulfonylaminochroman with sodium hydride and
methyl iodide.
Colorless crystalline substance,
melting point 102 - 1 06~C.
Example 66: 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-7-pyrrolidino-2,2-
dimethylchroman
o
O~
N
F
a) 4,~-Difluoro-2-hydroxyacetophenone
20 is obtained analogously to the procedure indicated in Example 63 b) from 3,4- difluorophenyl acetate and anhydrous, active aluminum chloride.
Colorless to slightly yellowish-colored crystalline substance,
melting point 43 - 46~C (crystallization under n-heptane).
The 3,4-difluorophenyl acetate used is obtained as a pale oil from 3,4-di-
2~ fluorophenol and acetic anhydride analogously to the procedure described inExample 63 a).
b) 6-Fluoro-7-pyrrolidino-2,2-dimethyl4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 4,5-
30 difluoro-2-hydroxyacetophenone and acetone in the presence of 1.1 mol equivalents
of pyrrolidine in acetonitrile as solvent, the fluorine atom in the 7-position being
exchanged for pyrrolidine in addition to the chromanone ring closure. For further
purification, the product can be separated by chromatography on silica gel and an
8: 1 mixture of toluene/ethyl acetate. Crystallization under n-heptane.
3~ Colorless to slightly yellow crystalline product,
CA 0220~477 1997-0~
57
melting point 96 - 98~C.
c) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro-7-
pyrrolidino-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.
Crystalline product,
melting point 148 -152~C.
d) 6-Fluoro-7-pyrrolidino-2,2-dimethyl4-aminochroman dihydrochloride
10 is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hyrogenation of 6-fluoro-7-pyrrolidino-2,2-dimethyl-4-chromanone oxime and work-up in the presence of hydrochloric acid.
Colorless crystalline product
Melting point: 124 - 137~C with decomposition.
e) 6-Fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonylaminochroman
is obtained analogously to the procedure indicated in Example 1 c) by reaction of 6-
fluoro-7-pyrrolidino-2,2-dimethyl-4-aminochroman dihydrochloride and
ethanesulfonyl chloride in the presence of TEA in THF.
20 Colorless crystalline product,
melting point 157 - 1 59~C (from a mixture of diisopropyl ether and methanol).
fl 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-7-pyrrolidino-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 2 by reaction of 6-
25 fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonylaminochroman with sodium
hydride and methyl iodide.
Colorless crystalline substance,
melting point 1 36 -1 38~C
30 Example 67: 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluorochroman
CA 0220~477 1997-0
58
O ~//
~N ,S~
F~
a) 6-Fluoro-4-chromanone oxime
10 is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro4-
chromanone and hydroxylamine hydrochloride.
Crystalline product,
melting point 106-107~C.
15 b) 6-Fluoro4-aminochroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 6-fluoro4-chromanone oxime and work-up in the presence of
hydrochloric acid.
Melting point: 252~C (decomposition).
c) 6-Fluoro4-ethylsulfonylaminochroman
is obtained analogously to the procedure indicated in Example 1 c) by reaction of 6-
fluoro4-aminochroman hydrochloride and ethanesulfonyl chloride in the presence
of TEA in THF.
25 Colorless crystalline substance,
melting point 1 07 -1 08~C.
d) 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluorochroman
is obtained analogously to the procedure indicated in Example 2 by reaction of 6-
30 fluoro4-ethylsulfonylaminochroman with sodium hyride and methyl iodide,
Colorless to pale yellow oil.
CA 0220~477 1997-0~
59
Example 68: 4-(N-Butyl-N-ethylsulfonyl)amino-6-fluorochroman
O~
/\~ N
F ~
is obtained analogously to the procedure indicated in Example 2 by reaction of 6-
~0 fluoro-4-ethylsulfonylaminochroman with sodium hydride and iodobutane.
Colorless to pale yellow oil.
Example 69: 4-(N-Ethylsulfonyl-N-ethyl)amino-6-fluoro-2,2-dimethyl-chroman
o
0 ~ l/
--N
F~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and ethyl iodide.
Amorphous oily product.
CA 0220~477 1997-0~
Example 70: 4-(N-Ethylsulfonyl-N-propyl)amino-6-fluoro-2,2-dimethyl-chroman
O ~//
~N,S~
F~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
10 ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and propyl iodide.
Amorphous oily product.
Example 71: 4-(N-Butyl-N-ethylsulfonyl)amino-6-fluoro-2,2-dimethyl-chroman
O ~ //
/--N ~~
F l,~, r~l=~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and butyl iodide.
Amorphous oily product.
2~ Example 72: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-
dimethylchroman
o
O ~ //
F3C~~N ,S~
F~
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61
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino4-fluoro-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide.
Amorphous oily product.
Example 73: 4-(N-Ethylsulfonyl-N-hexyl)amino-6-fluoro-2,2-dimethyl-chroman
o
O ~//
~~~ N--S
F
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and hexyl iodide.
15 Amorphous oily product.
Example 74: 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylenechroman
o
O~
N
F ~ ~ ~ , J,
25 a) 6-Fluoro-2,2-tetramethylene4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 5-fluoro-2-
hydroxyacetophenone and cyclopentanone in the presence of pyrrolidine in
acetonitrile as solvent.
Amorphous brown product.
b) 6-Fluoro-2,2-tetramethylene4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro-
2,2-tetramethylene4-chromanone and hydroxylamine hydrochloride.
Colorless to pale brown-colored crystalline substance,
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62
melting point 107 - 1 1 0~C.
c) 4-Amino~-fluoro-2,2-tetramethylenechroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
5 hydrogenation of 6-fluoro-2,2-tetramethylene4-chromanone oxime and work-up in
the presence of hydrochloric acid,
melting point: 259 - 261~C with decomposition.
d) 4-Ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman
1~ is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4-
amino-6-fluoro-2,~-tetramethylenechroman hydrochloride and ethanesulfonyl
chloride in the presence of TEA in THF.
Colorless crystalline substance,
melting point 111 - 113~C.
1~
e) 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-tetramethylenechroman
is obtained analogously to the procedure indicated in Example 2 from
4-ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman and methyl iodide.
Amorphous oily product.
Example 75: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-
tetramethylenechroman
o
O ~//
F3C ~~ N--S
F
30 is obtained analogously to the procedure indicated in Example 2 from 4-
ethylsulfonylamino-6-fluoro-2,2-tetramethylenechroman and 4,4,4-trifluorobutyl
iodide.
Viscous oily amorphous product.
CA 0220~477 1997-0~
63
Example 76: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-
pentamethylenechroman
o
O ~//
F3C N ~ S
F
1~
a) 6-Fluoro-2,2-pentamethylene-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 5-fluoro-2-
hydroxyacetophenone and cyclohexanone in the presence of pyrrolidine in
acetonitrile as solvent.
1~ Pale amorphous product.
b) 6-Fluoro-2,2- pentamethylene-4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6-fluoro-
2,2- pentamethylene4-chromanone and hydroxylamine hydrochloride.
20 Viscous amorphous product.
c) 4-Amino-6-fluoro-2,2- pentamethylenechroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 6-fluoro-2,2-pentamethylene-4-chromanone oxime and work-up in
25 the presence of hydrochloric acid,
melting point: 262-264~C with decomposition.
d) 4-Ethylsulfonylamino~-fluoro-2,2-pentamethylenechroman
is obtained analogous~y to the procedure indicated in Example 1 c) by reaction of 4-
30 amino-6-fluoro-2,2-pentamethylenechroman hydrochloride and ethanesulfonyl
chloride in the presence of TEA in THF.
Viscous amorphous product.
e) 4-~N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-
35 pentamethylenechroman
CA 0220~477 1997-0~
64
is obtained analogously to the procedure indicated in Example 2 from
4-ethylsulfonylamino-6-fluoro-2,2-pentamethylenechroman and 4,4,4-trifluorobutyliodide.
Amorphous oily product.
Example 77: 6-Ethyl4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman
o
O~
N
~o ''1,~"''
a) 5-Ethyl-2-hydroxyacetophenone
15 is obtained analogously to the procedure indicated in Example 63 b) from 4-
ethylphenyl acetate and anhydrous, active aluminum chloride.
Slightly yellowish-colored oil.
The 4-ethylphenyl acetate used is obtained as an oil from 4-ethylphenol and acetic
anhydride analogously to the procedure described in Example 63 a).
b) 6-Ethyl-2,2-dimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 5-ethyl-2-
hydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as
solvent.
25 Pale oily amorphous product.
c) 6-Ethyl-2,2-dimethyl~-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6-ethyl-2,2-
dimethyl4-chromanone and hydroxylamine hydrochloride.
30 Viscous oily amorphous product.
d) 4-Amino-6-ethyl-2,2-dimethylchroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
CA 0220~477 1997-0~
hydrogenation of 6-ethyl-2,2-dimethyl4-chromanone oxime and work-up in the
presence of hydrochloric acid,
melting point: 201-204~C.
e) 6-Ethyl4-N-ethylsuifonylamino-2,2-dimethylchroman
is obained analogously to the procedure indicated in Example 1 c) by reaction of 4-
amino-6-ethyl-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the
presence of TEA in THF.
Colorless crystalline substance,
1 0 melting point 1 04 -1 08~C.
fl 6-Ethyl~-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 2 from 6-ethyl-4-N-
ethylsulfonylamino-2,2-dimethylchroman and methyl iodide.
1~ Colorless, crystalline product,
melting point 76 - 77~C.
Example 78: 6-Ethyl4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2-
dimethylchroman
O
O ~//
F3C ~ N ~ S ~
2~ <
is obtained analogously to the procedure indicated in Example 2 from 6-ethyl4-N-ethylsulfonylamino-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide.
Colorless to pale yellow-colored oil.
Example 79: 7-Chloro4-[N-ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-6-fluoro-2,2-
dimethylchroman
CA 02205477 1997-05-15
66
~"S//
F3C N
Cl ~
is obtained analogously to the procedure indicated in Example 2 by reaction of 7-
10 chloro-6-fluoro-2,2-dimethyl-4-ethylsulfonylaminochroman with sodium hydride and
4,4,4-trifluorobutyl iodide.
~/iscous, pale yellow oil.
Example 80: 4-[N-Ethylsulfonyl-N-(4,4,4-trifluorobutyl)]amino-2,2,6-trimethylchroman
1~; 0
O ~//
F3C ~~ N--S ~
2~ '<
ls obtained analogously to the procedure indicated in Example 2 by reaction of 4-
ethylsulfonylamino-2,2,6-trimethylchroman with sodium hydride and 4,4,4-
trifluorobutyl iodide.
Viscous, pale yellow oil.
2~
Example 81: 6,7-Dichloro-4-[N-ethylsulfonyl- N-(4,4,4-trifluorobutyl)]amino -2,2-
dimethylchroman
o
O ~//
3D F3C ~~ N--S
Cl 1~
CA 0220~477 1997-0~
67
is obtained analogously to the procedure indicated in Example 2 by reaction of 6,7-
dichloro-4-N-ethylsulfonylamino -2,2-dimethylchroman with sodium hydride and
4,4,4-trifluorobutyl iodide.
Viscous, pale brown oil.
Example 82: 4-(N-Ethylsulfonyl-N-methyl)amino-6-phenyl-2,2-dimethyl-chroman
O ~//
a) 2-Hydroxy-5-phenylacetophenone
is obtained analogously to the procedure indicated in Example 63 b) from 4-
acetoxybiphenyl and anhydrous, active aluminum chloride. Slightly yellowish-
colored oil, which partially crystallizes. The 4-acetoxybiphenyl used is obtained as a
colorless crystalline solid from 4-hydroxybiphenyl and acetic anhydride analogously
to the procedure described in Example 63 a).
M.p. 84 - 86~C
b) 2,2-Dimethyl-6-phenyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 2-
hydroxy-5-phenylacetophenone and acetone in the presence of pyrrolidine in
25 acetonitrile as solvent.
Dark oily amorphous product, which partially crystallizes.
c) 2,2-Dimethyl-6-phenyl-4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 2,2-
30 dimethyl-6-phenyl-4-chromanone and hydroxylamine hydrochloride. Crystalline
solid,
m.p. 130 - 1 34~C.
CA 0220~477 1997-0~
68
d) 4-Amino-2,2-dimethyl-6-phenylchroman hydrochloride
ls obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 2,2-dimethyl-6-phenyl-4-chromanone oxime and work-up in the
presence of hydrochloric acid,
melting point: 213 - 214~C (decomposition).
e) 4-N-Ethylsulfonylamino-2,2-dimethyl-6-phenylchroman
is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4-
amino-2,2-dimethyl-6-phenylchroman hydrochloride and ethanesulfonyl chloride in
1D the presence of TEA in THF.
Colorless crystalline substance,
melting point 162 -164~C.
~) 4-(N-Ethylsulfonyl-N-methyl)amino-6-phenyl-2,2-dimethylchroman
1~ is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-2,2-dimethyl-6-phenylchroman and methyl iodide.
Colorless, crystalline product,
melting point 184 - 1 86~C.
Example 83: 4-[N-Ethylsulfonyl- N-(4,4,4-trifluorobutyl)]amino-6-phenyl-2,2-
dimethylchro, I ,a,)
C~ O~
2~ ~ N,S~
~,~1
is obtained analogously to the procedure indicated in Example 2 by reaction of 4-N-
3~ ethylsulfonylamino-2,2-dimethyl-6-phenylchroman with sodium hydride and 4,4,4-
trifluorobutyl iodide.
~olorless to pale yellow crystalline substance,
melting point 1 12 -1 1 4~C.
CA 0220~477 1997-0~
69
Example 84: 6,8-Difluoro4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-chroman
o
O~
N
F
a) 3,5-Difluoro-2-hydroxyacetophenone
is obtained analogously to the procedure indicated in Example 63 b) from 2,4-
difluorophenyl acetate and anhydrous, active aluminum chloride.
Colorless crystalline solid,
melting point 80-94~C.
The 2,4-difluorophenyl acetate used is obtained as a slightly yellowish-colored liquid
~rom 2,4-difluorophenol and acetic anhydride analogously to the procedure
described in Example 63 a).
b) 6,8-Difluoro-2,2-dimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 3,5-
difluoro-2-hydroxyacetophenone and acetone in the presence of pyrrolidine in
acetonitrile as solvent.
Dark oily amorphous product.
c) 6,8-Dlfluoro-2,2-dimethyl4-chromanone oxime
i~ obtained analogously to the procedure indicated in Example 1 a) from 6,8-
difluoro-2,2-dimethyl-4-chromanone and hydroxylamine hydrochloride.
Crystalline solid,
m.p. 124 - 1 37~C.
d) 4-Amino-6,8-difluoro-2,2-dimethylchroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
CA 0220~477 1997-0
hydrogenatlon of 6,8-difluoro-2,2-dimethyl-4-chromanone oxime and work-up in thepresence of hydrochloric acid,
melting point: ~ 31 0~C (sublimation from 300~C, 1 atm).
e) 4-N-Ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 1 c) by reaction of 4-
amino-6,8-difluoro-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride in the presence of TEA in THF.
Colorless crystalline substance.
1D Melting point 124 - 127~C.
fl 6,8-Difluoro-4-(N-ethylsulfonyl-N-methyl)amino-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman and methyl iodide.
1~ Colorless, crystalline product,
melting point 84 - 86~C.
Example 8~: 6,8-Difluoro-4-[N-ethylsulfonyl- N-(4,4,4-trifluorobutyl)]amino-2,2- dimethylchroman
2D O
O ~//
F3C ~~ N ,S~
F~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6,8-difluoro-2,2-dimethylchroman and 4,4,4-trifluorobutyl iodide.
30 Colorless, crystalline product,
melting point 127 - 129~C.
CA 0220~477 1997-0~
2,2-dlmethylchroman
o
O ~//
F3C N ,S~
GN ~
10 is obtained analogously to the procedure indicated in Example 2 by reaction of 6-
fluoro-7-pyrrolidino-2,2-dimethyl-4-N-ethylsulfonyl-aminochroman with sodium
hydride and 4,4,4-trifluorobutyl iodide.
Colorless crystalline substance,
melting point 137 - 140~C
Example 87: 6-Carboxy-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman
O~
OH --N
~ ~
is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4
25 (N-ethylsulfonyl-N-ethyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.
Colorless crystalline compound,
melting point 217-220~C.
Example 88: 6-Carboxy-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman
CA 02205477 1997-05-15
O ~//
OH N,S~
0
is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4-
(N-ethylsulfonyl-N-propyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.
Colorless crystalline compound,
melting point 165-169~C.
Example 89: 6-Carboxy4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-
dimethylchroman ~7 0
~ ~S
1 5 OH
~J~
2D is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4-
(N-cyclopropylmethyl-N-ethylsulfonyl)amino-6-methoxycarbonyl-2,2-
dimethylchro" ,an.
Colorless crystalline compound,
melting point 184 - 1 88~C.
Example 90: 6-Carboxy4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman
~ ~~
OH N
CA 0220~477 1997-0~
73
is obtained analogously to the procedure indicated in Example 23 by hydrolysis of 4-
(N-ethylsulfonyl-N-pentyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.
Colorless crystalline compound,
melting point 156-158~C.
Example 91: 6-Carboxy4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman
~ ~~ /1~
OH ,S
is obtained analogously to the procedure indicated in Example 23 by hydrolysis of
4(N-ethylsulfonyl-N- hexyl)amino-6-methoxycarbonyl-2,2-dimethylchroman.
Colorless crystalline compound,
melting point 154-1 58~C.
Example 92: 6-Carboxamido-4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman
2D o
0~//
~s ~1
is obtained analogously to the procedure described in Example 24 from 6-carboxy-~(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman, carbonyldiimidazole and
ammonia.
Colorless crystalline substance.
Melting point 173 - 175~C.
CA 0220~477 1997-0~
74
Example 93: 6-Carboxamido-4-(N-ethylsulfonyl-N-propyl)amino-2,2-
dimethylchroman
o
0~//
NH2 N~S~--
oJ~
is obtained analogously to the procedure described in Example 24 from 6-carboxy-4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman, carbonyldiimidazole and
ammonia.
Colorless crystalline substance.
Melting point 185 - 1 88~C.
Example 94: 6-Carboxamido4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino -2,2-
dimethylch~ oi"arl
~ o~ llo
NH2 N--S ~
o 1~
25 is obtained analogously to the procedure described in Example 24 from 6-carboxy-
4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman,
carbonyldiimldazole and ammonia.
Colorless crystalline substance.
Melting point 196 - 1 99~C.
CA 0220~477 1997-0~
Example 95: 6-Carboxamido4-(N-ethylsulfonyl-N-pentyl)amino-2,2-
dimethylchroman
~~ ~~ 11~
NH2 N~S~--
10 is obtained analogously to the procedure described in Example 24 from 6-carboxy-
~(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman, carbonyldiimidazole and
ammonia.
Colorless crystalline substance.
Melting point 168 - 1 72~C.
Example 96: 6-Carboxamido4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman
~"S//
NH N
23 1 2
0~
is obtained analogously to the procedure described in Example 24 from 6-carboxy-2~ 4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman, carbonyldiimidazole and ammonia.
Colorless crystalline substance.
Melting point 148 -152~C.
CA 0220~477 1997-0~
76
Example 97: 6-Cyano4-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethyl-chroman
0~//
N,S
~; NC' ~ ~,' ~ ~ ~
is obtained analogously to the procedure indicated in Example 25 from
10 6-carboxamido~-(N-ethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman and
subsequent purification by column chromatography on silica gel using a mixture of
10 parts of methylene chloride and 1 part of methanol as eluent.
Colorless to pale yellow crystalline substance,
melting point: 1 27 -1 30~C.
1~
Example 98: 6-Cyano4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethyl-chroman
o
0~//
\~N ,S
NC~ r ~ ' ~
is obtained analogously to the procedure indicated in Example 25 from
2~ 6-carboxamido4-(N-ethylsulfonyl-N-propyl)amino-2,2-dimethylchroman and
subsequent purification by column chromatography on silica gel using a mixture of
10 parts of methylene chloride and 1 part of methanol as eluent.
Colorless to pale yellow crystalline substance.
melting point: 1 27 -1 30~C.
Example 99: 6-Cyano4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-
dimethylchroman
CA 0220~477 1997-0~
~ O
~~
N
NC~ ~
is obtained analogously to the procedure indicated in Example 25 from
1 ~ 6-carboxamido4-(N-cyclopropylmethyl-N-ethylsulfonyl)amino-2,2-dimethylchroman
and subsequent purification by column chromatography on silica gel using a mixture
of 10 parts of methylene chloride and 1 part of methanol as eluent.
Colorless to pale yellow crystalline substance,
melting point: 127-130~C.
Example 100: 6-Cyano-4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethyl-chroman
~ N~ \--
NC ~ ,~, ~~
is obtained analogously to the procedure indicated in Example 25 from
25 6-carboxamido-4-(N-ethylsulfonyl-N-pentyl)amino-2,2-dimethylchroman and
subsequent purification by column chromatography on silica gel using a mixture of
10 parts of methylene chloride and 1 part of methanol as eluent.
Viscous oily liquid.
Example 101: 6-Cyano-4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman
CA 0220~477 1997-0~
78
~ O~ //o
N
NC ~ ~~
is obtained analogously to the procedure indicated in Example 25 from
10 6-carboxamido-4-(N-ethylsulfonyl-N-hexyl)amino-2,2-dimethylchroman and
subsequent purification by column chromatography on silica gel using a mixture of
10 parts of methylene chloride and 1 part of methanol as eluent.
Viscous yellow oily liquid.
Example 102: 4-(N-Ethoxycarbonylmethyl-N-ethylsulfonyl)amino-6-fluoro-2,2-
dimethylchroman
O
N
F ~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
2~ ethylsulfonylamino-6-fluoro-2,2-dimethylchroman and ethyl bromoacetate.
Colorless, crystalline product,
melting point 112 - 114~C.
Example 103:4-[N-Ethylsulfonyl-N-methyl]amino-6-fluoro-2,2-
30 pentamethylenechroman
CA 02205477 1997-05-15
79
O~
N
F~ ~ ~ ~
is obtalned analogously to the procedure indicated in Example 2 from
1D 4-ethylsulfonylamino-6-fluoro-2,2-pentamethylenechroman and methyl iodide.
Colorless crystalline compound,
melting point 73-74~C
Example 104: 4-(N-lsopropyloxycarbonylmethyl-N-ethylsulfonyl)amino-6-fluoro-2,2-1 ~ dimethylchroman
\~0~0 O
~ S -
~
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino~-fluoro-2,2-dimethylchroman and isopropyl bromoacetate.
2~ Colorless to pale yellow liquid.
Example 105: 4-(N-Ethylsulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman
o
1l,0
~N,S~
H3C
CA 0220~477 1997-0~
a) 6-Hydroxy-2,2-dimethyl-4-chromanone
is obtained analogously to the procedure indicated in Example 18 b) from 2,5-
dihydroxyacetophenone and acetone in the presence of pyrrolidine in acetonitrile as
solvent.
Crystalline compound,
melting point 147 -149~C.
b) 6-Methoxy-2,2-dimethyl-4-chromanone
a suspension of 0.03 mol of 6-hydroxy-2,2-dimethyl4-chromanone, 75 ml of acetone1û and 16.1 9 of anhydrous powdered potassium carbonate is treated with an excess of
3.6 ml of methyl iodide and the reaction mixture is heated at 50 - 55~C for 20 hours.
The solvent is removed by vacuum distillation, the residue is treated with water and
the oil which separates is extracted with ethyl acetate. After drying the organic
phase over anhydrous sodium sulfate, the solvent is removed by distillation and 6-
1~ methoxy-2,2-dimethyl-4-chromanone is obtained as an oily liquid.
c) 6-Methoxy-2,2-dimethyl-4-chromanone oxime
is obtained analogously to the procedure indicated in Example 1 a) from 6-methoxy-
2,2-dimethyl4-chromanone and hydroxylamine hydrochloride.
20 Crystalline solid,
m.p. 108 - 112~C.
d) 4-Amino-6-methoxy-2,2-dimethylchroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
2~ hydrogenation of 6-methoxy-2,2-dimethyl4-chromanone oxime and work-up in the
presence of hydrochloric acid,
melting point: 250 - 251~C.
e) 4-N-Ethylsulfonylamino-6-methoxy-2,2-dimethylchroman
30 is obtained analogously to the procedure indicated in Example 1 c) from 4-amino-6-
methoxy-2,2-dimethylchroman hydrochloride and ethansulfonyl chloride in the
presence of TEA in THF.
Colorless crystalline substance,
melting point 131 -133~C.
CA 0220~477 1997-0~
81
f) 4-(N-Ethylsulfonyl-N-methyl)amino-6-methoxy-2,2-dimethylchroman
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-6-methoxy-2,2-dimethylchroman and methyl iodide.
Colorless, crystalline product,
melting point 68 - 70~C.
Example 106: 4-N-Ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyl-oxychroman
o
S' ~
HN
H3C ~ S ' ~
a) 2,2-Dimethyl-6-methylsulfonyloxychromanone
a mixture of 0.03 mol of 6-hydroxy-2,2-dimethyl-4-chromanone, 16.1 9 of anhydrous
powdered potassium carbonate and 10 ml of methanesulfonic acid in 80 ml of
anhydrous DMF is heated at 80~C for 10 hours. The solvent is then removed by
distillation under reduced pressure and the residue is stirred, after addition of
150 ml of water, for 2 hours. The crystalline precipitate is filtered, washed several
20 times with water and dried in a stream of air.
Colorless solid,
melting point 108 - 110 ~C
~) 2,2-Dimethyl-6-methylsulfonyloxychromanone oxime
2~ is obtained analogously to the procedure indicated in Example 1 a) from 2,2-
dimethyl-6-methylsulfonyloxychromanone and hydroxylamine hydrochloride.
Crystalline solid,
m.p 166 - 1 67~C.
3D c) 4-Amino-6-methylsulfonyloxy-2,2-dimethylchroman hydrochloride
is obtained analogously to the procedure indicated in Example 1 b) by catalytic
hydrogenation of 2,2-dimethyl-6-methylsulfonyloxychromanone oxime and work-up
in the presence of hydrochloric acid,
melting point: 229 - 231 ~C.
CA 02205477 1997-05-15
e) 4-N-Ethylsulfonylamino-2,2-dimethyl~-methylsulfonyloxychroman
is obtained analogously to the procedure indicated in Example 1 c) from 4-amino~-
methylsulfonyloxy-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride
in the presence of TEA in THF.
Colorless crystalline subtance,
melting point 97 - 100~C.
Example 107: 4-tN-Ethylsulfonyl-N-methyl)amino-2,2-dimethyl-6-
methylsulfonyloxychroman
O
SZO
N ~
1~ "S1 'X
is obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-2,2-dimethyl~-methylsulfonyloxychroman and methyl iodide.
Colorless,
crystalline product,
melting point 137 - 1 39~C.
CA 02205477 1997-05-15
83
Exarnple 108: 4-~N-Methylsulfonyl-N-methyl)amino-2,~,6.7-tetramethylchrom~n
~N~ ;~0
vvay obtained analogously to th~ procedure indicated in Example 2 from ~N-
methylsulfonylamino-2,2,6,7-tetramethylchroman and ethyliodWe.
Colorless crystals, meltin~ polnt: 119-121~C.
The hydrochlotido of 4-Amino-2.2,B,7-tetramethylchrom~n (meltin~ point ~ 270~C)
was prepared by hydro~enation of 2.Z.6.7-t~t~methyl-4-chromanone oxime
Imeltin~ point 162-163~C~. The oxime v~as ~enerated by known rnethod~ as
described ~bove from the corraspondin~ 2.2,6,7-t~l~amsthyl~chromanone.
Conversion of ~Amino-2,2,6,7-tetramethylchr6",an with the correspondin~
alkylsulfonylchlorides as described in example 1 (variant 1) resulted in
methylsulfonylamlno-2,2,6,7-tet~amethylchrom~n (colorless oilJ and
ethyl~ulfonylamlno~,2,6,7-tetramethylchroman (colo~less oil) respectively.
Example 10g; 4~N-Methyl~ulfonyl-N-methyl~amino-2,2,ff,7-tetramethylchronlan
8~
~N ~ ; !o
was obtained analo~ously to th~ procedure indical~:J in example 2 from 4-N-
methylYulfonylamino-2,2,6,7-tetr~methylchroman and methyl;odide.
Colorless crystals, meltln~ point: 105-107~C
Ex~mple '110: 4(N-Ethylsu!fonyl-N-hexyl)amlno-2~6~7-tetramethylchroman
J
o
~o~
was obtained analosously to the procedure indicated in example 2 from ~N-
~thylsulfonylamino-2,2,ff,7-tetramethylchroman and hexyliodide.
Colorless oll.
CA 02205477 1997-05-15
84
Example 1 1 1; 4-~N-Ethylsulfonyl-N-ethyl)amino-2,2,6,7-tetramethylchroman
J
o
~o~
wa~ o~t~ined analogously to the procedure Indicated in example Z from 4-N-
ethylsulfonyl~mino-2,2,B,7-tetrsrnethylch~oman and ethylio~ide.
Colorless crystals, m~lting point: 93-95~C.
Example 112: ~N-Ethylsulfonyl-N-Butyl)amino-2,~,B,7-tettamethylchroman
8J
~ ~,8~
was obtalned an~lo~ously tO the procedure indicated in Ex~mple 2 from ~N-
Ethylsulfonylamino-2,2,6,7-tetramethylc~,ro",~n and Butyl iodide.
Colorles~ crystais, meltin~ point: 81-83~C.
Example 1 13 4-lN-~thylsulfonyl-N-methyl)amino-2~2~6~7-tetramethylGhr~ "an
~ , ~J
was obtained anal~gously to the procedure indicated in sxample 2 from ~N-
ethy~sulfonylarnino-2,2,6,7-tetr~methylchroman and methylio~ide.
Colorle~s crystals, meltin~ point: 132-134~C.
Examplo 1 14: 4-~1~1-Ethylsulfonyl-N-butylJ~mino-7-methoxy-2,2-dimethylchroman
llJ
~ ,S;~
~0~0~
CA 02205477 1997-05-15
Yvss o~tained analo~ou~ly to the procedure indicated In ex~nlple 2 fronl 4N-
ethylsulfonylsmino-7-methoxy-~,2-dimethylchrorn~n and butyl lodide.
Colorless oil.
The hydrochloride of ~amino-7-methoxy-2,2-dimethylchroman Im~ltin~ point 239 -
Z41 ~C) wa~ prepared by hydro~Qnation of 7-methoxy-2,2-dlmethYI-4-chromanOne
oxime lmeltin~ point 124 - 1 26~C~. The oxime was ~ener~ted by known methods
from the correspondin~ 7-methoxy-2,~-dimethyl-~chromanone.
Conver~ion of ~Amino-7-methoxy-2,2-Jin,etl.ylcl,ru,nan with the correspondin~
alkylsulfonylchlorides as described in Hxample 1 (variant 1) resul~ed in
methylsulfonylamino-7-methoxy-2,~-dimethylch~oman ~colorless oil) and
ethylsulfonylamino-7-methoxy-2,2-dimethylchromsn tmeltin~ point 111 -113~C)
respectively.
Example 115: 4-tN-Ethylsulfonyl-N-ethylJ~mino-7-methoxy-2~2-dimethylchroman
RJ
~ s~o
'o~oJ~
~as obt~in~d an~lo~ou~ly to the procedure indicated in example 2 from 4-N-
Ethyl~ulfonylamino-7-methoxy-2,2-dlmethylchroman and ethyliodide.
Colorles~ oil.
Example 11~: 4-(N-Ethylsulfonyl-N-methyl)amino-7-methoxy-2,2-dimethylc~,r~..nan
~J
~N~S~
~0~0~
W8S o~tained analo~ously to the procedure indicated in example 2 from ~N-
ethylsulfonylamino-7-methoxy-2,2-dimethylchroman and methyliodide.
Colorless oil.
CA 02205477 1997-05-15
86
Example 117: 4-(N-Ethylsulfonyl-N-methy!)amino-6-14,4,~trifluorobutyl)oxy-2,2-
dim~thylchroman
o~ "o
F ~N
F ~ ~~
L
~ 'o~~
was obt~ined analo~ously to the procedure indic~ted in Example 2 from 4-N-
Ethylsulfonylamino-6-~4,4,4-trifluorobutyl)oxy-2,2-dimethylchroman and
methyliodide. Colorless crystalline compound from mixture of n-heptane / diisopropyl
ether. Meltin~ point 68 - 72 ~C
q-N Ctl-ylsulfonylamino-6-~4,4,4trifluorobutyl~oxy-2,2-di-"ell"/lchroman ~meltin~
point 84 - 90~C) was obtained in the s~quence of synthetic steps indicated sbovestartin~ fronn 6-hydroxy-2,2dimethyl-4-chromanone lobtained from 2-
acetoxyhydroquinone and acetone, meltin~ point 147 -149~CJ vi~ 6-(4,~,~
trifluorobutyl)oxy-2,2-dim~thyl-4chromanone (obtained from 6-hydroxy-~,2dimethyl-
~chromanone and 4.4.4-trifluorobutyl iodide. meltin~ point 53-55~C) and 6-~4,4,4-
tr;fluorobutyl)oxy-2,2-d;.-,~Ll,yl-~chromanoneoxime ~obtained from 6-(4.4,4-
trifluorobutyl)oxy-2,Z-dimethyl-4chromanone ~nd hydroxylamine hydroch~oridc,
melting point 94- 97 ~C) and 4-~mino-B-(4,4,4-trifluorobu~yl)oxy-2,2-
dimethylchroman (obtained from 6-~4,4,4-trifluorob~Jtyl)oxy-2,Z-dimethyl-4-
chrom~noneoxime and cst~lytic hydro~enation vvith Raney nickel, melting point 47 -
~9 ~C) and followin~ teaction of 4-~mino-6-~4,4,4-trifluorobutyl~oxy-2,2-
dimethylchrom~n and ethanesulfonylchloride.
ExamplH 1 18; 6-~4-Bromoph~nyl)- ~(N-ethylsulfonyl-N-methyl)~mino-2,~-
dimethylchroman
0~ "0
Br~
was obtained analogously to the proced~re indic~ted in Example 2 frorn 6-(~
Bromophenyl)- ~N-ethylsulfonylamino-2,2-dlmethylchroman and methyliodide.
Meltin~ point 160- 170~C.
6-~4Bromophenyl)- 4-N-ethylsulfonyl~mino-2,2-dimethylchroman ~mel~in~ point 12~ -
13~~C) was obt~ined in the sequence of synthetic steps indicated above startin~
from 3-scetyl-4'bromo-4-hydroxybiph~nyl (obtained from 4'-bromo-4-
scetoxybiphenyl ~nd aluminum chloride by Friess rearran~em~nt, dark brovvn oil) vla
6-~4bromophenyl)- 2,2-dimethyl 4 chromanone ~obtained frorn 3-~cetyl-4'bromo-4-
hydroxybiphenyl and acetone, viscous oil) and ~-(4-bromophenyll- 2,Z-dimethyl-4-chrom~non oxime ~obtained from 6-~bromophenyl)- 2,2-dimethyl-4-chromanone,
vi~cous oil), and 6-~Bromophenyl~ Yrnino -2,2-dirnethylchroman hydrochloride
~obtained from 6-~4-bromophenyl)- 2,2-dimethyl-4chrornanon oxime and catalytic
CA 02205477 1997-05-15
87
hydro~enation with Raney nickel and treatmen~ with a solution of H~l in diethylether,
rnelting point 1~ - 170 ~C) and followin~ reaction of ~amino-6-~Bromophenyl)-
Z,2-dimethylchroman hydrochloride and ethanesulfonylchloride in presence of
triethylarnine .
Exarnple 119: 4-~N-Ethylsulfonyl-N-methyl)amino-2,Z-dimethyl-6-methoxychroman
~ ~0
N'
~~'~
~0
was obtained analo~ously to th~ procedure indicated in Example 2 fron~
~thylsulfonylamino-2,2-dimethyl-6-methox~/chrom~n und butyl iodide. Colorless
crystalllne product, meltin~ point 78- 80 ~C
Example 120: The en~ntiomers of ~ N-Ethylsulfonyl-rJ-methyl)amino-6-fluoro-
2,2-dimethylchroman and ~-)-4-(N-Ethylsulfonyl-N-methyl)amino-6-fluorb-Z,2-
dimethylchrorn~n ~talpha]= -~4,~~l
~rvere obtained by racemlG mixture of 4-(N-Ethylsulfonyl-N-methyl)amino-6-fluoro-2,2-
dimethylchroman by chiral chromato~taphy ~CSP Chiralpak AD 2~0~4.6, elution
solvent: n-l lexane + Ethanol: 40 + 1 ) .
Example 121: The en~ntiomers of (~ N-butYI N-ethylsulfonyl1amino-6-fluoro-2,2-dirnethylchrom~n and (-)-4-~N-butyl N-ethylsulfonyl)amino-6-fluoro-Z,2-
dimethylchrom~n ~[~lpha]- -53.5~~
were obtained by r~cernic mixture of ~(N-butyl N-ethylsulfonyl3amino-6-fluoro-2,2-
dlmethylchroman by chiral chl~i"~o~raphy ~CSP Chiralpak AD 2~0~4.6, elution
solvent: n-H0xane+Eth~nol; 80+1).
Examp~e 12~: 4-~N-Methylsulfonyl-N-isopropyl)amino-2,2,6-lli",~ ylchroman
~ S~-O
N ~
was obtained ~nalo~ously to the procedur~ indicated in Example 2 from 4-N-
methylsulfonyl~rnino-2,2,~-trimethylc~.ro~llan und isopropyl iodide. Colorless
crystalline product, m~ltin~ point 140 ~C.
CA 02205477 1997-05-15
88
~xarnple 123: 4[N Mell,ylsulfonyl-N-~3-methylbutyl~]amino-2,2,ff-trimethylchrom~n
0
S~O
was obtained analogousl~ to the proc~dure ind~c~t~d in Ex~mple 2 from 4-N-
methylsulfonylamino-2,2,6-trimethylGhroman und 3-methylbutyl iodide. Vi~cous oil.
Example 12~ [N-Eth~Jlsulfonyl-~ 3-ethoxypropyl)lamino -2,2,B~ "~tl,-~lchroman
~O O
E S~~
vvas obtained analo~ou~ly to the procedur~ indlcated in Example ~ f~om ~-N-
ethylsulfonylamino-2,2,6-trime~hylc~,ror"sn und 3-ethoxypropyl ~odlde. Viscous oil.
CA 0220~477 1997-0~
89
e) 4-N-Ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyloxychroman
is obtained analogously to the procedure indicated in Example 1 c) from 4-amino-6-
methylsulfonyloxy-2,2-dimethylchroman hydrochloride and ethanesulfonyl chloride
in the presence of TEA in THF.
Colorless crystalline subtance,
melting point 97 - 100~C.
Example 107: 4-(N-Ethylsulfonyl-N-methyl)amino-2,2-dimethyl-6-
methylsulfonyloxychroman
O
S~O
N
1~ H3C ~ S, O
ls obtained analogously to the procedure indicated in Example 2 from 4-N-
ethylsulfonylamino-2,2-dimethyl-6-methylsulfonyloxychroman and methyl iodide.
Colorless,
crystalline product,
melting point 137 -139~C.
CA 0220~477 1997-0
Pharmacological investigations:
ISK channels from man, rat or guinea-pig were expressed in Xenopus oocytes. For
this purpose, oocytes from Xenopus laevis were first isolated and defolliculated. The
oocytes were then injected with ISK encoding RNA synthesized in vitro. After 2 - 8
days ~f ISK protein expression, ISK currents were measured using the two
microelectrode voltage clamp technique. ISK channels were in this case generallyac~ivated using voltage jumps to -10 mV lasting 15 s and the bath was rinsed
through with a control solution of the following composition (mM): NaCI 96, KCI 2,
CaCI2 1.8, MgCI2 1, HEPES 5 (titrated with NaOH to pH 7.5). These experiments
were carried out at room temperature. The software employed for raising data andanalysis was: Geneclamp amplifier (Axon Instruments, Foster City, USA) and
MacLab D/A converter and software (AD Instruments, Castle Hill, Australia).
Chromanols were tested by adding them to the control solution at different
concer,lrations. The eflects of the chromanols were calculated as percentage
inhibition of the ISK control flux. The data were then extrapolated using the Hill
equation in order to determine the IC50 for the respective substances. The data are
given as average values with standard deviation (S.E.M.). n is the number of
experiments carried out. Statistical significance was determined by means of thepaired Student's t-test.
References:
Busch AE, Kopp H-G, Waldegger S, Samarzija 1, Su~brich H, Raber G, Kunzelmann
K, Ruppersberg JP and Lang F (1995) Inhibition of both exogenously expressed ISKand endogenous K+ channels in Xenopus oocytes by isosorbide dinitrate. J Physiol491: 735-741
Takumi T, Ohkubo H and Nakanishi S (1989) Cloning of a membrane protein that
induces a slow voltage-gated potassium current. Science 242:1042-1045
Varnum MD, Busch AE, Bond CT, Maylie J and Adelman JP (1993) The minK
channel underlies the cardiac potassium current and mediates species-specific
responses to protein kinase C [Proc Natl Acad Sci USA 90:~ 1528-11532].
CA 0220~477 1997-0~
91
NaHCO3, 20 mM HEPES, 2 mg/ml of glucose and 1 mg/ml of rabbit albumln for 30 -
45 min at 37~C, the pH of the mixture being adjusted to 7.4 using tris buffer. The
glandular tubes (gastric glands) were filtered through a nylon mesh to remove large
fragments and rinsed 3 times with incubation medium. The glandular tubes were
then suspended in the medium at a concentration of 2 - 4 mg of dry weighVml.
As a measure of the capability of the gastric glandular tubes to form acid, the
accumulatlon of 14C-aminopyrine (14C-AP) was determined (3). To do this, samplesof 1 ml o~ glandular tube suspension were incubated with 14C-AP (1 ,uM, 200,000
cpm) and the compound to be tested and treated for 20 - 30 min at 37~C in a
shaking water bath. Histamine (100 ,uM), dbcAMP (0.3 or 1 mM) or carbachol (100
~M) were then added, followed by a second incubation period of 30 - 45 min. The
incubation was then concluded by centrifuging the samples for half a minute. Thesupernatant liquid was removed and the pellets obtained were dissolved in 1 ml of
NaOH. Samples of the pellets and of the liquid supernatant were measured in a
scintillation counter. The AP ratio of the intraglandular and extraglandular
radioactivity was calculated according to Sack and Spenney (4). All determinations
were carried out in triplicate.
Result: 6-Cyano-4-(n-ethylsulfonyl-N-methyl)amino-2,2-dimethyl-3-chromanol
caused a co"cer,ll ation-dependent inhibition of stimulated AP accumulation withICso values of 20 yM after histamine and dbcAMP stimulation, and of 5 ,uM after
stimulation with carbachol.
References:
1. Berghlind, T., Obrink, K J. A method for preparing isolated glands from the rabbit
gastric mucosa, Acta Physiol. Scan. 96, 150 - 159 (1976)
2. Herling, A. W., Becht, M., Kelker, W., Ljungstrom, M., Bickel, M., Inhibition of 14C-
aminopyrine accumulation in isolated rabbit gastric glands by the H2-receptor
antagonist HOE 760 (TZU-0460). Agents and Actions 20: 35 - 39 (1987)
3. Berghlind, T., Helander, H. F., Obrink, K. J., effect of secretagogues on oxygen
consumption, aminopyrine accumulation and morphology in isolated gastric glands.Acta Physiol. Scand. 97 401 - 414 (1976)
4. Sack, J., Spenney, J. G., Aminopyrine accumulation by mammalian gastric
glands: an analysis of the technique. Am. J. Physiol. 243: G 313 - G 319 (1982).
CA 0220S477 1997-0~
92
Compound Example No.l[~suKrrloclllq
6-Cyano-4-[N-ethylsulfonyl-N-(4,4,4- 33 0.42
trifluorobutyl)]amino-2,2-dimethylchroman
4-(N-Butyl-N-ethylsulfonyl)amino4-cyano-2,2- 38 0.76
dimethylchroman
trans~-Cyano-4-(N-ethylsulfonyl-N- 293B ) 6.9 i 0.4
methylamino)-3-hydroxy-2,2-dimethylchroman
trans~-cyano4-(N-methylsulfonyl-N- 374B ) 19.2 i 1.2
methylamino)-3-hydroxy-2,2-dimethylchroman
trans~-Cyano~-[N-(dimethylamino)sulfonyl-N- 377B ) 14.6 + 0.5
methylamino]-3-hydroxy-2,2-dimethylchroman
trans~-Cyano-4-[N-(1-butylsulfonyl)-N-methyl- 360B ) 58.8 + 1.8
amino~-3-hydroxy-2,2-dimethylchroman
) E. Lohrmann, l. Burhoff, R.B. Nitschke, H.J. Lang, D. Mania, H.C. Englert, M.
Hropot, R. Warth, W. Rohm, M. Bleich, R. Greger, Pflugers-Arch - Eur. J. Physiol(1995) 429: 517 - 530.
Inhibltion of gastric acid secretion, antiulcer action:
Method: High pressure perfusion of the rat stomach was carried out according to the
description of Berglindh and Obrink (1) and using some modifications as reportedelsewhere (2). Rabbits (male and female, 2 - 3 kg) were killed painlessly under
anesthesia by cervical dislocation and the stomach was perfused as reported in the
literature (1). The mucosa of the stomach fundus was removed using a scraper andcut into smatl pieces by means of scissors. The mucosal fragments thus obtained
were treated with 1 mg/ml of collagenase in a medium consisting of 100 mM NaCI, 5
mM KCI, 0.5 mM NaH2PO4,1 mM Na2HPO4,1 mM CaCI2,1.5 mM MgC12, 20 mM
