Amphiphilic compounds with neuroprotective properties

Patent metadata

Field	Value
Publication number	US-10017535-B2
Application number	US-201515506318-A
Country	US
Kind code	B2
Filing date	Aug 25, 2015
Priority date	Aug 26, 2014
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

Amphiphilic compounds with tetradecahydrophenanthrene skeleton and their enantiomers, exhibiting neuroprotective effects, their use in methods of treatment of neuropsychiatric disorders associated with an imbalance in glutamatergic neurotransmitter system, such as ischemic damage of CNS, neurodegenerative changes and disorders of CNS, affective disorders, depression, post-traumatic stress disorder and diseases related to stress, anxiety, schizophrenia and psychotic disorders, pain, addiction, multiple sclerosis, epilepsy, glioma, and a pharmaceutical composition containing compound.

First claim

The invention claimed is:

1. An amphiphilic compound with tetradecahydrophenanthrene skeleton of general formula I,

wherein
R 1 is selected from the group comprising (—OSO 3 pyH), (—OSO 3 Na), (—OSO 3 H), NaOOC—R 6 —C(R 7 )—R 8 —, HOOC—R 6 —C(R 7 )—R 8 —, HOOC—C(R 7 )—R 8 —, or R 9 —R 10 —C(R)—R 12 —, where
R 6 represents straight or branched C 1 to C 6 alkylene or C 2 to C 6 alkenylene chain, unsubstituted or substituted with one or more halogen atoms or amino group or amino group protected by protecting groups,
or R 6 means trivalent —CH(CH 2 -) 2 alkylene that forms with the carbon carrying R 7 and with R 8 being nitrogen a five-membered ring;
R 7 represents atom of oxygen, nitrogen or sulphur bound by double bond, or two atoms of hydrogen,
R 8 represents an at least divalent atom,
R 9 represents a cationic group selected from guanidinyl derivatives of formula (a),

and quaternary ammonium groups of formula (b)

wherein R 13 to R 20 are selected from hydrogen atoms, linear or branched C 1 to C 6 alkyl, linear or branched C 2 to C 6 alkenyl,
R 10 represents straight or branched C 1 to C 6 alkylene or C 2 to C 6 alkenylene, wherein the alkylene and alkenylene are unsubstituted or substituted by 1 to 10 halogen atoms or by amino group which is primary or substituted by linear or branched C 1 to C 4 alkyl;
R 11 represents atom of oxygen, nitrogen or sulphur bound by double bond, or two atoms of
hydrogen, and
R 12 is selected from the group comprising oxygen, nitrogen and carbon atoms, and when R 12 is carbon or nitrogen, its further valences are occupied by hydrogen or hydrogens, while any of hydrogen is optionally replaced by C 1 to C 4 alkyl or C 2 to C 4 alkenyl;

R 2 represents hydrogen atom or methyl;
R 3 represents a) hydrogen atom, and then
i) R 4 and R 5 are hydrogen atoms, or
ii) one of R 4 and R 5 represents hydrogen atom and the other one represents a straight or branched C 1 to C 6 alkyl or C 2 to C 6 alkenyl chain, optionally substituted by 1 to 13 halogen atoms in case of said alkyl and by 1 to 9 halogen atoms in case of said alkenyl, or by atom of oxygen or sulphur bound by a double bond, while one of the methylene groups in the chain is optionally replaced by oxygen or sulphur atom; or
b) straight or branched C 1 to C 6 alkyl or C 2 to C 6 alkenyl, optionally substituted by 1 to 13 halogen atoms in case of alkyl or by 1 to 9 halogen atoms in case of alkenyl, or by atom of oxygen or sulphur bound by a double bond, while one of the methylene groups in the chain is optionally replaced by oxygen or sulphur atom, and then R 4 and R 5 are hydrogen atoms, or
c) C 5 or C 6 alicyclic or aromatic ring, while carbon atoms are optionally substituted by 1 to 8 atoms of halogen in case of C 5 alicyclic ring, or 1 to 10 halogen atoms in case of C 6 alicyclic ring or by 1 to 4 halogen atoms in case of C 5 aromatic ring or 1 to 5 halogen atoms in case of C 6 aromatic ring; and then
i) R 5 is selected from the group comprising hydrogen atom, linear or branched C 1 to C 6 alkyl, linear or branched C 2 to C 6 alkenyl, wherein said alkyl or alkenyl is optionally substituted by 1 to 13 halogen atoms in case of said alkyl and by 1 to 9 halogen atoms in case of said alkenyl, or by double-bond-bound atom of oxygen or sulphur, while one of the methylene groups in the chain is optionally replaced by oxygen or sulphur atom, or
ii) R 4 and R 5 represent alkylene or alkenylene substituent —(CH m ) n —, where n=3-4, m=1-2, forming with the parent carbon atoms of the skeleton at position 7 and 8 a saturated or unsaturated 5- or 6-membered cycle, wherein the hydrogen atoms of the alkylene or alkenylene substituent are optionally substituted at least by one halogen atom or linear or branched C 1 to C 4 alkyl or C 2 to C 4 alkenyl chain, wherein optionally one methylene group of the alkylene substituent forming the cycle is replaced by carbonyl group and the carbon atom at the adjoining position is optionally substituted by another methylene group, or one methylene group of the alkylene substituent forming the cycle is optionally replaced by oxygen or sulphur atom, while the sulphur atom is optionally functionalized by oxygen atom; or the hydrogens of one methylene group of the alkylene substituent are optionally replaced by —O—CH 2 —, thereby forming oxirane ring,
d) substituent —CH 2 —O—CH(CH 3 )— bound to the first carbon of an alkylene group —(CH 2 ) 3 — which is formed by R 4 and R 5 ; and enantiomers of compounds of general formula I,

with the proviso that compounds wherein R 1 represents HO 2 C—R 6 CR 7 —R 8 —, R 6 is —(CH 2 ) 2 —, R 7 is oxygen atom bound by double bond and R 8 is oxygen atom, while R 2 and R 3 are methyl groups, R 4 and R 5 together form group-(CH 2 ) 3 — forming with parent carbon atoms of tetradecahydrophenanthrene skeleton at position 7 and 8 a saturated five-membered ring; with absolute configuration 3R,5S,8S,9S,10S,13S,14S are excluded from formula I.

2. The amphiphilic compound of general formula I according to claim 1 , selected from:
pyridinium (2R,4aS,4bS,8aR,10aR)-4a-methyltetradecahydrophenanthren-2-yl 2-sulfate (8),
pyridinium (2R,4aS,4bS,7S,8S,8aS,10aR)-7-(methoxymethyl)-4a,7,8-trimethyltetradecahydrophenanthren-2-yl 2-sulfate (18),
4-(((2R,4aS,4bS,7S,8aS,10aR)-7-(methoxymethyl)-4a,7,8-trimethyltetradecahydrophenanthren-2-yl)oxy)-4-oxobutanoic acid (19),
pyridinium (2R,4aS,7S,8S,10aR)-7-(methoxycarbonyl)-4a,7,8-trimethyltetradecahydrophenanthren-2-yl 2-sulfate (22),
4-(((2R,4aS,4bS,7R,8aS,10aR)-4a,7-dimethyltetradecahydrophenanthren-2-yl)oxy)-4-oxobutanoic acid (34),
pyridinium (2R,4aS,4bS,7R,8aS,10aR)-4a,7-dimethyltetradecahydrophenanthren-2-yl 2-sulfate (35),
methyl (2S,4aS,4bS,7R,8aR,10aS)-2,4b-dimethyl-7-(sulfooxy)tetradecahydrophenanthren-2-carboxylate (40),
pyridinium (3R,5R,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 3-sulfate (49),
2-(((3R,5R,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-2-oxoethanoic acid (50),
2-(((3R,5R,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-2-oxopropanoic acid (51),
2-(((3R,5R,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)amino)-2-oxoacetic acid (59),
((3R,5R,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]fenanthren-3-yl)amino)-3-oxopropanoic acid (61),
4-(((3R,5R,8S,9S,10S,13S,14S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-N,N,N-trimethyl-4-oxobutan-1-ammonium chloride (62),
4-(((3R,5R,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-4-oxobutanoic acid (64),
3-(((3R,5R,8R,9S,10S,13R,14S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-3-oxopropanoic acid (65),
3-(((3R,5R,8R,10S,13S,14S)-10,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-3-oxopropanoic acid (67),
4-(((3R,5R,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylenhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-4-oxobutanoic acid (68),
4-(((3R,5R,8R,9S,10S,13S,14S)-10,13-dimethyl-17-methylenhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-4-oxopentanoic acid (69),
2-((3R,5R,8R,9S,10S,13S,14S)-10,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)acetic acid (74),
2-(((3R,5R,8R,9

Assignees

• Ustav Organicke Chemie A Biochemie Av Cr V V I
• Fyziologicky Ustav Av Hacek Over C R V V I
• Fyziologicky Ustav Av Cr V V I

Inventors

• Kudova Eva
• Chodounska Hana
• Kapras Vojtech
• Vyklicky Ladislav
• Vales Karel
• Jahn Ullrich

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title