Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Sulfur – selenium or tellurium compound
Reexamination Certificate
2001-09-26
2004-06-29
Desai, Rita (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Sulfur, selenium or tellurium compound
C514S602000, C558S033000, C558S048000, C558S051000, C564S084000
Reexamination Certificate
active
06756409
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.
Among the constituents of the hemp plant (
Cannabis sativa
), the one of most pharmacological importance is &Dgr;
9
-tetrahydrocannabinol (&Dgr;
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.
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.
Several classes of structures have been disclosed to date for cannabinoid receptor agonists: classical cannabinoids such as, for example, &Dgr;
9
-THC, nonclassical cannabinoids such as, for example, aminoalkylindoles, and eicosanoids. The latter includes the endogenous CB1 receptor agonist anandamide.
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.
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.
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.
It was an object of the present invention to provide cannabinoid receptor agonists with improved effect.
This object is achieved by the novel compounds according to the invention.
The present invention therefore relates to novel compounds of the general formula (I),
in which
R
1
denotes hydrogen, C
1
-C
4
-alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro,
R
2
denotes halogen, trifluoromethyl, trifluoromethoxy, cyano or nitro,
R
3
denotes C
4
-C
7
-alkyl which may be substituted one or more times by fluorine or chlorine,
R
4
denotes hydrogen or halogen, and
A denotes oxygen or NH.
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.
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.
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.
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.
The present invention also includes ammonium compounds which can be prepared by converting the free amines by alkylation.
For the purposes of the present invention, the substituents generally have the following meaning:
C
1
-C
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.
C
4
-C
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.
Halogen includes for the purposes of the invention fluorine, chlorine, bromine and iodine. Chlorine or fluorine is preferred.
Preference is given to compounds of the general formula (I)
in which
R
1
denotes hydrogen, fluorine, chlorine, methyl, trifluoromethyl, trifluoromethoxy, cyano or nitro,
R
2
denotes fluorine, trifluoromethyl, trifluoromethoxy, cyano or nitro,
R
3
denotes n-butyl, n-pentyl, 4,4,4-trifluorobut-1-yl or 5,5,5-trifluoropent-1-yl,
R
4
denotes hydrogen, and
A denotes oxygen.
Particular preference is given to compounds of the general formula (I)
in which
R
1
, R
2
, R
3
, R
4
and A have the abovementioned meaning, and
there is a hydrogen atom in position 4 of the phenyl ring substituted by R
1
and R
2
.
This can be illustrated by the following diagram:
Very particular preference is given to compounds of the general formula (I)
in which
R
1
, R
2
, R
3
, R
4
and A have the abovementioned meaning, and
R
1
and R
2
occupy positions 2 and 3 on the phenyl ring.
The positions of R
1
and R
2
on the phenyl ring can be illustrated by the following diagram:
Very particular preference is likewise given to compounds of the general formula (I)
in which
R
1
, R
2
, R
3
, R
4
and A have the abovementioned meaning, and
A is in position c of the benzene radical.
The position of A on the benzene radical can be illustrated by the following diagram:
Very particular preference is given to compounds of the general formula (I)
in which
R
1
, R
2
, R
3
, R
4
and A have the abovementioned meaning,
R
1
and R
2
occupy positions 2 and 3 on the phenyl ring, and
A is in position c of the benzene radical.
The positions of R
1
, R
2
and A can be illustrated by the following diagram:
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)
in which R
1
, R
2
, R
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
1
—SO
2
—R
3
(III),
in which
X
1
represents a suitable leaving group, and
R
3
has the abovementioned meaning.
The compounds of the general formula (II) are novel and can be prepared in analogy to generally known proces
De Vry Jean-Marie-Viktor
Denzer Dirk
Heil Markus
Lenfers Jan-Bernd
Lustig Klemens
Bayer Aktiengesellschaft
Desai Rita
Pellegrino Susan M.
Wright Sonya
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