Note: Descriptions are shown in the official language in which they were submitted.
- 1336891
- 1 -
Description
The use of substituted 3,4-dihydro-2H-benzopyrans as
remedies for obstructive functional disorders of the
lungs and/or disorders of the efferent urinary passages.
The invention relates to the use of 3,4-dihydro-2H-benzo-
tb]pyrans of the formula I
rx~
~ - C=O
Ar-SOn ~ R~2
in which
R1 represents H, OH, (C1-C2)-alkoxy, (C1-C2)-alkyl
or NR4R5, where R4 and R5 are identical or different
and represent H, (C1-C2)-alkyl or (C1-C3)-alkyl-
carbonyl,
R2 and R3 are identical or different and represent alkyl
having 1-4 carbon atoms,
Ar represents an aromatic or heteroaromatic system which
is unsubstituted or substituted by 1 to 3 identical or
different radicaLs (C1-C2)-alkyl, (C1-C2)-alkoxy,
halogen, trifluoromethyl, CN, NOz, CO-(C1-C2)-alkyl or
SOm-(C1-C2)-alkyl with m = 1 or 2,
n represents 1 or 2,
X represents a chain (CH2)r which can be interrupted
by a heteroatom 0, S or NR6, where R6 denotes H or
(C1-C4)-alkyl, and r represents the numbers 2, 3,
4 or 5,
' _ - 2 - 1336891
for the preparation of a remedy for obstructive func-
tional disorders of the lungs and/or disorders of the
efferent urinary passages.
An aromatic system Ar is preferably to be understood to
be phenyl, naphthyl or biphenylyl, and a 5- or 6-membered
heteroaromatic system Ar is preferably a radical of a 5-
or 6-membered 0, N and/or S heterocyclic ring, especially
furyl, thienyl, isothiazolyl, oxazolyl, isoxazolyl,
pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl or triazinyl.
Halogen is to be understood to be F, Cl, Br or I, prefer-
ably F and Cl.
Carbon atoms 3 and 4 of the 3,4-dihydro-2H-benzotb]pyran
system (also called "chroman system" hereinafter for
brevity) of the formula I are asymmetrically substituted.
In this connection, the invention relates only to those
compounds which have opposite configurations at these
centers, that is to say have a "trans" orientation of the
substituents on these carbon atoms. If one of the sub-
stituents R1, ArSOn, R2 and/or R3 contains centersof asymmetry, or if R2 and R3 are not the same (and
thus generate an asymmetric carbon atom), the invention
relates to compounds with centers both of the S and of
the R configuration.
The compounds can be in the form of optical isomers, di-
astereoisomers, racemates or mixtures thereof.
Preferably used are compounds of the formula I in ~hich
R1 to R3 and ArSOn have the abovementioned meanings,
but X represents a chain (CH2)r with r = 3 or 4.
Very particularly preferably used are those compounds in
which R1 to R3 have the abovementioned meanings, Ar
represents phenyl which is unsubstituted or substituted
3 1336891
as defined above, n represents 2, and X represents a
chain (CH2)r with r = 3 or 4.
t
Especially preferably used are those compounds in which
R1 denotes H, R2 and R3 represent (C1-C2)-alkyl,
S Ar represents phenyl which is unsubstituted or substituted
once by (C1-Cz)-alkyl, (C1-C2)-alkoxy or halogen,
n represents 2, and X represents a chain (CH2)r with r =
3 or 4.
Likewise preferred are compounds with R1 equal to H,
R2 and R3 equal to (C1-C2)-alkyl, X equal to (CH2)3r-
Ar equal to C6H4Cl, and n equal to 2, as well as those
with R1 equal to H, R2 and R3 equal to (C1-C2)-alkyl,
Ar equal to phenyl, n equal to 2, and X equal to (CH2)3.
EP 0,176,689 describes the use of benzopyrans for res-
piratory tract diseases and/or disorders of the gastro-
intestinal tract and/or of the uterus, with special
emphasis being placed on those disorders occurring in
smooth muscular contractions. EP 207,614 describes the
use of benzopyrans for incontinence. Furthermore, J.
Med. Chem. 1986, 29, 2194 - 2201 discloses that compounds
of this type may have hypotensive properties. It has now
been found, surprisingly, in pharmacological investiga-
tions that compounds I are likewise suitable for use as
remedies for respiratory tract diseases and/or disorders
of the efferent urinary passages.
Hence the invention relates to the use of the compounds
of the formula I for the treatment and prophylaxis of the
diseases detailed above; particularly preferred in this
connection are those diseases in which there is a dis-
turbance of the smooth muscular contractions of the parti-
cular organs, such as, for example, asthma, incontinence
or renal colic. Particularly important in this connec-
tion are those compounds I whose hypotensive properties
are less pronounced.
4 1336891
The invention is furthermore directed at a pharmaceutical
product for the treatment of obstructive functional dis-
orders of the lungs, ~hich contains a compound I as
active substance besides customary additives, as ~ell as
S at a compound I for use for the treatment of obstructive
functional disorders of the lungs and/or of the efferent
ur1nary passages.
Very particularly preferred is the use of 3,4-dihydro-2,2-
dimethyl-6-(2-chlorophenylsulfonyl)-trans-4-(2-oxo-1-
pyrrolidinyl)-2H-benzo[b]pyran-3-ol for the preparation
of a remedy for disorders of the efferent urinary pass-
ages and the use of 3,4-dihydro-2,2-dimethyl-6-phenyl-
sulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]pyran-
3-ol for the preparation of a remedy for obstructive
respiratory tract diseases.
The invention furthermore embraces the use of the com-
pounds according to the invention for the preparation of
pharmaceuticals ~hich are used for the treatment and
prophylaxis of the abovementioned diseases.
The compounds I can be prepared by the follouing pro-
cesses:
by
a) reacting compounds of the formula II
O~ II
Ar-S ~ ~ ~r
R1 ~ ~ R23
in ~hich R1 to R3 and ArSOn are as defined above, ~ith
lactams of the formula III
- 1~36891
(N)~O I I I
b) reacting compounds of the formula IV
Ar-SOn ~ ~ IV
in ~hich R1 to R3 and ArSOn are as defined above,
with the lactams of the formula III,
c) acylating compounds of the formula V
NX2
AsSOn ~2R3 ( V )
in ~hich R1 to R3 and ArSOn are as defined above,
to give the compounds VI
RN ~ X-Y
ArSOn ~ ~ R3 VI
in ~hich Y is a leaving group such as, for example,
chlorine or bromine, and R1 to R3 and ArSOn are as
defined above, and cyclizing the latter to give the
compounds I,
d) oxidizing compounds of the formula VII
( ~);H2
R ~O~R13i VI I
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in which R1 to R3 and ArSOn are as defined above, to
give the compounds I.
~here the compounds I are prepared by methods a) or b),
this is carried out by reacting the compounds II or IV in
a suitable solvent, preferably in dipolar aprotic sol-
vents such as, for example, dimethyl sulfoxide or THf,
with the lactams III, preferably with the action of bases
such as, for example, sodium hydride, potassium tert.-
butylate or similar bases known to be suitable for lactam
N-alkylations. The temperature for this reaction can be
varied ~ithin ~ide limits; it is preferably carried out
between 0 and room temperature or at temperatures
which may be slightly above room temperature.
Lactams of the formula III are known in many cases, or
they can readily be prepared by methods known from the
literature. Compounds II or IV are new. They can be
prepared, for example, by the following synthetic route:
Compounds of the formula VIII
o
1~ ~ R3 VIII
in ~hich R1, R2 and R3 are as defined above, are reacted
with acid chlorides Ar-SOn-Cl in a type of Friedel-
Crafts acylation in a manner known per se to give com-
pounds of the formula IX
~ V ~ R2 IX
in which R1, R2, R3 and Ar and n are as defined above.
The latter are converted by reductions under standard
conditions, for example by NaBH4 in methanol, into the
- 7 ~ 1336891
compounds X
- OH
Rl~RR3 X
~hich are then subjected to elimination of ~ater, for
example by pyridine/phosphorus oxychloride, resulting in
compounds of the formula XI:
~ R3
Compounds XI can no~ easily be converted by standard
methods into the epoxides IV or the bromohydrins II.
If in this reaction sequence R means NH2 or OH, protec-
tive groups may be necessary, such as, for example, thedimethylaminomethylene group for NH2 or the acetyl or
methyl group for the OH group. These are eliminated
again at suitable stages, preferably after the reactions
described in process a) or b) have been carried out, by
conventional methods.
Chromenes of the formula XI are, in some cases, prepared
in a manner kno~n per se by thermally induced cyclization
of the corresponding propargyl ethers XII
ArSOn~@~ C~ X I I
. ~1 O~R3
R2
These in turn can be prepared in a manner known per se
from the phenols XIII and the propargyl chlorides XIV.
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~ 8 -
R2
~ ~rSOn ~ HC - C - C - Cl
R1 OH
XIII XIV
It is possible and particularly beneficial to use pro-
cesses c) and d) ~hen the final products I are desired
as pure enantiomers. Compounds V and VII are, in con-
trast to compounds I, basic and thus able to form saltswith organic acids. It is possible, by crystallization
~ith a suitable optically pure acid such as, for example,
(I)-mandelic acid or (~)-lactic acid, in a manner kno~n
per se to obtain them as pure enantiomers, and convert
them by processes c) and d) into final products I as pure
enantiomers.
Ho~ever, final products I can also be obtained as pure
enantiomers from racemic final products I by conventional
methods of racemate resolution such as, for example,
chromatographic separation using chiral phases, or
derivatization of the racemic products ~ith optically
pure acid derivatives (ester formation via the 3-hydroxy
group of the chroman system) or ~ith optically pure iso-
cyanates (carbamate formation via the 3-hydroxy group).
The diastereoisomeric isocyanates or esters obtained in
this way can be separated by conventional methods
(crystallization or chromatography) and converted into
the optically pure final compounds I with elimination of
the optically active auxiliary group on the 3-OH group.
Separation of the diastereomeric 3-menthoxyacetates has
proven particularly advantageous in this connection.
As already mentioned, the compounds I can be used accord-
ing to the invention as agents for the treatment of
obstructive respiratory tract diseases and/or for the
treatment of disorders of the efferent urinary passages.
- 1336891
In this connection, pharmaceuticals which contain the
compounds I can be administered orally, parenterally,
intravenously, rectally or by inhalation, with the pre-
ferred administration form being dependent on the disease
which is to be treated. In this connection, the com-
pounds I can be used alone or together with pharmaceuti-
cal auxiliaries, specifically both in veterinary and in
human medicine.
The expert is familiar, on the basis of his expert know-
ledge, with the auxiliaries which are suitable for the
desired pharmaceutical formulation. Besides solvents,
gel-formers, suppository bases, tablet auxiliaries and
other active substance vehicles, it is possible to use,
for example, antioxidants, dispersants, emulsifiers,
antifoam agents, flavorings, preservatives, solubilizers
or pigments.
For a form for oral use, the active compounds are mixed
with the additives suitable for this purpose, such as
excipients, stabilizers or inert diluents, and converted
by the customary methods into suitable administration
forms such as tablets, coated tablets, hard gelatin cap-
sules, aqueous, alcoholic or oily suspensions or aqueous,
alcoholic or oily solutions. Examples of inert vehicles
which can be used are gum arabic, magnesia, magnesium
Z5 carbonate, potassium phosphate, lactose, glucose or
starch, especially corn starch. This preparation can be
carried out both as dry and as wet granules. Examples
of suitable oily excipients or solvents are vegetable
or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the
active compounds are converted, if desired with the sub-
stances customary for this purpose, such as solubilizers,
emulsifiers or other auxiliaries, into a solution, sus-
pension or emulsion. Examples of suitable solvents are
water, physiological saline or alcohols, for example
o- 1336891
ethanol, propanol or gLycerol, as well as sugar solutions
- such as glucose or mannitol solutions, or else a mixture
of the various solvents mentioned.
Examples of pharmaceutical formulations suitable for
administration in the form of aerosols or sprays are
solutions, suspensions or emulsions of the active sub-
stance of the formula I in a pharmaceutically acceptable
solvent such as, in particular, ethanol or water, or a
mixture of such solvents. The formulation can, if
required, also contain other pharmaceutical auxiliaries
such as surfactants, emulsifiers and stabilizers, as well
as a propellant gas. A formulation of this type normally
contains the active substance in a concentration of about
0.1 to 10, in particular of about 0.3 to 3, X by weight.
The dosage of the active substance of the formula I which
is to be administered, and the frequency of administra-
tion, depend on the strength of action and duration of
action of the compound used, and, additionally, on the
nature and severity of the disease which is to be treated,
as well as on the sex, age, weight and individual res-
ponse of the mammal which is to be treated. On average,
the recommended daily dose of a compound of the formula
I for a patient weighing about 75 kg is at least 0.1 mg,
preferably at least 1 mg, up to a maximum of 100 mg,
preferably up to a maximum of 10 mg. In this connection,
several, for example up to 4, single doses a day may be
necessary for acute episodes of the disease, for example
for attacks of asthma or of renal colic, whereas one dose
may also suffice for prophylaxis.
In this connection, the compounds I can be administered
alone or in combination ~ith other compounds, for example
when used for obstructive respiratory tract disorders
with 32-agonists such as salbutamol, or with theo-
phylline or with disodium cromoglycate.
1336891
~hen used for disorders of the efferent urinary passages,
- examples of partners in the combination are those having
antibacterial or analgesic activity.
The compounds of the formula I compiled in the table
S which follows are particularly well suited:
1) 2,2-dimethyl-3,4-dihydro-7-methoxy-6-(p-chlorophenyl-
sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]-
pyran-3-ol,
2) 2,2-dimethyl-3,4-dihydro-6-(p-chlorophenylsulfonyl)-
trans-4-(2-oxo-1-piperidinyl)-ZH-benzoCb]pyran-3-ol,
3) 2,2-dimethyl-3,4-dihydro-6-(p-nitrophenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
4) 2,2-dimethyl-3,4-dihydro-6-(p-cyanophenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
5) 2,2-dimethyl-3,4-dihydro-6-(p-methoxyphenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
6) 2,2-dimethyl-3,4-dihydro-6-(p-trifluoromethylphenyl-
sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-
pyran-3-ol,
7) 2,2-dimethyl-3,4-dihydro-6-(p-methylsulfonylphenyl-
sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-
pyran-3-ol,
8) 2,2-dimethyl-3,4-dihydro-6-(p-acetylphenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
9) 2,2-dimethyl-3,4-dihydro-7-methylamino-6-phenylsulf-
onyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-
3-o~,
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~ - 12 -
10) 2,2-dimethyl-3,4-dihydro-7-fluoro-6-phenylsulfonyl-
- trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol,
11) 2,2-diethyl-3,4-dihydro-7-fluoro-6-phenylsulfonyl-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
12) 2,2-dimethyl-7-chloro-3,4-dihydro-6-phenylsulfonyl-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
13) 2,2-dimethyl-3,4-dihydro-6-(4-chloro-3-methylphenyl-
sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-
pyran-3-ol,
14) 2,2-dimethyl-3,4-dihydro-6-(4-chlorophenylsulfonyl)-
trans-4-(5-oxo-3-thiazolidinyl)-2H-benzoCb]pyran-3-ol,
15) 2,2-dimethyl-3,4-dihydro-trans-4-(4-methyl-2-oxo-1-
piperazinyl)-6-phenylsulfonyl-2H-benzoCb]pyran-3-ol,
16) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4-
(2-oxo-1-morpholinyl)-2H-benzotb]pyran-3-ol,
17) 2,2-dimethyl-3,4-dihydro-6-phenylsulfonyl-trans-4-
(5-oxo-3-oxazolinyl)-2H-benzotb]pyran-3-ol,
18) 3,4-dihydro-2,2-dimethyl-6-(p-fluorophenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
19) 3,4-dihydro-2,2-dimethyl-6-(o-fluorophenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
20) 3,4-dihydro-2,2-dimethyl-6-(3-pyridylsulfonyl)-trans-
4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
21) 3,4-dihydro-2,2-dimethyl-6-(2-pyrimidinylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol,
22) 3,4-dihydro-2,2-dimethyl-6-(2-furylsulfonyl)-trans-
- 13 - 1336891
4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol.
Example 1
3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]pyran-3-ol
S 4.3 9 (0.0097 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-
7-methoxy-6-(p-tolylsulfonyl)-2H-benzo~b~pyran-4-ol are
dissolved in 28 ml of dimethyl sulfoxide, and 3.5 ml of
2-pyrrolidinone (0.0465 mole) and 0.78 9 of sodium
hydride (80% suspension in oil) tO.0325 mole) are added,
and the mixture is stirred at 40C for 3 hours. It is
left to stand overnight and then poured onto ice-water
and filtered with suction. The precipitate is recrystal-
lized from isopropanol. ~hite crystals of me~ting point:
263 - 65C.
Preparation of the starting compound:
3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolyl-
sulfonyl)-2H-benzo[b]pyran-4-ol is obtained from 2,2-
dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-chromene and
N-bromosuccinimide in a 9:1 mixture of dimethyl sulf-
oxide and H20. Melting point: 200-201C
2,2-Dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-chromene
is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulf-
onyl)chroman-4-ol with phosphorus oxychloride/pyridine
in benzene. Melting point: 132 - 33C
2,2-Dimethyl-7-methoxy-6-(p-tolylsulfonyl)chroman-4-ol
is obtained from 2,2-dimethyl-7-methoxy-6-(p-tolylsulf-
onyl)chroman-4-one with NaPH4 in ethanol.
Melting point: 196 - 97C
2,2-Dimethyl-7-methoxy-6-(p-tolylsulfonyl)chroman-4-one
is obtained from 2,2-dimethyl-7-methoxychroman-4-one and
p-toluenesulfonyl chloride in the presence of aluminum
~ - 14 - 1336891
chloride in methylene chloride.
Melting point: 221 - 23C.
Example 2
3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-
trans-4-(2-oxo-1-piperidinyl)-2H-benzo~b]pyran-3-ol
5 9 (0.011 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-7-
methoxy-6-(p-tolylsulfonyl)-2H-benzo~b]pyran-4-ol are
dissolved in 32 ml of dimethyl sulfoxide, and 4.9 9 of
valerolactam (0.0526 mole) and 0.8 9 (0.033 mole) of NaH,
80~ suspension in oil, are added, and the mixture is
stirred at 40C for 5 hours. It is poured into ice-
water and filtered ~ith suction. The residue is extrac-
ted by boiling several times ~ith methanol.
White crystals of melting point: 261 - 63C
Example 3
3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo~b]pyran-3-ol
The compound is prepared in analogy to Example 1 from 3-
bromo-3-,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfon-
yl-2H-benzcrb]pyran-4-ol.
White crystals of melting point: 227 - 29C
Separation of the antipodes, Example 3a
1.075 9 (0.0025 mole) of (+)-3,4-dihydro-2,2-dimethyl-7-
methoxy-6-phenylsulfonyl-trans-4-(2-oxo-1-pyrrolidinyl)-
2H-benzo~b]pyran-3-ol are dissolved in 5 ml of 1,2-di-
chlorobenzene, and 0.9 9 of S(-)-1-phenylethyl isocyanate
is added, and the mixture is stirred at 140C for about
12 h. The complete mixture is subsequently chromato-
graphed on silica gel with the solvent system toluene/
ethyl acetate 1:1. The diastereomeric carbamate ~hich
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~ - 15 -
migrates slo~er can be enriched and obtained pure by
crystallization from toluene (melting point 243-245C).
Hydrolysis ~ith NaOH in EtOH at 80C results in (+)-
3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-3-ol of
melting point: 209-211C and C~]D = + 109 (c = 0.28;
CHCl3)
Preparation of the starting material:
3-Bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-phenyl-
sulfonyl-2H-benzo[b]pyran-4-ol is obtained from 2,2-
dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene and N-
bromosuccinimide in a 9:1 mixture of dimethyl sulfoxide
and H20. Melting point: 202 - 203C.
2,2-Dimethyl-7-methoxy-6-phenylsulfonyl-2H-chromene is
obtained from 2,2-dimethyl-4-hydroxy-7-methoxy-6-phenyl-
sulfonylchromene ~ith pyridine/phosphorus oxychloride in
benzene. Melting point: 140 - 41C.
2,2-Dimethyl-4-hydroxy-7-methoxy-6-phenylsulfonylchroman
is obtained from 2,2-dimethyl-7-methoxy-6-phenylsulfonyl-
chroman-4-one ~ith sodium borohydride in methanol.
Melting point: 146 - 147C.
2,2-Dimethyl-7-methoxy-6-phenylsulfonylchroman-4-one is
obtained from phenylsulfonyl chloride, 2,2-dimethyl-7-
methoxychroman-4-one and aluminum chloride in methylene
chloride.
Melting point: 223 - 25C
Example 4
3,4-Dihydro-2,2-dimethyl-6-(4-methylphenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol
0.75 9 (0.025 mole) of 80% NaH is introduced into 8.2 9
1336891
r--~
(0.02 mole) of 3-bromo-3,4-dihydro-2,Z-dimethyl-6-(4-
methylphenylsulfonyl)-2H-benzoCb]pyran-4-ol in 30 ml of
dimethyl sulfoxide. After stirring at 20 for one hour,
a further 0.75 9 (0.025 mole) of 80% NaH and 1.9 ml
(0.025 mole) of 2-pyrrolidone are added, and the mixture
is stirred at 40 for 45 minutes and at 20 for 6 hours.
It is introduced into ice-water and then the precipitate
is filtered off with suction, dried and recrystallized
from methanol several times.
Crystals of melting point: 242 - 243C.
Preparation of the starting material
3-Bromo-3,4-dihydro-2,2-dimethyl-6-(4-methylphenyl-
sulfonyl)-2H-benzoCb]pyran-4-ol
14.2 9 (0.08 mole) of freshly recrystallized N-bromo-
succinimide are introduced into 12.6 9 (0.04 mole) of
2,2-dimethyl-6-(4-methylphenylsulfonyl)chromene in a
solution composed of 70 ml of dimethyl sulfoxide and
1.4 ml of water while cooling (isopropanol/dry ice) at
about 15C. The temperature rises transiently to 27.
It is cooled to 20C and, after stirring for one hour,
introduced into ice/ethyl acetate. The ethyl acetate
phase is washed several times with water and dried over
Na2S04. The bromohydrin deri~ative crystallizes on
concentration. Crystals of melting point: 141 - 142C.
Example 5
3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-trans-4-(2-oxo-
1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol
A solution of 6.3 9 (0.02 mole) of 3,4-dihydro-2,2-di-
methyl-3,4-epoxy-6-phenylsulfonyl-2H-benzotb]pyran in
20 ml of DMS0 is added dropwise, at 20, to a suspension
of 0.6 9 (0.02 mole) of 80% NaH in 10 ml of DMS0. Then
2.3 ml (0.03 mole) of 2-pyrrolidinone are added, and the
mixture is stirred at 45 for one hour. After it has
~~ - 17 - 1336891
stood at 20 overnight it is introduced into ice-water.
The precipitate is filtered off with suction, washed to
neutrality, dried and chromatographed on silica gel with
methylene chloride/methanol 19:1. 30 ml fractions are
S colLected. Fractions 12-25 are concentrated, and the
residue is recrystallized from acetonitrile.
Melting point: 201-202
Preparation of the starting material:
3,4-Dihydro-2,2-dimethyl-3,4-epoxy-6-phenylsulfonyl-2H-
benzoCb]pyran is obtained from 3-bromo-3,4-dihydro-2,2-
dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol with NaH
in DMS0.
Melting point: 103-105
3-Promo-3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-
benzoCb]pyran-4-ol is obtained from 2,2-dimethyl-6-
phenylsulfonyl-2H-chromene and N-bromosuccinimide in a
9:1 mixture of dimethyl sulfoxide and HzO.
Melting point: 126
2,2-Dimethyl-6-phenylsulfonyl-2H-chromene, with melting
point 70-71, was prepared by known methods from 4-
phenylsulfonylphenyl 1,1-dimethylpropargyl ether. This
ether is obtained, likewise in a known manner, from 4-
phenylsulfonylphenol and 3-methy!-3-c~orobutyne.
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-
1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol (Example Sa)
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-
1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol is esterified with
(-)-menthoxyacetyl chloride by standard methods. The
diastereomeric esters are separated on a silica gel
column with methylene chlor;de/ethyl acetate (9:1) and
hydrolyzed by stirring at 20 with alcoholic sodium
ethylate solution. After dilution with cold water, the
precipitate is filtered off with suction and washed to
1336891
- 18 -
neutrality and triturated ~ith ether.
(+)-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-4-(2-oxo-
1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol
Melting point: 122-123 ta]D = ~ 39.5 (c = 1, ethanol)
Example 6
6-(4-Chlorophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-
methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-
3-ol
The compound is prepared in analogy to Example 1 from 3-
bromo-6-(4-chlorophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-
7-methoxy-2H-benzo~b]pyran-4-ol.
~hite crystals with melting point: 260-262C
Preparation of the starting compounds:
In analogy to Example 1:
3-Bromo-6-(4-chlorophenylsulfonyl)-3,4-dihydro-2,2-
dimethyl-7-methoxy-2H-benzoCb]pyran-4-ol ~ith melting
point: 175-177C
6-(4-Chlorophenylsulfonyl)-2,2-dimethyl-7-methoxychromene
~ith melting point: 142-143C
Example 7
6-(4-Bromophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-7-
methoxy-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzotb]pyran-
3-ol
In analogy to Example 1 from 3-bromo-6-(4-bromophenyl-
sulfonyl)-3,4-dihydro-2,2-dimethyl-7-methoxy-2H-benzo[b]-
pyran-4-ol.
White crystals of melting point: 281-282C.
Example 8
3,4-Dihydro-2,2-dimethyl-7-methoxy-6-~4-methoxyphenyl-
sulfonyl)-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]-
- 19 - 1336891
pyran-3-ol
The compound is prepared in anaLogy to Example 1 from 3-
bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(4-methoxy-
phenylsulfonyl)-2H-benzoCb]pyran-4-ol and has a melting
point of 286-287C.
Example 9
3,4-Dihydro-2,2-dimethyl-7-methoxy-6-(2-thienylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol
In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-
dimethyl-7-methoxy-6-(2-thienylsulfonyl)-2H-benzoCb]pyran-
4-ol, melting point: 135-136C.
Example 10
3,4-Dihydro-2,2-dimethyl-7-ethoxy-6-phenylsulfonyl-trans-
4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol
In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-
dimethyl-7-ethoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol,
melting point: 197-198C.
Example 11
3,4-Dihydro-2,2-dimethyl-7-methoxy-6-phenylsulfonyl-
trans-4-(2-oxo-1-piperidinyl)-2H-benzoCb]pyran-3-o-
In analogy to Example 2 from 3-bromo-3,4-dihydro-2,2-
dimethyl-7-methoxy-6-phenylsulfonyl-2H-benzoCb]pyran-4-
ol. ~hite crystals of melting point: 157-158C.
Example 12
6-(4-Cyanophenylsulfonyl)-3,4-dihydro-2,2-dimethyl-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol
In analogy to Example 1 from 3-bromo-6-(4-cyanophenyl-
sulfonyl)-3,4-dihydro-2,2-dimethyl-2H-benzotb]pyran-4-ol.
~hite crystals of melting point: 234-235C.
- 20 - 1 3 3 6 8 9 1
_
Preparation of the starting material:
3-Bromo-6-(4-cyanophenylsuLfonyl)-3,4-dihydro-2,2-
dimethyl-2H-benzotb]pyran-4-ol is obtained as described
in Example 3 from 6-(4-cyanophenylsulfonyl)-2,2-dimethyl-
3-chromene.
Melting point: 157-158C.
Example 13
3,4-Dihydro-2,2-dimethyl-6-(2-methoxyphenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol
In analogy to Example 1 from 3-bromo-3,4-dihydro-2,2-
dimethyl-6-(2-methoxyphenylsulfonyl)-2H-benzoCb~pyran-4-
ol. ~hite crystals of melting point: 196-198C.
Example 14
3,4-Dihydro-2,2-dimethyl-6-(2-methylphenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol
In analogy to Example 1. ~hite crystals of melting point:
214-216C.
Example 15
3,4-Dihydro-2,2-dimethyl-6-(2-chlorophenylsulfonyl)-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol
In analogy to Example 1. ~hite crystals of melting
point: 85-87C
Example 16
Preparation of 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-
trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo[b]pyran-3-ol
(compound of Example 5 by process variant c)
A solution of 3-bromo-3,4-dihydro-2,2-dimethyl-6-phenyl-
sulfonyl-2H-benzo[b]pyran-4-ol in ethanol is shaken under
a pressure of 8 bar of NH3 at 50 in an autoclave for
8 hours. The mixture is cooled and then evaporated to
1336891
- 21 - -
dryness and recrystallized from ethyl acetate. 4-Amino-
- 3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzo[b]-
pyran-3-ol of melting point: 160-163C is obtained and
is immediately subjected to acylation with 4-chlorobutyr-
yl chloride. For this purpose, the substance is dis-
solved together with the acid chloride in CH2Cl2 and
stirred in a two-phase mixture with 2N sodium hydroxide
solution at room temperature for 24 hours. The usual
working up results in 4-(4-chlorobutyrylamino)-3,4-di-
hydro-2,2-dimethyl-6-phenylsulfonyl-2H-benzoCb]pyran-4-ol
of melting point 155-157C. Cyclization to give the
title compound is carried out by dissolving the substance
in tetrahydrofuran, addition of a stoichiometric amount
of 80Z NaH suspension in oil and stirring the mixture at
room temperature for 24 hours. The final product is
identical to the product obtained by process b). Melting
point: 200-201C. If 4-amino-3,4-dihydro-2,2-dimethyl-
6-phenylsulfonyl-2H-benzoCb]pyran-3-ol is subjected to
racemate resolution, it is possible to obtain from its
(+) enantiomer the pure (+) enantiomer from Example 5a
with the data indicated there.
Example 17
3,4-Dihydro-2,2-dimethyl-6-phenylsulfoxy-trans-4-(2-oxo-
1-pyrrolidinyl)-2H-benzoCb]pyran-3-ol
In analogy to Example 1. Melting point: 211 - 212C
Pharmacological data
a) Effect on respiratory tract disorders
Effect on histamine-induced bronchoconstriction in
guinea-pigs
Method:
Uhite guinea-pigs of both sexes and weighing bet~een 450
and 550 9 were anesthetized with 60 mg/kg pentobarbital
1336891
22 -
i.p. After tracheotomy, they were ventilated with a
Starling pump (from Braun, Melsungen). The tidal volume
~as selected for generous ventilation of the lungs. The
ventilation pressure was adjusted to 80 mm H20 with the
S aid of a water column (Rosenthal and Dervinis). The
breathing rate was 30 breaths/min. An excess of avail-
able respiratory air can pass through a bypass in the
inhalation tube to a washbottle which is designed as a
water pressure-relief valve. ~hen air is blown by the
Starling pump through the inhalation tube into the lungs
they are inflated until the pressure in the system has
reached the value set by the height of the water column
(80 mm H20). The continuing inflow of air flo~s through
the pressure-relief valve into the washbottle. This
excess air which escapes into the bottle after the set
pressure has been exceeded is measured with the aid of a
piston recorder and is taken as a measure of the change
in the airway resistance. Measurement was carried out in
a manner slightly modified from the original Konzett-
Rossler method, in that the piston recorder was replacedby a Fleisch dynamic pressure tube (type 0000). The
difference in pressure which occurred was detected with a
Statham PM 97 TC differential pressure transducer. A
Hellige multichannel pen recorder was used to record the
measurements.
The test substances are administered as aerosol ~ith the
aid of an ultrasonic atomizer (Monaghan M 650). The
atomizer chamber is interpolated in the inhalation tube
of the ventilation pump and allows the animals to inhale
the aerosol for 1 min. The volume to be atomized is
0.02 ml/min.
Used for atomization is a physiological saline solution
to which the substance to be tested is added in the form
of a solution in propanediol.
It is ensured, in a control experiment, that the solvent
~ - - Z3 - 1336891
propanediol/physiological saline solution has no action
itself.
Eronchoconstriction is induced by doses of histamine di-
hydrochloride (6 - 12 ~g/kg i.v.). Injection is through
S a catheter introduced into the jugular vein. The dose
is selected so that a respiratory "overflow" of 60% of
the offered tidal volume occurs during the histamine-
induced bronchoconstriction. The histamine doses are
given at intervals of 5 minutes. After at least 3 well-
reproduced bronchoconstrictions, the test substances areadministered as aerosol for 1 min and, after an action
time of 2 min, the bronchoconstriction is induced ane~
and repeated at intervals of S minutes.
The degree of inhibition of the histamine-induced broncho-
constriction after pretreatment with the test substance
is regarded as a measure of the bronchodilator activity
and is reported as Z change from the control.
All results are subjected to linear regression, and the
IDso is determined.
Results:
% inhibition of histamine-induced bronchoconstriction
Compound Dose n % inhibition
Example Sa 1 ~g/kg 6 14 + 4
(+)-3,4-dihydro-2,2- 3 ~g/kg 6 35 ~ 4
25 dimethyl-6-phenyl- 10 ~g/kg 6 77 + 7
sulfonyl-trans-4-
(2-oxo-1-pyrrolidinyl)-
2H-benzotb]pyran-3-ol
IDso: 4-39 ~g/kg
~ - 24 - 1336891
b) Efferent urinary passages
Effect on the KCl-induced rhythmic contractions of
the guinea-pig ureter in vitro
Method:
Male guinea-pigs were sacrificed by a blow to the back of
the neck and exsanguination from the carotids. The two
ureters were immediately removed, avoiding the region
near the renal pelvis because of the pacemaker activity
present there. Pieces 2 cm long were first freed of
connective tissue in a Petri dish containing Tyrode solu-
tion and then suspended in a 25 ml organ bath (from Rhema
Labortechnik, Hofheim), in each case with a tension of
4.9 mN (= 0.5 p). The organ bath contained Tyrode solu-
tion of the following composition (mmol/l): NaCl 137,
KCl 2.68, MgS04 1.05, CaCl2 1.8, NaH2P04 0.41,
NaHC03 11.9, glucose 5.55, which was maintained at
37C and through which carbogen (95% 2~ 5% C02) was
bubbled.
The contractions were measured isometrically using Gould/
Statham UC2 pickups. After an equilibration time of at
least 15 minutes, KCl was added to the organ bath to
reach a concentration of 4 x 10 2 mol/l. The agonist
was left in the bath for 2 minutes, during which phasic
contractions occurred without bringing about any note-
worthy increase in the basic line tension.
Rinsing was then carried out for 1 minute, the rhythmiccontractions ceasing immediately. After a second run
with addition of agonist and the rinsing procedure, the
test substance (benzopyran derivative) ~as added to the
organ bath (in the form of a solution in 0.1 ml of
ethanol; the final concentration was 10 7 mol/l in all
cases) and was allowed to act for one minute before KCl
was added. The subsequent rinsing procedure was followed
by two final additions of agonist/rinsing procedures.
` 1336891
_ Z5
The following parameters were determined in each of the
two-minute periods during which KCl acted: 1. mean force
of contraction, 2. frequency of contractions and 3. pro-
duct of mean force and frequency of contractions.
The criteria for exclusion were mean forces of contrac-
tion below 4 mN or frequencies of below 2/min in more
than one of the four periods in ~hich only the agonist
KCl was present in the bath. Evaluation was of the per-
centage inhibition with the test substance compared with
the mean value from the two initial runs.
Besides the arithmetic mean (x), the standard error of
the mean (SEM) was calculated.
Results:
n = number of ureters
Mean force Frequency v k . v n
Compound of con- (%) (%)
traction
k (%)
3,4-Dihydro-2,2- 68 + 11 67 ~ 1485 1 7 4
dimethyl-6-(2-chloro-
~enylsulfonyl)-
trans-4-(2-oxo-1-
pyrrolidinyl)-2H-
benzotb]pyran-3-ol
Example 15
Reference: R. Schiantarelli and ~. Murmann, Arznei-
mittel-Forschung/Drug Research 30, 1102 -
1109 (1980)
