U.S. patent application number 10/850507 was filed with the patent office on 2004-10-28 for phenoxyphenyl alkanesulphonates.
This patent application is currently assigned to Bayer Aktiengesellschaft. Invention is credited to De Vry, Jean-Marie-Viktor, Denzer, Dirk, Heil, Markus, Lenfers, Jan-Bernd, Lustig, Klemens, Mauler, Frank, Meier, Heinrich, Naab, Paul, Voerste, Arnd.
Application Number | 20040214886 10/850507 |
Document ID | / |
Family ID | 7657564 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040214886 |
Kind Code |
A1 |
Heil, Markus ; et
al. |
October 28, 2004 |
Phenoxyphenyl alkanesulphonates
Abstract
The invention relates to novel phenoxyphenyl alkanesulphonates,
processes for their preparation, their use for producing
medicaments for the treatment and/or prophylaxis of diseases, in
particular for the treatment of states of pain and
neurodegenerative disorders
Inventors: |
Heil, Markus; (Leichlingen,
DE) ; Meier, Heinrich; (Wuppertal, DE) ; Naab,
Paul; (Wuppertal, DE) ; Voerste, Arnd; (Koln,
DE) ; De Vry, Jean-Marie-Viktor; (Rosrath, DE)
; Denzer, Dirk; (Solingen, DE) ; Mauler,
Frank; (Overath, DE) ; Lustig, Klemens;
(Wuppertal, DE) ; Lenfers, Jan-Bernd; (Wuppertal,
DE) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Aktiengesellschaft
Leverkusen
DE
|
Family ID: |
7657564 |
Appl. No.: |
10/850507 |
Filed: |
May 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10850507 |
May 20, 2004 |
|
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|
09965708 |
Sep 26, 2001 |
|
|
|
6756409 |
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Current U.S.
Class: |
514/517 ;
558/44 |
Current CPC
Class: |
A61P 25/08 20180101;
C07C 311/09 20130101; A61P 25/20 20180101; A61P 11/06 20180101;
A61P 25/16 20180101; A61P 1/04 20180101; A61P 1/14 20180101; A61P
25/18 20180101; A61P 25/06 20180101; A61P 37/02 20180101; A61P 1/08
20180101; A61P 9/10 20180101; A61P 25/00 20180101; A61P 25/28
20180101; C07C 309/65 20130101; C07C 311/08 20130101; A61P 29/00
20180101; A61P 27/06 20180101; A61P 25/04 20180101 |
Class at
Publication: |
514/517 ;
558/044 |
International
Class: |
A61K 031/255; C07C
37/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 26, 2000 |
DE |
10047486.1 |
Claims
1-6. (Cancelled).
7. Compounds of the general formula (II) 55in which R.sup.1 is
hydrogen, C.sub.1-C.sub.4-alkyl, halogen trifluoromethyl,
trifluoromethoxy, cyano or nitro; R.sup.2 is halogen,
trifluoromethyl, trifluoromethoxy, cyano or nitro; R.sup.4 is
hydrogen or halogen; and A denotes oxygen or NH.
8-11. (Cancelled).
Description
[0001] The invention relates to novel phenoxyphenyl
alkanesulphonates, processes for their preparation, their use for
producing medicaments for the treatment and/or prophylaxis of
diseases, in particular for the treatment of states of pain and
fleurodegenerative disorders.
[0002] Among the constituents of the hemp plant (Cannabis sativa),
the one of most pharmacological importance is
.DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC) which causes
the essential effects of cannabis on the human central nervous
system (CNS). Potential historical and contemporary therapeutic
applications of cannabis products comprise inter alia analgesia,
emesis, anorexia, glaucoma and movement disorders.
[0003] To date, two subtypes of cannabinoid receptors and one
splice variant have been identified. CB1 and CB2 receptors have
seven transmembrane regions and belong to the family of G
protein-coupled receptors. The CB1 receptor and the splice variant
CB1a are mainly localized in the central nervous system. The CB2
receptor has been found mainly in the peripheral tissue, especially
in leucocytes, spleen and macrophages.
[0004] Several classes of structures have been disclosed to date
for cannabinoid receptor agonists: classical cannabinoids such as,
for example, .DELTA..sup.9-THC, nonclassical cannabinoids such as,
for example, aminoalkylindoles, and eicosanoids. The latter
includes the endogenous CB1 receptor agonist anandamide.
[0005] WO-A-98/37061, WO-A-00/10967 and WO-A-00/10968 describe
certain aryloxyphenyl alkanesulphonates as cannabinoid receptor
agonists for the treatment of neurodegenerative disorders.
[0006] U.S. Pat. No. 3,462,473, Biochem. Pharmacol. 1972, 21,
1127-1134, Fed. Proc. Fed. Amer. Soc. Exp. Biol. 1971, 30, 841-847
and J. Pharm. Sci. 1973, 62, 1780-1784 disclosed certain
p-phenoxyphenyl alkanesulphonates and their hypocholesterolaemic or
hypolipidaemic effect.
[0007] In addition, certain phenoxyphenyl alkanesulphonates and
their use as herbicides (1), antimicrobial agents (2), lubricants
(3), sensitizers for heat-sensitive paper (4) and synthetic
intermediates (5) are known: (1) EP-A-0 023 725; U.S. Pat. No.
3,929,903; U.S. Pat. No. 4,415,354; Chem. Abstr. 1979, 91, 175034
(JP-A-54066631); Chem. Abstr. 1981, 94, 156552 (JP-A-55154953);
Chem. Abstr. 1981, 95, 168773 (JP-A-56046859); Chem. Abstr. 1981,
95, 168789 (JP-A-56079665); Chem. Abstr. 1989, 111, 2678
(JP-A-63104903); (2) DE-A-14 93 776; DE-A-21 31 754; U.S. Pat. No.
3,629,477; U.S. Pat. No. 3,772,445; U.S. Pat. No. 3,850,972;
CH-B-450 347; CH-B-459 656; Chem. Abstr. 1975, 83, 72725
(JP-B-50003375); (3) U.S. Pat. No. 3,346,612; (4) U.S. Pat. No.
4,837,197; (5) Chem. Abstr. 1997, 127, 26629 (JP-A-09087210);
Tetrahedr. 1990, 46. 4161-4164, J. Am. Chem. Soc. 1998, 39,
435-436.
[0008] It was an object of the present invention to provide
cannabinoid receptor agonists with improved effect.
[0009] This object is achieved by the novel compounds according to
the invention.
[0010] The present invention therefore relates to novel compounds
of the general formula (I), 1
[0011] in which
[0012] R.sup.1 denotes hydrogen, C.sub.1-C.sub.4-alkyl, halogen,
trifluoromethyl, trifluoromethoxy, cyano or nitro,
[0013] R.sup.2 denotes halogen, trifluoromethyl, trifluoromethoxy,
cyano or nitro,
[0014] R.sup.3 denotes C.sub.4-C.sub.7-alkyl which may be
substituted one or more times by fluorine or chlorine,
[0015] R.sup.4 denotes hydrogen or halogen, and
[0016] A denotes oxygen or NH.
[0017] The compounds according to the invention may exist in
stereoisomeric forms which either are related as image and mirror
image (enantiomers) or are not related as image and mirror image
(diastereomers). The invention relates to the enantiomers or
diastereomers or respective mixtures thereof. These mixtures of
enantiomers and diastereomers can be separated into
stereoisomerically uniform components in a known manner.
[0018] The compounds according to the invention may also be in the
form of their salts. Reference may generally be made here to salts
with organic or inorganic bases or acids.
[0019] For the purposes of the present invention, physiologically
acceptable salts are preferred. Physiologically acceptable salts of
the compounds according to the invention may be salts of the
substances according to the invention with mineral acids,
carboxylic acids or sulphonic acids. Particularly preferred
examples are salts with hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methanesulphonic acid,
ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,
naphthalenedisulphonic acid, acetic acid, propionic acid, lactic
acid, tartaric acid, citric acid, fumaric acid, maleic acid or
benzoic acid.
[0020] Physiologically acceptable salts may likewise be metal or
ammonium salts of the compounds according to the invention.
Particularly preferred examples are sodium, potassium, magnesium or
calcium salts, and ammonium salts derived from ammonia or organic
amines such as, for example, ethylamine, di- and triethylamine, di-
and triethanolamine, dicyclohexylamine, dimethylaminoethanol,
arginine, lysine, ethylenediamine or 2-phenylethylamine.
[0021] The present invention also includes ammonium compounds which
can be prepared by converting the free amines by alkylation.
[0022] For the purposes of the present invention, the substituents
generally have the following meaning:
[0023] C.sub.1-C.sub.4-Alkyl represents for the purposes of the
invention a straight-chain or branched alkyl radical having 1 to 4
carbon atoms. Examples which may be mentioned are: methyl, ethyl,
n-propyl, isopropyl, n-butyl, i-butyl, s-butyl and t-butyl.
[0024] C.sub.4-C.sub.7-Alkyl represents for the purposes of the
invention a straight-chain or branched alkyl radical having 4 to 7
carbon atoms. Examples which may be mentioned are: n-butyl,
i-butyl, s-butyl, t-butyl, i-pentyl, n-pentyl, hexyl, or heptyl.
Preference is given to n-butyl, n-pentyl and n-hexyl.
[0025] Halogen includes for the purposes of the invention fluorine,
chlorine, bromine and iodine. Chlorine or fluorine is
preferred.
[0026] Preference is given to compounds of the general formula
(I)
[0027] in which
[0028] R.sub.1 denotes hydrogen, fluorine, chlorine, methyl,
trifluoromethyl, trifluoromethoxy, cyano or nitro,
[0029] R.sup.2 denotes fluorine, trifluoromethyl, trifluoromethoxy,
cyano or nitro,
[0030] R.sup.3 denotes n-butyl, n-pentyl, 4,4,4-trifluorobut-1-yl
or 5,5,5-trifluoropent-1-yl,
[0031] R.sup.4 denotes hydrogen, and
[0032] A denotes oxygen.
[0033] Particular preference is given to compounds of the general
formula (I)
[0034] in which
[0035] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and A have the
abovementioned meaning, and
[0036] there is a hydrogen atom in position 4 of the phenyl ring
substituted by R.sub.1 and R.sup.2.
[0037] This can be illustrated by the following diagram: 2
[0038] Very particular preference is given to compounds of the
general formula (I)
[0039] in which
[0040] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and A have the
abovementioned meaning, and
[0041] R.sup.1 and R.sup.2 occupy positions 2 and 3 on the phenyl
ring.
[0042] The positions of R.sup.1 and R.sup.2 on the phenyl ring can
be illustrated by the following diagram: 3
[0043] Very particular preference is likewise given to compounds of
the general formula (I)
[0044] in which
[0045] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and A have the
abovementioned meaning, and
[0046] A is in position c of the benzene radical.
[0047] The position of A on the benzene radical can be illustrated
by the following diagram: 4
[0048] Very particular preference is given to compounds of the
general formula (I)
[0049] in which
[0050] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and A have the
abovementioned meaning,
[0051] R.sup.1 and R.sup.2 occupy positions 2 and 3 on the phenyl
ring, and
[0052] A is in position c of the benzene radical.
[0053] The positions of R.sup.1, R.sup.2 and A can be illustrated
by the following diagram: 5
[0054] In addition, a process for preparing compounds of the
general formula (I) has been found and is characterized in that a
compound of the general formula (II) 6
[0055] in which R.sup.1, R.sup.2, R.sup.4 and A have the
abovementioned meaning, is reacted in an inert solvent in the
presence of a suitable base and, where appropriate, in the presence
of a phase-transfer catalyst with a compound of the general formula
(III)
X.sup.1--SO.sub.2--R.sup.3 (III),
[0056] in which
[0057] X.sup.1 represents a suitable leaving group, and
[0058] R.sup.3 has the abovementioned meaning.
[0059] The compounds of the general formula (II) are novel and can
be prepared in analogy to generally known processes by initially
reacting a compound of the general formula (IV) with a compound of
the general formula (V) 7
[0060] in which
[0061] R.sup.1, R.sup.2 and R.sup.4 have the abovementioned
meaning,
[0062] a) Y represents a hydroxyl group and X represents a suitable
leaving group
[0063] or conversely
[0064] b) Y represents a suitable leaving group and X represents a
hydroxyl group,
[0065] and
[0066] E represents a nitro group or a group of the formula
--O--R.sup.5,
[0067] in which
[0068] R.sup.5 represents a suitable hydroxyl protective group,
[0069] in an inert solvent in the presence of a suitable base and,
where appropriate, in the presence of a copper(I) or copper(II)
compound to give a compound of the general formula (VI) 8
[0070] in which R.sup.1, R.sup.2, R.sup.4 and E have the
abovementioned meaning,
[0071] and
[0072] [A] then, in the case where E represents a nitro group,
reducing the latter under suitable conditions by conventional
methods to give a compound of the general formula (IIa) 9
[0073] in which R.sup.1, R.sup.2 and R have the abovementioned
meaning,
[0074] or
[0075] [B] in the case where E represents a group of the formula
--O--R.sup.5, removing the protective group R.sup.5 under suitable
conditions by conventional methods to liberate a compound of the
general formula (IIb) 10
[0076] in which R.sup.1, R.sup.2 and R.sup.4 have the
abovementioned meaning.
[0077] The compounds of the general formula (II) can also be
prepared by reacting a compound of the general formula (IV) with a
compound of the general formula (VII) 11
[0078] in which
[0079] R.sup.1, R.sup.2, R.sup.4, A, X and Y have the
abovementioned meaning,
[0080] in an inert solvent in the presence of a suitable base and,
where appropriate, in the presence of a copper(I) or copper(II)
compound.
[0081] The processes according to the invention can be illustrated
by way of example by the following diagram: 12
[0082] Inert solvents for the purpose of the invention are solvents
which are unchanged or are only inconsiderably changed under the
chosen reaction conditions.
[0083] Examples of inert solvents suitable for the process
(II)+(III).fwdarw.(I) are ethers such as, for example, diethyl
ether, glycol monomethyl or dimethyl ether, dioxane or
tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene,
cyclohexane or petroleum fractions or halogenated hydrocarbons such
as methylene chloride, chloroform, tetrachloromethane, or dimethyl
sulphoxide, dimethylformamide, hexamethylphosphoramide, ethyl
acetate, pyridine, triethylamine or picoline. It is likewise
possible to use mixtures of the said solvents, where appropriate
also with water. Methylene chloride, methylene chloride/water,
tetrahydrofuran, dioxane and dioxane/water are particularly
preferred.
[0084] Bases suitable for reaction (II)+(III).fwdarw.(I) are
organic amines, in particular tri-(C.sub.1-C.sub.6)-alkylamines
such as, for example, triethylamine or diisopropylethylamine, or
heterocycles such as pyridine, methylpiperidine, piperidine or
N-methylmorpholine, alkali metal and alkaline earth metal
hydroxides or carbonates such as, for example, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate or
alcoholates such as, for example, sodium methanolate or sodium
ethanolate. Triethylamine, pyridine and sodium hydroxide are
preferred.
[0085] The bases are generally employed in an amount of from 0.1
mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on
1 mol of the compounds of the general formula (II).
[0086] The process (II)+(III).fwdarw.(I) can also where appropriate
be carried out in the presence of a phase-transfer catalyst.
Quaternary ammonium salts, preferably tetrabutylammonium bromide,
for example are suitable as phase-transfer catalyst.
[0087] Suitable as leaving group X.sup.1 is, for example, halogen,
preferably chlorine.
[0088] The reactions can be carried out under atmospheric pressure
but also under elevated or reduced pressure (for example 0.5 to 3
bar). They are generally carried out under atmospheric
pressure.
[0089] The process (II)+(III).fwdarw.(I) is carried out in a
temperature range from 0.degree. C. to 100.degree. C., preferably
at 0.degree. C. to 30.degree. C.
[0090] Examples of inert solvents which have proved suitable for
the processes (IV)+(V).fwdarw.(VI) and (IV)+(VII).fwdarw.(II) are
the following: organic solvents such as ethers, such as, for
example, diethyl ether, glycol monomethyl or dimethyl ether,
dioxane or tetrahydrofuran, or hydrocarbons such as benzene,
toluene, xylene, cyclohexane or petroleum fractions or halogenated
hydrocarbons such as methylene chloride, chloroform,
tetrachloromethane, or dimethyl sulphoxide, dimethylformamide,
N-methylpyrrolidone, hexamethylphosphoramide, ethyl acetate,
pyridine, triethylamine or picoline. It is likewise possible to use
mixtures of the said solvents, where appropriate also with water.
Pyridine, N-methylpyrrolidone, dimethylformamide and dimethyl
sulphoxide are particularly preferred.
[0091] The processes (IV)+(V).fwdarw.(VI) and
(IV)+(VII).fwdarw.(II) can also where appropriate be carried out in
the presence of a copper(I) or copper(II) compound. Copper(I)
iodide and copper(II) oxide are preferred.
[0092] Bases suitable for the processes (IV)+(V).fwdarw.(VI) and
(IV)+(VII).fwdarw.(II) are alkali metal carbonates and
bicarbonates, in particular sodium and potassium carbonates, alkali
metal hydroxides, in particular sodium hydroxide, or organic
amines, in particular tri-(C.sub.1-C.sub.6)-alkylamines such as,
for example, triethylamine. Potassium hydroxide, sodium hydroxide
and potassium carbonate are particularly preferred.
[0093] The bases are generally employed in an amount of from 0.1
mol to 5 mol, preferably from 1 mol to 3 mol, in each case based on
1 mol of the compounds of the general formula (IV) or (V).
[0094] A suitable leaving group X in process (IV)+(V).fwdarw.(VI)
variant a) or Y in process (IV)+(V).fwdarw.(VI) variant b) is, for
example, halogen or a sulphonato group such as, for example,
triflate. Fluorine, chlorine or bromine are preferred.
[0095] The reactions can be carried out under atmospheric pressure
but also under elevated or reduced pressure (for example 0.5 to 5
bar). They are generally carried out under atmospheric
pressure.
[0096] The reactions are carried out in a temperature range from
20.degree. C. to 200.degree. C., preferably at 100.degree. C. to
160.degree. C.
[0097] Methods for reducing an aromatic nitro group for process
step (VI).fwdarw.(IIa) are known (for example R. C. Larock,
"Comprehensive Organic Transformations", New York, 1989, pp.
411-415 and the literature cited therein).
[0098] The introduction of hydroxyl protective groups and methods
for elimination thereof are known (for example T. W. Greene, P. G.
M. Wuts, "Protective Groups in Organic Synthesis", 2.sup.nd Ed.,
New York, 1991 and the literature cited therein; J.Org. Chem. 1999,
64, 9719-9721).
[0099] Examples of suitable protective group R.sup.5 for the
reaction sequence (IV)+(V).fwdarw.(VI).fwdarw.(IIb) are methyl,
benzyl, allyl, methoxymethyl, 2-trimethylsilylethoxymethyl or
trimethylsilyl. Methyl and benzyl are preferred.
[0100] The compounds of the general formula (III) are commercially
available, known from the literature or can be synthesized in
analogy to processes known from the literature (compare, for
example, J. Chem. Soc. C 1968, 1265; Chem. Ber. 1967, 100, 1696;
fluorinated alkanesulphonyl chlorides can be obtained, for example,
as described in WO-A-98/37061 or DE-A-19 422 64).
[0101] The compounds of the general formulae (IV), (V) and (VII)
are known or can be prepared by known processes.
[0102] The compounds of the general formulae (IV) and (V) are
commercially available, known from the literature or can be
prepared in analogy to processes known from the literature
(compare, for example, J. March, "Advanced Organic Chemistry",
4.sup.th Ed., Wiley, 1992, pages 531-534 and 1295 and the
literature cited therein; Synthesis 1990, 1145-1147).
[0103] Surprisingly, the compounds according to the invention show
a valuable range of pharmacological actions which could not have
been predicted.
[0104] They are distinguished by being highly effective cannabinoid
receptor agonists with high metabolic stability and high oral
bioavailability. They are thus particularly suitable for oral
therapy.
[0105] They can be employed alone or in combination with other
medicaments for the prophylaxis and treatment of acute and/or
chronic pain (for a classification, see "Classification of Chronic
Pain, Descriptions of Chronic Pain Syndromes and Definitions of
Pain Terms", 2.sup.nd edition, Meskey and Begduk, editors;
IASP-Press, Seattle, 1994) and neurodegenerative disorders, in
particular for the treatment of cancer-induced pain and chronic
neuropathic pain like, for example, that associated with diabetic
neuropathy, postherpetic neuralgia, peripheral nerve damage,
central pain (for example as a consequence of cerebral ischaemia)
and trigeminal neuralgia, and other chronic pain such as, for
example, lumbago, backache (low back pain) or rheumatic pain. These
substances are in addition also suitable for the therapy of primary
acute pain of any origin and of secondary states of pain resulting
therefrom, and for the therapy of states of pain which were
formerly acute and have become chronic.
[0106] Suitable for combination with the compounds according to the
invention for the treatment of acute and/or chronic pain are, for
example, opiates, for example tramadol, morphine, dihydrocodeine,
dextropropoxyphen, tricyclic antidepressants, for example
amitriptyline, anticonvulsants, for example carbamazepine,
gabapentine, non-steroidal antiinflammatory drugs (NSAIDs), for
example aspirin, ibuprofen, naproxen, including COX-2 inhibitors,
for example rofecoxib, celecoxib.
[0107] The compounds according to the invention are likewise also
suitable for the therapy of primary and/or secondary pathological
states of the brain, for example during or after cerebral
vasospasms, migraine, spasticity, hypoxia and/or anoxia whose
origin has not previously been mentioned, perinatal asphyxia,
autoimmune diseases, metabolic and organic disorders which may be
associated with damage to the brain, and damage to the brain as a
consequence of primary brain disorders, for example epilepsy and
atherosclerotic and/or arteriosclerotic changes. The compounds
according to the invention are likewise suitable for the treatment
of chronic or psychiatric disorders such as, for example,
depression, gastric ulcers, neurodegenerative disorders such as,
for example, Alzheimer's, Parkinson's or Huntington's disease,
multiple sclerosis, amyotrophic lateral sclerosis (ALS),
neurodegeneration due to acute and/or chronic viral or bacterial
infections and multi-infarct dementia.
[0108] They can furthermore be employed in medicaments for the
treatment of emesis, nausea, glaucoma, asthma, anorexia,
convulsions, rheumatism, sedation and movement disorders.
[0109] The substances according to the invention are also suitable
for the treatment of disorders which are caused by bacterial and/or
viral infections which are based on direct and/or indirect changes
in the immune system or on dysregulation with involvement of the
immune system, such as, for example, for local or systemic
autoimmune diseases (for example lupus erythematosus in all its
variants), inflammatory and/or autoimmunologically related
disorders of the joints (for example rheumatoid arthritis,
inflammations related to trauma), inflammatory and/or
autoimmunologically related disorders of the skeletal and muscular
systems, inflammatory and/or autoimmunologically related
pathological processes of the internal organs (for example Crohn's
disease, ulcerative colitis, glomerulonephritis) and of the
external organs (for example allergic reactions due to intake of
airborne antigens) and of the central nervous system (for example
multiple sclerosis, Alzheimer's disease, psychiatric disorders) and
of the sensory organs, primary and/or secondary and/or
autoimmunological disorders of the blood-forming system and of the
immune system (for example rejection reactions, AIDS) itself, and
for cutaneous disorders of inflammatory and/or immunological origin
in humans and animals. These substances also act on the indirect
symptoms of these disorders such as, for example, pain.
[0110] They are preferably used for the treatment of pain,
spasticity, cerebral ischaemias and craniocerebral trauma.
[0111] The in vitro action of the compounds according to the
invention on cannabinoid receptors can be shown by the following
bioassays:
[0112] 1. Rats CB1 Luciferase Reporter Gene Test
[0113] Stock cultures of a rat CHOCB1 reporter cell line were
prepared by the method described in WO-A-98/37061, page 55 et
seq.
[0114] The following test protocol was used for the substance
screening: the stock cultures were cultivated in 50% of Dulbecco's
modified Eagle medium/50% F-12 (DMEM/F12) with 10% FCS at
37.degree. C. under 10% CO.sub.2 and split 1:10 after 2 to 3 days
in each case. Test cultures were seeded with 5 000 cells per well
in 96-well plates and cultured at 37.degree. C. for 70 hours. The
cultures were then cautiously washed with phosphate-buffered saline
and reconstituted with serum-free Ultra-CHO medium (Bio-Whittaker).
The substances dissolved in DMSO were diluted 1.times. in medium
and pipetted into the test cultures (maximum DMSO final
concentration in test mixture: 0.5%). 20 minutes later, forskolin
was added and the cultures were then incubated in an incubator at
37.degree. C. for 3 hours. The supernatants were then removed and
the cells were lysed by adding 25 .mu.l of lysis reagent (25 mM
tris phosphate, pH 7.8 with 2 mM DTT, 10% glycerol, 3% Triton
X100). Immediately thereafter luciferase substrate solution (2.5 mM
ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mM
MgSO.sub.4, 15 mM DTT, pH 7.8) was added and briefly shaken, and
the luciferase activity was measured using a Hamamatsu camera
system.
[0115] To inactivate G.sub.i proteins, the test cultures were
treated with 5 ng/ml (final concentration) pertussis toxin for 16
hours before the test.
[0116] The IC.sub.50 values were calculated using the GraphPadPrism
program (Hill equation, specifically: one-site competition).
[0117] Example 17 shows an IC.sub.50 of 0.81 nM in this test.
[0118] 2. hCB2 Luciferase Reporter Gene Test
[0119] CHOluc9 cells were stably transfected with the human CB2
receptor. Transfection, clone selection and test development were
carried out in analogy to the work on the rat CB1 receptor. The
following test protocol was used for pharmacological
characterization of the cells and for substance testing:
[0120] The stock cultures were cultivated in 50% of Dulbecco's
modified Eagle medium/50% F-12 (DMEM/F12) with 10% FCS at
37.degree. C. under 10% CO.sub.2 and split 1:10 after 2 to 3 days
in each case. Test cultures were seeded with 5 000 cells per well
in 96-well plates in DMEM/F12 medium with 5% FCS and cultured at
37.degree. C. for 70 hours. The medium was then removed from the
cultures and replaced by serum-free Ultra-CHO medium
(Bio-Whittaker). The substances dissolved in DMSO (200.times.final
concentration) were pipetted into the test cultures (maximum DMSO
final concentration in test mixture: 0.5%). 20 minutes later,
forskolin was added and the cultures were then incubated in an
incubator at 37.degree. C. for 3.5 hours. The supernatants were
then removed and the cells were lysed by adding 25 .mu.l of lysis
reagent (25 mM tris phosphate, pH 7.8 with 2 mM DTT, 10% glycerol,
3% Triton X100). Immediately thereafter 50 .mu.l of luciferase
substrate solution, doubly concentrated, (5 mM ATP, 1 mM luciferin,
0.2 mM coenzyme A, 10 mM tricine, 1.35 mM MgSO.sub.4, 15 mM DTT, pH
7.8) were added and briefly shaken, and the luciferase activity was
determined using a photomultiplier camera measuring system
(Hamamatsu).
[0121] The IC.sub.50 values were calculated using the GraphPad
Prism.TM. program (Hill equation; specifically one-site
competition).
[0122] 3. Binding to Rat Cortex Membranes
[0123] Membrane protein is prepared from various tissues and from
cells by standard methods. Buffer, labelled ligand, DMSO or test
substance are pipetted together, then 100 .mu.g of protein are
added, and the mixture is thoroughly mixed and incubated in a
waterbath at 30.degree. C. for 60 min. After completion of the
incubation time, the reaction is stopped by adding ice-cooled
incubation buffer to each tube. Filtration is followed by washing
with 3/4 ml of incubation buffer. The filters are transferred into
minivials, and the radioactivity is determined in a liquid
scintillation counter.
[0124] The metabolic stability of the compounds according to the
invention can be found in the following in vitro assay:
[0125] 4. Microsomal Stability Investigations
[0126] The metabolic stability of the compounds according to the
invention can be measured in rat liver microsomes (in analogy to J.
Pharmacol. Exp. Ther. 1997, 283. 46-58).
[0127] To determine the microsomal stability and extrapolate to the
maximum possible bioavailability (Fmax) owing to the first-pass
effect in the liver (phase 1 reactions), the substance is incubated
in low concentration with microsomal protein, with addition of
cofactors, at 37.degree. C. for 15 minutes.
[0128] The incubation and the sampling take place on a modified
automatic pipettor from Canberra Packard.
[0129] As comparison with an example from WO-A-98/37061 shows, the
compounds according to the invention are more metabolically stable
in this test:
1TABLE 1 13 R.sup.1 R.sup.2 Fmax [%] Example 304 from CH.sub.3
CH.sub.3 2 WO-A-98/37061 Example 15 Cl CH.sub.3 4 Example 17 H
OCF.sub.3 40
[0130] The bioavailability of the compounds according to the
invention, and other pharmacokinetic parameters, can be determined
in vivo in the following way:
[0131] 5. Pharmacokinetics in the Rat
[0132] a) Intravenous Infusion
[0133] The substance is infused through a Braunule in a lateral
tail vein directly into the blood stream over 15 minutes. A
calibrated 20 ml syringe is used for accurate administration of the
chosen dose and volume. A Braun Melsungen No. 152440/1 pump is used
for the infusion.
[0134] b) Oral Administration
[0135] The substance is administered as bolus by gavage.
[0136] c) Sampling and Workup
[0137] Blood and Plasma
[0138] Blood samples are collected from catheterized animals
jugular vein) in heparinized tubes. The blood is centrifuged and
the plasma is prepared in a suitable manner for analysis
(LC-MS-MS). The plasma is stored at <-15.degree. C. until
analysed.
[0139] d) Pharmacokinetic Results
[0140] Microsomal data (rat liver microsomes) predict a maximum
possible availability of up to 100%.
[0141] The pharmacokinetic parameters for Example 22 derived from
the in vivo experiments (rat) are:
[0142] Oral data: (dose: 3 mg/kg): AUC.sub.stand: 0.102 kg*h/l,
C.sub.max,stand: 0.0198 kg/l, t.sub.max: 2.29 h, t.sub.1/2: 2.36 h,
F: 33%.
[0143] i.v. data: (dose: 0.3 mg/kg): AUC.sub.stand: 0.307 kg*h/l,
C.sub.max,stand: 0.5978 kg/l, V.sub.ss: 4.12 l/kg, t.sub.1/2: 1.6
h.
[0144] The meanings herein are:
[0145] AUC.sub.stand: the area, standardized to a dose of 1 mg/kg,
under the plasma concentration/time curve;
[0146] C.sub.max,stand: the maximum plasma concentration after a
single administration, standardized to a dose of 1 mg/kg;
[0147] t.sub.max: the time at which the maximum plasma
concentration is reached after a single dose;
[0148] t.sub.1/2: terminal half-life;
[0149] F: bioavailability; in this case the percentage, compared
with i.v. administration, of the dose which is systemically
available;
[0150] V.sub.ss: apparent volume of distribution at the steady
state.
[0151] The in vivo effect of the compounds according to the
invention can be shown, for example, in the following animal
models:
[0152] 6. Hypothermia (Rat)
[0153] The in vivo agonistic effect on the CB1 receptor was
examined in the rat hypothermia assay.
[0154] Five minutes after determining the basal body temperature
via an oesophageal temperature probe, the test substance is
administered (orally). A control group receives, likewise orally,
only the solvent for the test substances (Cremophors EL
1-10%+distilled water). The body temperature is measured 120 and
240 minutes after oral administration. The size of the group for
each dose is 5-7 animals (rats).
[0155] Rat Hypothermia Agonism Test
2 Example ED.sub.-1.degree. C..sup.a) [mg/kg] 22 10 .sup.aEffective
dose for reducing the body temperature by 1.degree. C.
[0156] The suitability of the compounds according to the invention
for the treatment of states of pain can be shown in the following
animal models:
[0157] 7. Axotomy of Sciatic Branches in the Rat (Chronic Pain
Model)
[0158] Under pentobarbital anaesthesia, the trifurcation of a
sciatic nerve is exposed, and the peroneal and tibial branches are
axotomized after the nerves have been ligated proximal of the
axotomy site. Control animals undergo a sham operation. After the
operation, the axotomized animals develop chronic mechanical
hyperalgesia. This hyperalgesia is tested, comparing with
sham-operated animals, with the aid of a pressure transducer
(electronic von Frey anesthesiometer, IITC Inc.--Life Science
Instruments, Woodland Hills, Calif., USA).
[0159] The substance is administered by various administration
routes (i.v., i.p., orally, i.t., i.c.v., transdermally) at various
times before the pain testing.
[0160] Example 22 reduces the hyperalgesia in the model at a
minimally effective dose of 1 mg/kg orally (acute administration,
60 minutes before the test).
[0161] The suitability of the compounds according to the invention
for example for the treatment of neurodegenerative disorders can be
shown in the model of permanent focal cerebral ischaemia in the rat
(MCA-O) or in the model of subdural haematoma in the rat (SDH)
(WO-A-98/37061, page 60 et seq.).
[0162] The novel active substances can be converted in a known
manner into conventional formulations such as tablets, coated
tablets, pills, granules, aerosols, syrups, emulsions, suspensions
and solutions by use of inert, nontoxic, pharmaceutically suitable
carriers or solvents. In these the therapeutically active compound
should be present in each case in a concentration of about 0.5 to
90% by weight of the complete mixture, that is to say in amounts
which are sufficient to achieve the stated dose range.
[0163] The formulations are produced for example by extending the
active substances with solvents and/or carriers, where appropriate
with use of emulsifiers and/or dispersants, it being possible to
use, for example in the case where water is used as diluent, where
appropriate organic solvents as auxiliary solvents.
[0164] Administration takes place in a conventional way, preferably
orally, transdermally or parenterally, in particular perlingually
or intravenously. However, it can also take place by inhalation
through the mouth or nose, for example with the aid of a spray, or
topically through the skin.
[0165] In general, it has proved advantageous to administer amounts
of about 0.001 to 10 mg/kg on oral administration, preferably about
0.005 to 1 mg/kg of body weight, to achieve effective results.
[0166] It may nevertheless be necessary where appropriate to
deviate from the stated amounts, in particular depending on the
body weight and the mode of administration, on the individual
response to the medicament, the nature of its formulation and the
time or interval over which administration takes place. Thus, in
some cases it may be sufficient to make do with less than the
aforementioned minimum amount, whereas in other cases the upper
limit mentioned must be exceeded. In the case of administration of
larger amounts, it may be advisable to distribute these in several
individual doses over the day.
[0167] The determination of the retention time of starting
compounds and preparation examples by HPLC took place under the
following conditions:
[0168] Column: Kromasil C18 60*2; volume injected 1.00 .mu.l; flow
rate: 0.75 ml/min; eluent: A=0.1M aq H.sub.3PO.sub.4, B=CH.sub.3CN;
gradient [t(min): A/B)]: 0:90/10; 0.5: 90/10; 4.5:10/90; 6.5:10/90;
7.5:90/10.
Abbreviations
[0169] aq. aqueous
[0170] CH cyclohexane
[0171] TLC thin layer chromatograph
[0172] DCI direct chemical ionization (in MS)
[0173] DCM dichloromethane
[0174] EA ethyl acetate
[0175] EI electron impact ionization (in MS)
[0176] ESI electrospray ionization (in MS)
[0177] HPLC high pressure, high performance liquid
chromatography
[0178] Me methyl
[0179] MW molecular weight
[0180] MS mass spectroscopy
[0181] NMR nuclear magnetic resonance spectroscopy
[0182] R.sub.f retention index (in TLC)
[0183] R.sub.t retention time (in HPLC)
Starting Compounds
EXAMPLE I
3-methoxy-1-(3-methyl-2-nitrophenoxy)benzene
[0184] (diphenyl ether Synthesis--Method A)
[0185] 14.7 g (96.0 mmol) of 3-methyl-2-nitrophenol, 53.9 g (288
mmol) of 3-bromoanisole and 18.3 g (96.0 mmol) of potassium
carbonate are introduced into about 600 ml of pyridine and heated
to about 140.degree. C. The mixture is allowed to cool slightly,
and 18.3 g (96 mmol) of copper(I) iodide are added. The mixture is
stirred at about 140.degree. C. for about 60 h. After removal of
the solvent in vacuo, the residue is taken up in toluene and again
evaporated. The residue is taken up in dichloromethane and filtered
through kieselguhr. Washing with further dichloromethane is
followed by washing successively with 5N HCl, 2N NaOH, 5N HCl,
water and brine. The crude product obtained after drying over
magnesium sulphate and concentration in vacuo is purified by
Kugelrohr distillation.
[0186] Yield: 3.50 g (13%; HPLC purity 94%)
[0187] R.sub.f: 0.28 (cyclohexane/ethyl acetate 5:1)
[0188] MS (EI): 259 (100%, [M].sup.+)
[0189] HPLC: retention time=4.94 min
[0190] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta./ppm=2.37 (s, 3H),
3.78 (s, 3H), 6.1-6.65 (m, 2H), 6.67-6.74 (m, 1H), 6.83 (d, J=8 Hz,
1H), 6.99 (d, J=8 Hz, 1H), 7.14-7.32 (m, 2 H).
EXAMPLE II
3-methoxy-1-[2-(trifluoromethyl)phenoxy]benzene
[0191] (diphenyl ether Synthesis--Method B)
[0192] 50.0 g (222 mmol) of 2-bromobenzotrifluoride, 27.6 g (222
mmol) of 3-methoxyphenol and 30.7 g (222 mmol) of potassium
carbonate are introduced into about 450 ml of pyridine and briefly
heated to about 100.degree. C. The mixture is allowed to cool
slightly, and 17.7 g (222 mmol) of copper(II) oxide are added. The
mixture is stirred under reflux (bath temperature about 140.degree.
C.) for about 48 h. After removal of the solvent in vacuo, the
residue is taken up in dichloromethane and extracted with 2N
hydrochloric acid. The organic phase is then washed with 1N sodium
hydroxide solution and water. The crude product obtained after
drying over magnesium sulphate and concentration in vacuo is
purified by Kugelrohr distillation.
[0193] Yield: 37.2 g (62%; HPLC purity 98%)
[0194] R.sub.f: 0.47 (cyclohexane/ethyl acetate 5:1)
[0195] MS (EI): 268 (100%, [M].sup.+)
[0196] HPLC: Retention time=5.14 min
[0197] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta./ppm=3.79 (s, 3H),
6.56-6.65 (m, 2 H), 6.71 (ddd, J=8 Hz, 2 Hz, 1 Hz, 1H), 6.97 (d,
J=8 Hz, 1H), 7.17 (t, J=8 Hz, 1H) 7.25 (t, J=8 Hz, 1H), 7.46 (td,
J=8 Hz, 1 Hz, 1H), 7.66 (d, J=8 Hz, 1H).
EXAMPLE III
1-(2-cyano-3-(trifluoromethyl)phenoxyl-3-methoxybenzene
[0198] (diphenyl ether Synthesis--Method C)
[0199] Under argon, 10.7 g (52.1 mmol) of
2-chloro-6-(trifluoromethyl)benz- onitrile [Example 5 in DE-A-38 36
159; 2-chloro-6-(trichloromethyl)benzoni- trile can be prepared
from 2,6-dimethylbenzonitrile as in Example 3 in DE-A-2 214 058]
are introduced into anhydrous DMF and, after addition of 7.19 g
(52.1 mmol) of potassium carbonate and 6.46 g (52.1 mmol) of
3-methoxyphenol, stirred at 100.degree. C. for 5 h. Then 500 ml of
2N NaOH and 200 ml of saturated brine are added. After extraction
twice with about 300 ml of ether, the combined organic phases are
dried over magnesium sulphate, evaporated in vacuo and flash
chromatographed on 450 g of silica gel with toluene as mobile
phase. Product fractions are evaporated to dryness and a little
ether is added to the remaining oil. The crystals which form are
filtered off with suction and washed with pentane.
[0200] Yield: 9.36 g (57%; HPLC purity 96%)
[0201] R.sub.f: 0.39 (toluene)
[0202] Melting point: 68.degree. C.
[0203] HPLC: Retention time=4.89 min
[0204] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta./ppm=3.72 (s, 3H),
6.62-6.87 (m, 3H), 7.08 (d, J=8 Hz, 1H), 7.33 (t, J=8 Hz, 1H), 7.44
(d, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 1H).
EXAMPLE IV
1-[2-chloro-3-(trifluoromethyl)phenoxy]-3-nitrobenzene
[0205] (diphenyl ether Synthesis--Method D)
[0206] Under argon, 1.00 g (5.09 mmol) of
2-chloro-3-(trifluoromethyl)phen- ol is introduced into 10 ml of
DMF, and 0.72 g (5.09 mmol) of 3-fluoronitrobenzene and 0.70 g
(5.09 mmol) of potassium carbonate are added. The mixture is heated
to reflux for about 16 h. After cooling, the mixture is added to 50
ml of 2N sodium hydroxide solution and, after stirring for one
hour, 20 ml of sodium chloride solution are added and stirring is
continued for 30 minutes. The mixture is then extracted with
dichloromethane, and the organic phase is dried over magnesium
sulphate and concentrated in vacuo. Purification by chromatography
on silica gel in cyclohexane/ethyl acetate 20:1 as mobile phase
affords 0.69 g (42%, HPLC purity: 100%) of the target compound.
[0207] R.sub.f: 0.39 (cyclohexane/ethyl acetate 2:1)
[0208] MS (EI): 317 (100%, [M].sup.+)
[0209] HPLC: Retention time=5.22 min
[0210] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta./ppm=7.51 (dd,
J=8 Hz, 2 Hz, 1H), 7.56-7.83 (m, 5H), 8.05 (dd, J=8 Hz, 2 Hz,
1H).
[0211] The following Examples V-XIII are prepared from the
appropriate starting compounds in an analogous manner corresponding
to process methods A or B for the starting compounds:
3TABLE I HPLC purity in R.sub.f- Ex. Method/ %/ (mobile No. Target
structure MW yield in % R.sub.t in min. phase) MS V 14 293.2 B/ 15
94/ 5.55 0.53 (CH/EA 20:1) DCI/NH.sub.3: 293 (100%, [M + H].sup.+)
VI 15 259.3 A/ 59 96/ 5.05 0.31 (CH/EA 2:1) EI: 259 (100%,
[M].sup.+) VII 16 268.2 B/ 62 98/ 5.14 0.47 (CH/EA 2:1) EI: 268
(100%, [M].sup.+) VIII 17 269.1 A/ 45 78/ 5.36 0.51 (CH/EA 2:1) EI:
268 (90%, [M].sup.+) IX 18 248.7 A/ 70 96/ 5.54 0.55 (CH/EA 5:1)
EI: 248 (100%, [M].sup.+) X 19 234.7 A/ 61 73/ 5.09 0.46 (CH/EA
2:1) DCI/NH.sub.3: 235 (100%, [M + H].sup.+) XI 20 360.3 B/ 45 96/
5.67 0.53 (CH/EA 5:1) ESI: 361 (100%, [M + H].sup.+) XII 21 302.7
A/ 77 89/ 5.36 0.55 (CH/EA 2:1) EI: 302 (100%, [M].sup.+) XIII 22
360.3 B/ 57 96/ 5.83 0.14 (CH/EA 2:1) EI: 360 (26%, [M].sup.+)
EXAMPLE XIV
3-(3-methyl-2-nitrophenoxy)phenol
[0212] (methyl ether Cleavage--Method A)
[0213] Under argon, 500 mg (1.93 mmol) of
1-methoxy-3-(3-methyl-2-nitrophe- noxy)benzene are introduced into
2 ml of anhydrous dichloromethane, and the solution is cooled to
-20.degree. C. At this temperature, 5.8 ml of a 1M solution of
boron tribromide in dichloromethane are added. The mixture is
allowed to reach 0.degree. C. and is stirred for 1 h. Addition of
water is followed by extraction with dichloromethane three times.
The combined organic phases are washed with sodium bicarbonate
solution, dried over magnesium sulphate and concentrated in vacuo.
Chromatographic purification on silica gel in cyclohexane/ethyl
acetate 30:1 as mobile phase affords 424 mg (89%) of the target
compound.
[0214] R.sub.f: 0.18 (cyclohexane/ethyl acetate 2:1)
[0215] MS (EI): 245 ([M].sup.+)
[0216] HPLC: Retention time=4.40 min
[0217] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta./ppm=2.37 (s, 3H),
4.88 (broad s, 1H), 6.54 (t, J=2 Hz, 1H), 6.57-6.66 (m, 2H), 6.85
(d, J=8 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 7.19 (t, J=8 Hz, 1H), 7.27
(t, J=8 Hz, 1H).
EXAMPLE XV
3-[2-cyano-3-(trifluoromethyl)phenoxy]phenol
[0218] (methyl ether Cleavage--Method B)
[0219] Under argon, 10.0 g (34.1 mmol) of
1-(2-cyano-3-trifluoromethylphen- oxy)-3-methoxybenzene are
introduced into anhydrous dichloromethane, and 13.9 g (37.5 mmol)
of tetra-n-butylammonium iodide are added. After cooling to
-78.degree. C., 120 ml of a 1N solution of boron trichloride in
dichloromethane are slowly added dropwise, not allowing the
temperature to rise above -70.degree. C. The mixture is allowed to
warm to RT within 2 h. The reaction mixture is poured onto 300 ml
of ice-water, the mixture is extracted three times with
dichloromethane, and the organic phase is washed 2.times. with
saturated sodium bicarbonate solution and 1.times. with brine.
Drying over magnesium sulphate is followed by flash chromatography
on about 400 g of silica gel with dichloromethane. Pentane is added
to the resulting oily product, which is left to crystallize.
[0220] Yield: 7.75 g (96%; HPLC purity 96%)
[0221] R.sub.f: 0.16 (CH.sub.2Cl.sub.2)
[0222] Melting point: 108.degree. C.
[0223] HPLC: Retention time=4.41 min
[0224] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta./ppm=5.13 (s, 1H),
6.59-6.78 (m, 3H), 7.11 (d, J=8 Hz, 1H), 7.28 (t, J=8 Hz, 1H), 7.45
(d, J=8 Hz, 1H), 7.58 (t, J=8 Hz, 1H).
EXAMPLE XVI
3-[2-chloro-3-(trifluoromethyl)phenoxy]phenol
[0225] (methyl ether Cleavage--Method C)
[0226] 600 mg (1.98 mmol) of
3-methoxy-1-[2-chloro-3-(trifluoromethyl)phen- oxy]-benzene are
introduced into 6 ml of acetic acid and, after addition of 3.60 ml
of 48% strength aqueous hydrobromic acid, heated to reflux for 4 h.
Cooling is followed by dilution with water and extraction with
ethyl acetate. The organic phases are washed three times with water
and then dried over magnesium sulphate and concentrated in vacuo.
Chromatography on silica gel in dichloromethane/cyclohexane 2:1 as
mobile phase affords 484 mg (81%, HPLC purity 96%) of the target
compound.
[0227] R.sub.f: 0.39 (cyclohexane/ethyl acetate 2:1)
[0228] MS (EI): 288 ([M].sup.+)
[0229] HPLC: Retention time=4.80 min
[0230] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta./ppm=6.37 (t,
J=2 Hz), 6.44 (ddd, J=8 Hz, 2 Hz, 1 Hz, 1H), 6.59 (ddd, J=8 Hz, 2
Hz, 1 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 7.39 (dd, J=8 Hz, 1 Hz, 1H),
7.56 (t, J=8 Hz, 1H), 7.68 (dd, J=8 Hz, 1 Hz, 1H), 9.69 (s,
1H).
EXAMPLE XVII
3-[3-(trifluoromethyl)phenoxy]phenol
[0231] (benzyl ether Cleavage--Method D)
[0232] 1.70 g (4.72 mmol) of
3-benzyloxy-1-[3-(trifluoromethyl)phenoxy]-be- nzene are suspended
in 135 ml of tetrahydrofuran and 15 ml of ethanol in a
hydrogenation vessel and, after addition of 170 mg of Pd 10% on
carbon, hydrogenated under 1 atm of hydrogen at ambient temperature
overnight. For working up, the catalyst is filtered off through
kieselguhr, and the filtrate is concentrated and flash
chromatographed on 130 g of silica gel in a cyclohexane/ethyl
acetate gradient from 10:1 to 1:1.
[0233] Removal of the solvent affords 1.27 g (99%, HPLC purity 95%)
of the target compound.
[0234] R.sub.f: 0.28 (cyclohexane/ethyl acetate 5:1)
[0235] MS (EI): 270 ([M].sup.+)
[0236] HPLC: Retention time=4.78 min
[0237] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta./ppm=4.97 (s, 1H),
6.53 (t, J=2 Hz, 1H), 6.56-6.67 (m, 2H), 6.85-7.01 (m, 3H), 7.22
(t, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H).
[0238] The following Examples XVIII-XXV are prepared in an
analogous way corresponding to process methods A, C or D:
4TABLE II HPLC purity in R.sub.f Ex. Method/ %/ (mobile No. Target
structure MW yield in % R.sub.t in min. phase) MS XVIII 23 279.1 C/
79 92/ 4.93 0.21 (CH/EA 10:1) EI: 278 (100%, [M].sup.+) XIX 24
245.2 C/ 75 100/ 4.46 0.24 (CH/EA 5:1) DCI/NH.sub.3: 263 (100%, [M
+ NH.sub.4]) XX 25 254.2 C/ 99 98/ 4.56 0.56 (CH/EA 2:1) EI: 254
(100%, [M].sup.+) XXI 26 255.1 C/ 49 91/ 4.72 0.20 (CH/EA 5:1) EI:
254 (43%, [M].sup.+) XXII 27 220.7 C/ 80 94/ 4.44 0.21 (CH/EA 5:1)
EI: 220 (61%, [M].sup.+) XXIII 28 245.2 A/ 89 99/ 4.4 0.18 (CH/EA
2:1) DCI/NH.sub.3: 263 (100%, [M + NH.sub.4].sup.+) XXIV 29 234.7
C/ 64 96/ 4.83 0.39 (CH/EA 2:1) EI: 234 (100%, [M].sup.+) XXV 30
270.2 D/ 98 95/ 4.65 0.29 (CH/EA 2:1) EI: 270 (100%, [M].sup.+)
EXAMPLE XXVI
3-[2-chloro-3-(trifluoromethyl)phenoxy]aniline
[0239] Under argon, 630 mg (1.98 mmol) of
1-[2-chloro-3-(trifluoromethyl)p- henoxy]-3-nitrobenzene are
introduced with 625 mg (9.09 mmol) of ammonium formate and 31.5 mg
of 10% palladium/carbon catalyst into 7 ml of methanol. The mixture
is heated to reflux for two hours. Cooling is followed by
filtration through kieselguhr, washing with methanol, and the
filtrate is concentrated. The residue is taken up again in
dichloromethane and extracted three times with water, and the
organic phases are dried over magnesium sulphate and
reconcentrated. Chromatographic purification on silica gel in
cyclohexane/ethyl acetate 6:1 as mobile phase affords 458 mg (72%,
HPLC purity 90%) of the target compound.
[0240] R.sub.f: 0.48 (cyclohexane/ethyl acetate 1:1)
[0241] MS (ESI): 288 (22%, [M+H].sup.+)
[0242] HPLC: Retention time=4.41 min
[0243] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta./ppm=5.28 (s,
2H), 6.11-6.19 (m, 2H), 6.38 (ddd, J=(Hz, 2 Hz, 1 Hz, 1H), 7.03 (t,
J=8 Hz, 1H), 7.33 (dd, J=8 Hz, 1 Hz, 1H), 7.54 (t, J=8 Hz, 1H),
7.63 (dd, J=8 Hz, 1 Hz).
EXAMPLE XXVII
1-[2-cyano-3-(trifluoromethyl)phenoxy]-3-hydroxybenzene
[0244] (diphenyl ether Synthesis--Method E)
[0245] Resorcinol [44.0 g (0.4 mol)] is partly dissolved in 170 ml
of N-methylpyrrolidone, and potassium hydroxide [min. 85% pure;
34.5 g (0.52 mol)] and then
2-chloro-6-(trifluoromethyl)benzonitrile [20.5 g (0.1 mol)] are
added. The mixture is stirred at 60-65.degree. C. for 2.5 h. After
addition of 300 ml of toluene and 400 ml of water, the aqueous
phase is separated off and extracted once more with 300 ml of
toluene. The combined organic phases are dried over MgSO.sub.4 and,
after filtration, concentrated. Digestion of the oily residue with
150 ml of water, filtration and drying affords pale brownish
crystals.
[0246] Yield: 22 g (79% of theory; compare Example XV)
PREPARATION EXAMPLES
Example 1
3-[2-cyano-3-(trifluoromethyl)phenoxy]phenyl
4,4,4-trifluoro-1-butanesulph- onate
[0247] 31
[0248] (sulphonic ester--Method A)
[0249] Under argon, 7.70 g (27.6 mmol) of
3-[2-cyano-3-(trifluoromethyl)ph- enoxy]phenol are dissolved in 60
ml of dichloromethane, and then 4.32 g (13.1 mmol) of
tetrabutylammonium bromide and 3.95 ml of 45% strength NaOH are
added to the solution. At 0.degree. C., 6.64 g (31.5 mmol) of
4,4,4-trifluorobutane-1-sulphonyl chloride, dissolved in 20 ml of
dichloromethane, are added in one portion. The solution becomes
yellow to orange in colour and is stirred for 1 h. After subsequent
dilution with water, it is extracted three times with
dichloromethane. The combined organic phases are washed with brine
and dried over magnesium sulphate. Purification takes place by
flash chromatography on 360 g of silica gel in a stepwise gradient
from 1:1 to 1:4 cyclohexane/dichloromethane as mobile phase. Rotary
evaporation leaves an oily residue which is induced to crystallize
by adding pentane.
[0250] Yield: 1.sup.st fraction 9.21 g (74%, HPLC purity 100%)
[0251] 2.sup.nd fraction 2.29 g (18%, HPLC purity 97%)
[0252] R.sub.f: 0.56 (CH.sub.2Cl.sub.2)
[0253] Melting point: 60-61.degree. C.
[0254] MS (ESI): 454 ([M+H].sup.+)
[0255] HPLC: Retention time=5.08 min
[0256] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta./ppm=2.2-2.5 (m,
4H), 3.39 (t, J=7 Hz, 2H), 7.0-7.3 (m, 4H), 7.50 (t, J=8 Hz, 1H),
7.53 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz).
Example 2
3-(3-methyl-2-nitro-phenoxy)phenyl n-pentanesulphonate
[0257] 32
[0258] (sulphonic ester--Method B)
[0259] To 200 mg (0.82 mmol) of 3-(3-methyl-2-nitrophenoxy)phenol
in 5 ml of dichloromethane at room temperature are added firstly 1
ml of 40% strength tetrabutylammonium hydroxide solution and then,
after stirring for 5 min, 153 mg (0.90 mmol) of n-pentanesulphonyl
chloride. After stirring for 1.5 h, 0.5 ml of 10% strength
NaHCO.sub.3 solution is added, the mixture is filtered through a 3
g extrelut cartridge (Merck Darmstadt, Order No. 115095), and the
cartridge is washed several times with dichloromethane.
Chromatographic purification on silica gel in cyclohexane/ethyl
acetate 30:1 as mobile phase affords 255 mg (82%, HPLC purity 99%)
of the target compound.
[0260] R.sub.f: 0.35 (cyclohexane/ethyl acetate 2:1)
[0261] MS (ESI): 380 (100%, [M+H].sup.+)
[0262] HPLC: Retention time=5.29 min
[0263] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta./ppm=0.93 (t, J=7
Hz, 3H), 1.30-1.51 (m, 4H), 1.89-2.02 (m, 2H), 2.39 (s, 3H),
3.18-3.28 (m, 2H), 6.85-7.42 (m, 7H).
Example 3
N-{3-[2-Chloro-3-(trifluoromethyl)phenoxy]phenyl}-4,4,4-trifluorobutane-1--
sulphonamide
[0264] 33
[0265] (sulphonamide--Method C)
[0266] Under argon, 100 mg (0.35 mmol) of
3-[2-chloro-3-(trifluoromethyl)p- henoxy]aniline are introduced
into 1 ml of dichloromethane. 106 mg (1.04 mmol) of triethylamine
and 77 mg (0.37 mmol) of 4,4,4-trifluorobutane-1-s- ulphonyl
chloride, dissolved in 1 ml of dichloromethane, are added, and the
mixture is stirred at room temperature. After four days, a further
0.3 equivalent of 4,4,4-trifluorobutanesulphonyl chloride is added,
and stirring is continued for three days. The mixture is then
extracted three times with 2N hydrochloric acid and once with
saturated brine. The organic phase is dried over magnesium sulphate
and concentrated in vacuo. Chromatographic purification on silica
gel in dichloromethane/cyclohexane 7:2 as mobile phase affords 96
mg (54%, HPLC purity 90%) of the target compound.
[0267] R.sub.f: 0.33 (cyclohexane/ethyl acetate 2:1)
[0268] MS (DCI/N.sub.3): 479 (100%, [M+NH.sub.4].sup.+)
[0269] HPLC: Retention time=8.34 min
[0270] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta./ppm=1.80 -1.93
(m, 2H), 2.31-2.50 (m, 2H), 3.25 (t, J=8 Hz, 2H), 6.75 (dd, J=8 Hz,
2 Hz, 1H), 6.85 (t, J=2 Hz, 1H), 7.03 (dd, J=8 Hz, 1 Hz), 7.38 (t,
J=8 Hz, 1H), 7.43 (dd, J=8 Hz,1 Hz, 1H), 7.58 (t, J=8 Hz, 1H), 7.72
(dd, J=8 Hz, 1 Hz, 1H), 10.04 (s, 1H).
[0271] The following Examples 4 to 24 are prepared from the
appropriate starting compounds in an analogous manner corresponding
to the Preparation Example process methods A, B or C:
5TABLE III HPLC purity in R.sub.f Ex. Target Method/ %/ (mobile No.
structure MW yield in % R.sub.t in min. phase) MS 4 34 453.3 A/ 61
97/ 5.15 0.33 (CH/EA 5:1) ESI: 453 (79%, [M + H].sup.+) 5 35 379.4
A/ 76 94/ 5.36 0.63 (CH/EA 1:1) DCI/NH.sub.3: 397 (100%, [M +
NH.sub.4].sup.+) 6 36 419.4 B/ 78 100/ 5.12 0.69 (toluene/EA 5:1)
ESI: 420 (100%, [M + H].sup.+) 7 37 413.3 A/ 103 89/ 5.83 0.52
(CH/EA 2:1) DCI/NH.sub.3: 430 (100%, [M + H].sup.+) 8 38 428.4 A/
67 97/ 5.24 0.32 (CH/EA 2:1) ESI: 451 (100%, [M + Na].sup.+), ESI:
429 (89%, [M + H].sup.+) 9 39 388.4 A/ 79 94/ 5.47. 0.53 (CH/EA
2:1) ESI: 349 (35%, [M + H].sup.+) 10 40 354.9 B/ 63 81/ 5.44 0.45
(CH/EA 2:1) DCI/NH.sub.3: 372 (100%, [M + NH.sub.4].sup.+) 11 41
349.8 B/ 67 81/ 5.2 0.37 (CH/EA 2:1) DCI/NH.sub.3: 412 (100%, [M +
NH.sub.4].sup.+) 12 42 389.3 B/ 76 100/ 5.64 0.48 (CH/EA 2:1)
DCI/NH.sub.3: 406 (100%, [M + NH.sub.4].sup.+) 13 43 429.2 B/ 72
97/ 5.38 0.31 (CH/EA 2:1) DCI/NH.sub.3: 446 (100%, [M +
NH.sub.4].sup.+) 14 44 368.9 B/ 84 93/ 5.77 0.49 (CH/EA 2:1)
DCI/NH.sub.3: 386 (100%, [M + NH.sub.4].sup.+) 15 45 408.9 B/ 69
92/ 5.5 0.38 (CH/EA 2:1) DCI/NH.sub.3: 426 (100%, [M +
NH.sub.4].sup.+) 16 46 419.4 B/ 81 98/ 5.07 0.23 (CH/EA 2:1) ESI:
420 (100%, [M + H].sup.+) 17 47 444.4 A/ 91 93/ 5/33 0.25 (CH/EA
5:1) ESI: 445 (100%, [M + H].sup.+) 18 48 404.4 A/ 17 98/ 5.65
DCI/NH.sub.3: 422 (100%, [M + NH.sub.4].sup.+) 19 49 444.4 A/ 29
96/ 5.4 0.26 (CH/EA 5:1) ESI: 445 (57%, [M + H].sup.+) 20 50 404.4
A/ 24 70/ 5.7 DCI/NH.sub.3: 422 (100%, [M + NH.sub.4].sup.+) 21 51
413.4 A/ 95 100/ 5.1 0.33 (DCM/MeOH 100:3) ESI: 414 (100%, [M +
H].sup.+) 22 52 462.8 A/ 86 97/ 5.4 0.36 (CH/DCM 2:1) ESI: 463
(80%, [M + H].sup.+) 23 53 422.9 A/ 97 100/ 5.62 0.49 (CH/EA 2:1)
DCI/NH.sub.3: 440 (100, [M + NH.sub.4].sup.+) 24 54 421.9 C/ 48 91/
7.94 0.42 (CH/EA 2:1) DCI/NH.sub.3: 439 (100%, [M +
NH.sub.4].sup.+)
[0272] The abovementioned examples show the following .sup.1H-NMR
spectroscopic data:
6TABLE IV Example .sup.1H-NMR (300 MHz): &/ppm 17 CDCl.sub.3;
2.17-2.42 (m, 4H); 3.33 (t, J=7Hz, 2H); 6.88 (t, J=2Hz; 1H)
6.92-6.95 (m, 1H); 7.01-7.05 (ddd, H=8Hz, 2Hz, 0.5Hz; 1H); 7.09
(dd, J=8Hz, 2Hz, 1H); 7.18-7.39 (m, 4H). 21 DMSO-d.sub.6; 0.86 (t,
J=7Hz, 3H); 1.24-1.43 (m, 4H); 1.80 (quin, 2H); 3.56 (t, J=7.5Hz,
2H); 7.29-7.38 (m, 4H); 7.61 (t, J=8Hz, 1H); 7.77 (d, H=7.5Hz, 1H);
7.88 (t, J=8Hz, 1H). 22 DMSO-d.sub.6; 2.02 (quin, 2H); 2.46 (m,
2H); 3.69 (t, J=7.5Hz, 2H); 7.02-7.08 (m, 3H); 7.17-7.20 (dd,
J=8Hz, 2Hz, 1H); 7.48-7.63 (m, 3H); 7.72-7.75 (dd, J=8Hz, 1Hz, 1H).
23 DMSO-d.sub.6; 0.86 (t, J=7Hz, 3H); 1.33 (m, 4H); 1.78 (quin,
2H); 3.52 (t, J=7.5Hz, 2H); 7.02-7.06 (m, 2H); 7.15-7.18 (m, 1H);
7.48-7.64 (m, 3H); 7.72-7.75 (dd, J=8*Hz, 1Hz, 1H).
* * * * *