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AU741636B2 - New amino alcohol derivatives, process for the production thereof and medicaments and reagents containing these compounds - Google Patents

New amino alcohol derivatives, process for the production thereof and medicaments and reagents containing these compounds Download PDF

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Publication number
AU741636B2
AU741636B2 AU43841/97A AU4384197A AU741636B2 AU 741636 B2 AU741636 B2 AU 741636B2 AU 43841/97 A AU43841/97 A AU 43841/97A AU 4384197 A AU4384197 A AU 4384197A AU 741636 B2 AU741636 B2 AU 741636B2
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Prior art keywords
ethyl
amino
propyl
denotes
piperidin
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AU4384197A (en
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Nikolaos Dimoudis
Walter-Gunar Friebe
Bernhard Knipp
Uwe Michaelis
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Medigene AG
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Roche Diagnostics GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
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  • Genetics & Genomics (AREA)
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  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to new amino alcohol derivatives, process for the production thereof and medicaments and reagents containing these compounds. The subject of the invention is medicaments having the general formula (I) wherein A can mean hydrogen, a group NR1R2, a group NR1(CH2)pNR3R4, a group (C=NH)NH2 or a pyridinyl radical, B and D can be identical or different and stand each for a binding, a C1 to C6-alkylene radical or a group NR5-C2-C6-alkylene, C can mean piperidindiyl or piperazindiyl, W and X are identical or different and stand each for a carbonyl group, Y and Z can be identical or different and stand each for a saturated or unsaturated hydrocarbon radical with 7-24 carbon atoms, R1 to R5 can be identical or different and stand each for hydrogen or a C1 to C6 alkyl radical, m stands for a whole number 0, 1, or 2 and if m = 2 both radicals C independently from another can also mean piperidindiyl and piperazindiyl, n and o can be identical or different and stand each for a whole number 2, 3 or 4 and p means a whole number from 2 to 6, as well as their physiologically compatible salts, with the proviso that no hydrazine derivatives are comprised and that m be not 0, when A means hydrogen or a group (C=NH)NH2 and B and D are identical or different and represent a binding or an alkylene radical.

Description

New amino alcohol derivatives, process for their production and pharmaceutical preparations and reagents containing these compounds The present invention concerns new amino alcohol derivatives, a process for their production as well as pharmaceutical preparations and reagents which contain these substances.
The invention concerns pharmaceutical agents of the general formula I 0 (CH2)n-- O-C-Y A-B- Cm D-N 0
II
(CH
2 )o-0-C-Z in which A denotes hydrogen, a group NRIR 2 a group NR (CH 2 )pNR3R4, or a pyridinyl residue, B and D are the same or different and each denotes a bond, a C 1 to C 6 alkylene residue or a group
NR
5
-C
2 to C 6 alkylene, C denotes piperidinediyl, 2 Y and Z are the same or different and each denotes a saturated or unsaturated hydrocarbon residue with 7 to 24 carbon atoms,
R
1 to R 5 are the same or different and each represents hydrogen or a C 1 to C 6 alkyl residue, m is an integer 0, 1 or 2 and if m equals 2 both residues C can be the same or different, n and o are the same or different and each denotes the integers 2, 3 or 4 and p denotes an integer from 2 to 6 as well as physiologically tolerated salts thereof, provided that hydrazine derivatives are not included and that m cannot be 0 if A denotes hydrogen and B and D being the same or different represent a bond Sor an alkylene residue.
optionally substituted several-fold with straightchained or branched
C
1
-C
6 3 Values of 1 or 2 are preferred for m. Compounds of the general formula I are just as preferred which contain more than 2 nitrogens or, if A-denotes (C=NH)NH 2 those that contain more than 3 nitrogens.
The invention in addition concerns new amino alcohol derivatives of the general formula I 0 (CH2)---O-C-Y A-B--C-D-N 0
(CH
2 )o O-C-Z in which A denotes hydrogen, a group NR 1
R
2 a group :NRI(CH2)pNR3R4, or a pyridinyl residue, B and D are the same or different and each denotes a bond, a C 1 to C 6 alkylene residue or a group
NR
5
-C
2 to C 6 alkylene, S:C denotes piperidinediyl, Y and Z are the same or different and each denotes a saturated or unsaturated hydrocarbon residue with 7 to 24 carbon atoms,
R
1 to R 5 are the same or different and each represents -4 hydrogen or a C 1 to C 6 alkyl residue, in is an integer 0, 1 or Z~and if m equals 2 both residues C can be the same or different, n and o are the same or different and each denotes the integers 2, 3 or 4 and p denotes an integer from 2 to 6 as well as physiologically tolerated salts thereof, provided that hydrazine derivatives are not included that m cannot be 0 if A denotes hydrogen or a group 0: NR 1
R
2 and B and D being the same or different represent a bond or an alkylene residue and in the case that m 1, the group A-B cannot be hydrogen or C,-C 4 alkyl and that it does not include the compounds octadecanoic acid-[ (3-diethylamino-propyl) imino']bis (methyl-2, 1-ethanediyl) -ester-hydrochloride octadecanoic acid-[ (3-dimethylamino-propyl) imino]di-3, 1propanediyl ester-dihydrochioride octadecanoic acid-[ (3-dilethylamino-propyl) imino]di-3, 1propanediyl ester octadeca'noic acid- [(23-dimethylamino-propyl) imino]di-2, 1ethanediyl ester-hydrochloride docosanoic acid-2-[(3-dimethylaiInakp t oX.lJ-[2-[ (1oxododecyl) oxy] ethyl] amino] ethyl ester hexadecanoic acid- (e thylmethylamino) ethyl] imino]di- 2, 1-ethanediyl ester octadecanoic acid-[ [3-(dimethylaxnino)propyl] imino]di- 2,1-ethanediyl ester oct-adecanoic acid-[ [3-(diluethylainino)propyl] iiino]di- 2, 1-ethan ediyl ester-dihydrochioride T A-octadecanoic acid [[37(dimethylanino) propyl] imino]di- 5 2,1-ethanediyl ester N,N-Bis[3-(dodecyloxy)propyl]-1,2-ethanediamine octadecanoic acid-[ [2-[(2-aminethyl) amino]ethyl] imino]di-2,1-ethanediyl ester stearic acid-iminobis-(ethyleneiminoethylene)-estermonoacetate.
Within the sense of the present invention the following meanings in compounds of formula I are preferred independently of one another. This applies to compounds as well as to medicaments that contain such compounds and likewise also to the respective therapeutic applications of these compounds.
r
A
B and D
C
m
Y
Z
n and o denotes NH 2 or N(CH 3 2 or are the same or different and denote a bond, a C 1
-C
3 alkylene residue or if m=0 an
N(CH
3
)C
3 to C 4 alkylene residue or denotes piperidinediyl or denotes 0 or 1 or denotes C 1 3
H
2 7 or C 1 7
H
3 3 or denotes C 13
H
2 7 or C 1 7
H
3 3 or each denote 2.
Compounds are especially preferred which fulfil all the above-mentioned meanings simultaneously.
The compounds of formula I have valuable pharmacological properties and in particular they can facilitate the transport of biologically active molecules into prokaryotic or eukaryotic cells. They are therefore particularly suitable for introducing proteins, nucleic acids such as e.g. DNA, cDNA, mRNA, PNA, antisense 6 polynucleotides and therapeutically active low molecular compounds such as peptide hormones, cytostatic agents and antibiotics into target cells within or outside of the organism. The new compounds according to the invention are therefore particularly suitable for the efficient treatment of mammals by gene therapy preferably of human patients. These compounds are also suitable for the production of drug combinations in cancer therapy, antiviral therapy, infection therapy and in diseases caused by dysregulation. In contrast to viral carriers for gene constructs, non-viral gene ferries often have only a low immunogenicity. The efficiency and persistency of the gene expression mediated by non-viral gene ferries has, however, not yet been satisfactory. In addition to improving gene expression, the compounds of the general formula I have the advantage that they can be degraded relatively easily due to the C 2
-C
4 -alkyl-O chains on the tertiary nitrogen N of formula I.
Apart from the compounds listed in the examples, the invention concerns in particular all substances which have all possible combinations of the meanings of the variables mentioned in the examples.
The process according to the invention for the production of compounds of formula I is characterized in that a compound of the general formula II
(CH
2 n 0 H A B Cm D N
(CH
2 )o 0 H (II), in which A, B, C, D, m, n and o have the above-mentioned 7 meaning is reacted with a compound of the general formula III and a compound of the general formula IV E W Y G X Z (III) (IV) in which W, X, Y and Z have the above-mentioned meaning and E and G represent reactive residues, and subsequently if desired a protecting group contained in A, B or D is cleaved-off, a hydrogen atom representing A is converted into a group (C=NH)NH 2 a compound present as an acid addition salt is converted into the free base or a compound present as a base is converted by neutralization with a non-toxic acid into a physiologically tolerated salt.
The reactive residues E and G are nucleofuge groups such as for example halogen atoms, sulfonate or sulfate groups or acidic residues of activated esters, anhydrides or mixed anhydrides.
It is expedient to react compounds of formula II with compounds of formulae III and IV in an inert solvent such as an ether, for example tetrahydrofuran or an amide such as dimethylformamide or in pyridine optionally in the presence of a base such as triethylamine or ethyldiisopropylamine or an alkali alcoholate, however, the reagents of the general formulae III or IV can be used undiluted or, if W and X represent a carbonyl group, an acid such as acetic acid or trifluoroacetic acid can be used as the solvent.
8 Cleavage of a protecting group contained in A, B or D is carried out depending on the chemical characteristics of this group, for example by acidic or basic hydrolysis or hydrogenolysis. An acid cleavable protecting group is for example the tert.-butoxycarbonyl residue.
A hydrogen atom representing A can for example be converted into an amidino group by reaction with cyanamide or pyrazol-l-carboxamidine.
The majority of the starting compounds of the general formula II are new (especially if m represents 1 or 2) and are also a subject matter of the invention. They can be produced from known starting materials by methods known in the literature.
Potential pharmacologically acceptable salts are in particular salts with non-toxic inorganic or organic acids such as for example hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, lactic acid, citric acid, malic acid, benzoic acid, salicylic acid, malonic acid, maleic acid, succinic acid or diaminocaproic acid.
The salts are obtained in the usual manner for example by neutralizing the compounds of formula I with the corresponding acids.
In order to produce pharmaceutical preparations or transfer reagents the compounds according to the invention are combined individually or as a combination, if desired using co-lipids, with a biologically active molecule, for example a polynucleotide, in a suitable ratio and administered in vivo or in vitro in a liquid preferably aqueous, or solid preferably lyophilized 9 form. The in vivo administration can be carried out orally, parenterally, topically, transmucosally or by introduction into a body cavity-of the patient. A delayed release from a biologically degradable matrix or administration as an aerosol or inhalable powder application is also possible.
The administered dose depends on the age, health and weight of the recipient, the extent of the disease, the type of other treatments which may be carried out at the same time, the frequency of the treatments and the type of the desired effect and can be determined experimentally by a person skilled in the art.
The following compounds are preferred within the sense of the invention in addition to the substances mentioned in the examples: 1. Oleic acid-2-[(2-oleoyloxy-ethyl)-piperidin-4-ylmethyl)-amino]-ethyl ester 2. Tetradecanoic acid-2-[(2-tetradecanoyloxy-ethyl)piperidin-4-yl-methyl)-amino]-ethyl ester 3. Dodecanoic acid-2-[(2-dodecanoyloxy-ethyl)piperidin-4-yl-methyl)-amino]-ethyl ester 4. Oleic acid-2-[(2-oleoyloxy-ethyl)- [1,4']bipiperidinyl-4-yl-amino]-ethyl ester Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)- [3-[1,4']bipiperidinyl-4-ylamino)-propyl]-amino}ethyl ester 10 6. Dodecanoic acid-2-{ (2-dodecanoyloxy-ethyl) ]bipiperidinyl-4-ylamino) -propyl] -amino}ethyl ester 7. Oleic acid-2-{(2-oleoyloxy-ethyl)-[3-(3,4,5,6tetrahydro-2H- bipyridinyl-4-ylamino) -propyl] aminol}-ethyl ester 8. Dodecanoic acid-2-[ {3-[3-dimethylamino-propyl) methyl-amino] -propyl}- (2-dodecanoyloxy-ethyl) amino] -ethyl ester 9. Tetradecanoic acid-2-[ (3-dimethylamino-propyl) methyl-amino] -propyl}- (2-tetradecanoyloxy-ethyl) amino] -ethyl ester Dodecanoic acid-2-[ (3-diethylamino-propyl) methyl-amino] -propyl}- (2-dodecanoyloxy-ethyl) amino] -ethyl ester 11. Tetradecanoic acid-2-[ (3-diethylamino-propyl) methyl-amino] -propyl} -(2-tetradecanoyloxy-ethyl) amino] -ethyl ester 12. Dodecanoic acid-2-{ [3-(4-amino-butylamino) -propyl] (2-dodecanoyloxy-ethyl) -amino }-ethyl ester 13. Dodecanoic acid-2-{ (2-dodecanoyloxy-ethyl) amino-ethyl) -piperidin-4-yl] -amino }-ethyl ester 14. Oleic acid-2-{ (2-oleoyloxy-ethyl)-[l-(2-aminoethyl) -piperidin-4-yl]-amino}-ethy1 ester 11 Dodecanoic acid-2-{ (2-dodecanoyloxy-ethyl) (2amino-ethyl) -piperidin-4-yl-methyl] -amino}-ethyl ester 16. Oleic acid-2-{ (2-oleoyloxy-ethyl) -[1-(2-aminoethyl) -piperidin-4-yl-methyl] -amino}-ethyl ester 17. Dodecanoic acid-2-{ (2-(4-amino-piperidin-1-yl) ethyl]-(2-dodecanoyloxy-ethyl) -amino}-ethyl ester 18. Dodecanoic acid-2-{ [4-(4-amino-piperidin-1-yl) butyl] -(2-dodecanoyloxy-ethyl) -amino}-ethyl ester 19. Tetradecanoic acid-2-{ (4-amino-piperidin-l-yl) ethyl] -(2-tetradecanoyloxy-ethyl) -amino}-ethyl ester Tetradecanoic acid-2-{ (4-amino-piperidin-l-yl) butyl] -(2-tetradecanoyloxy-ethyl) -amino}-ethyl ester 21. Oleic acid-2-{[2-(4-amino-piperidin-l-yl)-ethyl]- (2-oleoyloxy-ethyl) -amino }-ethyl ester 22. Oleic acid-2-{[4-(4-amino-piperidin-l-yl)-butyl]- (2-olecyloxy-ethyl) -amino }-ethyl ester 23. Oleic acid-2-{ (2-oleoyloxy-ethyl)-[l-(2-aminoethyl) -piperidin-4-yl]-amino}-ethyl ester 24. oleic acid-2-{ (2-oleoyloxy-ethyl)-[l-(3-aminopropyl) -piperidin-4-yl-methyl] -amino}-ethyl ester 12 Oleic acid-2-{(2-oleoyloxy-ethyl)-[l-(2-aminoethyl)-piperidin-4-yl-methyl]-amino}-ethyl ester 26. 4-Dimethylamino-l-{3-[bis-(2-tetradecyloxy-ethyl)amino]-propyl}-piperidine 27. 4'-{[Bis-(2-tetradecanoyloxy-ethyl)]-amino}- [4,1']bipiperidine-l-carboxamidine Example 1 Decanoic acid-2-{(2-decanoyloxy-ethyl)-[3-(4-methylpiperazin-l-yl)-propyl]-amino}-ethyl ester-hydrochloride 2.1 ml (15 mmol) triethylamine is added to a solution of 1.35 g (5.5 mmol) 2-{(2-hydroxy-ethyl)-[3-(4-methylpiperazin-l-yl)-prpyl]-amino}-ethanol in 30 ml tetrahydrofuran, a solution of 2.3 ml (11 mmol) decanoyl chloride in 20 ml tetrahydrofuran is added dropwise and it is heated for 20 h to reflux. After cooling it is filtered, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel. 1.28 g of the desired compound is eluted as an oil with ethyl acetate/methanol 1:1, this is dissolved in ethyl acetate and admixed with excess ethereal hydrogen chloride solution. After concentrating the solution by evaporation the precipitate is removed by filtration and 1.3 g of the title compound (42 of theory) of melting point 208-212 0 C is isolated.
The 2-{(2-hydroxy-ethyl)-[3-(4-methyl-piperazin-l-yl)propyl]-amino}-ethanol used as the starting material can be obtained as follows: 13 mg potassium iodide is added to a solution of 4.1 g mmol) diethanolamine and 7.8 g (44 mmol) 3-(4methyl-piperazin-l-yl)-propyl chloride in 40 ml dimethyl-formamide and heated for 5 h to 60 0 C. After concentrating in a vacuum, the residue is chromatographed on silica gel. 2.7 g (27 of theory) of the desired compound is eluted as an oil using ethyl acetate/methanol 1:1.
Example 2 Oleic acid-2-{(2-oleoyloxy-ethyl)-[3-(4-methylpiperazin-l-yl)-propyl]-amino}-ethyl ester-hydrochloride The title compound is obtained as an oil in an analogous manner to that described in example 1 from hydroxy-ethyl)-[3-(4-methyl-piperazin-l-yl)-propyl]amino}-ethanol and oleoyl chloride in a yield of 35 Example 3 Oleic acid-2-[(2-oleoyloxy-ethyl)-(3,4,5,6-tetrahydro- 2H-[l,4']bipyridinyl-4-yl-amino]-ethyl esterhydrochloride The title compound is obtained as a viscous oil in an analogous manner to that described in example 1 from 2-hydroxyethyl-(3,4,5,6-tetrahydro-2H-[l,4']bipyridinyl- 4-yl)-amino]-ethanol and oleoyl chloride in a yield of 53 The 2-hydroxy-ethyl-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-amino]-ethanol used as the 14 starting material can be obtained as follows: a) A mixture of 62.9 g (0.33 mol) l-benzyl-piperidin-4one, 34.8 g diethanolamine and 300 ml toluene is heated for 2 h to reflux on a water separator. After 5 ml water has been separated, it is concentrated and the residue is distilled in a vacuum. 73.2 g 2-(8-benzyl-l-oxa-4,8diaza-spiro[4.5]-dec-4-yl)-ethanol (80 of theory) of b.p.
0 08 185-190 0 C is isolated.
b) A solution of 87.6 g (0.32 mol) of the previously described compound in 900 ml methanol is hydrogenated over 2 g platinum dioxide and subsequently over 2 g percent palladium carbon at 4 bar hydrogen pressure.
After the calculated amount of hydrogen has been taken up, it is filtered and concentrated. 55.0 g (91 of theory) 2-[(2-hydroxy-ethyl)-(piperidin-4-yl)-amino]ethanol remain as an oil.
c) A mixture of 24 g (127 mmol) of the previously described compound and 7.2 g (64 mmol) 4-chloro-pyridine is heated for 2 h to 1500C, subsequently taken up in N sodium hydroxide solution and extracted with dichloro methane and methanol. After concentrating the extract and triturating with ethyl acetate, 14.3 g (91 of theory) 2-[2-hydroxy-ethyl-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-amino]-ethanol of m.p. 126-1280C remain.
Example 4 Tetradecanoic acid-2-[(2-tetradecanoyloxy-ethyl)- (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amino]ethyl ester-hydrochloride 15 The title compound is obtained in an analogous manner to that described in example 1 in a 51 yield as an amorphous powder of melting range 100-120 0 C from hydroxy-ethyl)-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl- 4-yl)-amino]-ethanol and tetradecanoyl chloride.
Example Dodecanoic acid-2-[(2-dodecanoyloxy-ethyl)-3,4,5,6tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amino]-ethyl ester-hydrochloride The title compound is obtained as an amorphous powder in an analogous manner to that described in example 1 from 2-[(2-hydroxy-ethyl)-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-amino]-ethanol and dodecanoyl chloride in a yield of 48 Example 6 Oleic acid-2-[(2-oleoyloxy-ethyl)-(3,4,5,6-tetrahydro- 2H-[1,4']bipyridinyl-4-yl-methyl)-amino]-ethyl esterhydrochloride The title compound is obtained as an oil in an analogous manner to that described in example 1 from hydroxy-ethyl)-(3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl- 4-yl-methyl)-amino]-ethanol and oleoyl chloride in a yield of 37 The 2-hydroxyethyl-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-amino]-ethanol used as the starting material can be obtained as follows: 16 a) A mixture of 23.8 g (0.1 mol) l-benzoyl-4chloromethyl-piperidine and 21.0 g (0.1 mol) diethanolamine is heated for 1 h to 150 0 C, subsequently N sodium hydroxide solution is added and it is extracted with dichloromethane. After concentration by evaporation, 30.4 g (99 of theory) 2-[(2-hydroxyethyl)-(l-benzoyl-piperidin-4-yl-methyl)-amino]-ethanol remain as an oil.
b) 30.3 g of the previously described compound is heated with 200 ml 6 N hydrochloric acid for 5 h to reflux.
After cooling it is washed with diethyl ether, the aqueous phase is concentrated, it is made alkaline with N sodium hydroxide solution, extracted with dichloromethane, dried and concentrated by evaporation. 16.0 g (79 of theory) 2-[(2-hydroxy-ethyl)-(piperidin-4-ylmethyl)-amino]-ethanol remain as an oil.
c) 2-[(2-Hydroxy-ethyl)-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl-methyl)-amino]-ethanol is obtained as an oil analogously to the process described under 3c) from the previous compound and 4 chloropyridine in a 44 yield.
Example 7 Tetradecanoic acid-2-[(2-tetradecanoyloxy-ethyl)- (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl-methyl)amino]-ethyl ester-hydrochloride The title compound is obtained as an oil in an analogous manner to that described in example 1 from hydroxy-ethyl)-(3,4,5,6-tetrahydro-2H-[l,4']bipyridinyl- 4-yl-methyl)-amino]-ethanol and tetradecanoyl chloride 17 in an 86 yield.
Example 8 Dodecanoic acid-2-[(2-dodecanoyloxy-ethyl)-(3,4,5,6tetrahydro-2H-[1,4']bipyridinyl-4-yl-methyl)-amino]ethyl ester-hydrochloride The title compound is obtained as an oil in an analogous manner to that described in example 1 from hydroxy-ethyl)-(3,4,5,6-tetrahydro-2H-[l,4']bipyridinyl- 4-yl-methyl)-amino]-ethanol and dodecanoyl chloride in an 81 yield.
Example 9 Oleic acid-2-[(2-oleoyloxy-ethyl)-(3-piperidin-l-ylpropyl)-amino]-ethyl ester The title compound is obtained as an oil in an analogous manner to that described in example 1 from hydroxy-ethyl)-(3-piperidin-1-yl-propyl)-amino]-ethanol Organomet. Chem. 251, 289 (1983)) and oleoyl chloride in a 39 yield.
Example Dodecanoic acid-2-{[3-(4-amino-piperidin-l-yl)-propyl]- 2-dodecanoyloxy-ethyl)-amino}-ethyl ester g (5 mmol) dodecanoyl chloride is added dropwise to a solution of 0.7 g (2 mmol) 2-{[3-(4-amino-piperidin-l- 18 yl)-propyl]-2-hydroxy-ethyl)-amino}-ethanolhydrochloride in 10 ml trifluoroacetic acid and it is stirred for 18 h at room temperature. It is concentrated by evaporation, admixed with 10 ml cold 1 N sodium hydroxide solution, extracted with ethyl acetate, concentrated by evaporation and chromatographed on silica gel. 0.87 g (71 of theory) of the desired compound is eluted as an oil with ethyl acetate/methanol 4:1.
The 2-{[3-(4-amino-piperidin-l-yl)-propyl]-(2-hydroxyethyl)-amino}-ethanol-hydrochloride used as the starting material can be obtained as follows: a) A mixture of 56.2 g (0.2 mol) 4-benzamido-l-(3chloro-propyl)-piperidine, 19.8 g (0.19 mol) diethanolamine, 16.6 g (0.12 mol) potassium carbonate and 500 ml n-propanol are heated for 32 h to reflux. It is filtered, the filtrate is concentrated by evaporation and chromatographed on silica gel. 33.2 g (48 of theory) 2-{[3-(4-benzamido-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol is eluted with ethyl acetate/methanol 9:1 as an amorphous solid substance.
b) 17.2 g (0.05 mol) of the previous compound is refluxed for 18 h with 190 ml 6 N hydrochloric acid. It is allowed to cool, washed with dichloromethane and the aqueous phase is concentrated by evaporation. 17.0 g (96 of theory) 2-{[3-(4-amino-piperidin-l-yl)-propyl]- (2-hydroxy-ethyl)-amino}-ethanol-hydrochloride remain as an oil.
19 Example 11 Tetradecanoic acid-2-{[3-(4-amnrio-piperidin-l-yl)propyl]-(2-tetradecanoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in a 64 yield in an analogous manner to that described in example from 2-{[3-(4-amino-piperidin-l-yl)-propyl-(2-hydroxyethyl)-amino}-ethanol-hydrochloride and tetradecanoyl chloride.
Example 12 Oleic acid-2-[(2-oleoyloxy-ethyl)-(2-piperidin-4-ylethyl)-amino]-ethyl ester-hydrochloride 3.1 ml (9.5 mmol) oleoyl chloride is added to a solution of 0.95 g (3.8 mmol) 2-[(2-hydroxy-ethyl)-(2-piperidin- 4-yl-ethyl)-amino]-ethanol-hydrochloride in 20 ml dimethylformamide and heated for 4 h to 50 0 C. It is concentrated by evaporation and chromatographed on silica gel. 0.4 g (14 of theory) of the title compound is eluted as an oil with ethyl acetate/methanol 9:1.
The 2-[(2-hydroxy-ethyl)-(2-piperidin-4-yl-ethyl)amino]-ethanol used as a starting material can be obtained as follows: g activated ruthenium oxide is added to a solution of 57 g (0.27 mol) 2-[(2-hydroxy-ethyl)-(2-pyridin-4-ylethyl)-amino]-ethanol (Chem. Abstr. 1960, 13129) in 700 ml methanol and hydrogenated for 16 h at 100 0 C and 150 bar hydrogen pressure. It is filtered, concentrated 20 by evaporation and chromatographed on silica gel. 47.9 g (82 of theory) of the desired compound is eluted as an oil with methanol.
Example 13 Tetradecanoic acid-2-[(2-tetradecanoyloxy-ethyl)-(2piperidin-4-yl-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 71 yield in an analogous manner to that described in example from 2-[(2-hydroxy-ethyl)-(2-piperidin-4-yl-ethyl)amino]-ethanol and tetradecanoyl chloride.
Example 14 Dodecanoic acid-2-[(2-dodecanoyloxy-ethyl)-(2-piperidin- 4-yl-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 90 yield in an analogous manner to that described in example from 2-[(2-hydroxy-ethyl)-(2-piperidin-4-yl-ethyl)amino]-ethanol and dodecanoyl chloride.
Example Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[2- (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-yl)-ethyl]amino}-ethyl ester The title compound is obtained as an oil in a 95 yield in an analogous manner to that described in example 21 from 2-{(2-hydroxy-ethyl)-[2-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-ethyl]-amino}-ethanol and tetradecanoyl chloride. Example 16 Dodecanoic acid-2-{(2-dodecanoyloxy-ethyl)-[2-(3,4,5,6tetrahydro-2H-[1,4']bipyridinyl-4-yl)-ethyl]-amino}ethyl ester The title compound is obtained as an oil in a 65 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[2-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-ethyl]-amino}-ethanol and dodecanoyl chloride.
Example 17 Tetradecanoic acid-2-[(2-tetradecanoyloxy-ethyl)- [1,4']bipiperidinyl-4-yl-amino]-ethyl ester The title compound is obtained as an oil in a 35 yield in an analogous manner to that described in example from 2-[(2-hydroxy-ethyl)-[1,4']bipiperidinyl-4-ylamino]-ethanol and tetradecanoyl chloride.
The 2-[(2-hydroxy-ethyl)-[l,4']bipiperidinyl-4-ylamino]-ethanol used as a starting material can be obtained as follows: 24 g (90 mmol) of the 2-[2-hydroxy-ethyl-(3,4,5,6tetrahydro-2H-[1,4']bipyridinyl-4-yl)-amino]-ethanol described under 3c) is hydrogenated on ruthenium oxide 22 analogously to the process described in example 12. 17 g of theory) of the desired compound is isolated as an oil.
Example 18 Dodecanoic acid-2-[(2-dodecanoyloxy-ethyl)- [1,4']bipiperidinyl-4-yl-amino]-ethyl ester The title compound is obtained as an oil in a 32% yield in an analogous manner to that described in example from 2-[(2-hydroxy-ethyl)-[1,4']bipiperidinyl-4-ylamino]-ethanol and dodecanoyl chloride.
Example 19 Oleic acid-2-{(2-oleoyloxy-ethyl)-[2-(3,4,5,6tetrahydro-2H-[1,4']bipyridinyl-4-yl)-ethyl]-amino}ethyl ester-hydrochloride The title compound is obtained as an oil in a 57% yield in an analogous manner to that described in example 1 from 2-{(2-hydroxy-ethyl)-[2-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-yl)-ethyl]-amino}-ethanol and oleoyl chloride.
Example Oleic acid-2-[(2-oleoyloxy-ethyl)-(1'-methyl- [1,4']bipiperidinyl-4-yl)-amino]-ethyl ester The title compound is obtained as an oil in a 37 yield 23 in an analogous manner to that described in example 1 from 2-[(2-hydroxy-ethyl)-(l'-methyl-[1,4']bipiperidinyl-4-yl)amino]-ethanol and oleoyl chloride.
The 2-[(2-hydroxy-ethyl)-(l'-methyl-[1,4']bipiperidinyl- 4-yl)-amino]-ethanol used as a starting material can be obtained as follows: a) 5.4 g (20 mmol) of the 2-[(2-hydroxy-ethyl)- [1,4']bipiperidinyl-4-yl-amino]-ethanol described in example 17 is refluxed for 5 h with 20 ml ethyl formate and 1 ml water and subsequently concentrated by evaporation. 6.2 g (quantitative) 2-[(2-hydroxy-ethyl)- (1'-formyl-[1,4']bipiperidinyl-4-yl)-amino]-ethanol remain as an oil.
b) 6.0 g (20 mmol) of the previously described compound is added dropwise to a suspension of 2.9 g lithium tetrahydridoaluminate in 150 ml tetrahydrofuran and subsequently refluxed for 3 h. After standing overnight, ethyl acetate and saturated saline solution are added, it is filtered and the filtrate is concentrated by evaporation. It is chromatographed on silica gel and 1.8 g (32 of theory) 2-[(2-hydroxy-ethyl)-(l'-methyl- [1,4']bipiperidinyl-4-yl)-amino]-ethanol is eluted as an oil with ethyl acetate/methanolic ammonia 9:1.
Example 21 Dodecanoic acid-2-{(2-dodecanoyloxy-ethyl)-[1-(3-aminopropyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 37 yield 24 in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[1-(3-amino-propyl)-piperidin- 4-yl]-amino}-ethanol and dodecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[l-(3-amino-propyl)-piperidin- 4-yl]-amino}-ethanol used as a starting material can be obtained as follows: a) A mixture of 5.5 g (29 mmol) of the 2-[(2-hydroxyethyl)-(piperidin-4-yl)-amino]-ethanol described in 3b), ml methanol and 1.9 ml (29 mmol) acrylonitrile is stirred for 24 g at room temperature and subsequently concentrated in a vacuum. 6.7 g (96 of theory) hydroxy-ethyl)-[l-(2-cyano-ethyl)-piperidin-4-yl]amino}-ethanol remain as an oil.
b) 6.7 g (28 mmol) of the previously described compound is hydrogenated over Raney-nickel in 150 ml methanolic ammonia at 100 0 C and 100 bar hydrogen pressure. It is filtered, concentrated by evaporation and 6.8 g (quantitative) 2-{(2-hydroxy-ethyl)-[l-(3-amino-propyl)piperidin-4-yl]-amino}-ethanol is obtained as an oil.
Example 22 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(3amino-propyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 34 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(3-amino-propyl)-piperidin- 4-yl]-amino}-ethanol and tetradecanoyl chloride.
25 Example 23 Dodecanoic acid-2-{(2-dodecanoyloxy-ethyl)-[l-(3-aminopropyl)-piperidin-4-yl-methyl]-amino}-ethyl ester The title compound is obtained as an oil in a 44 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[1-(3-amino-propyl)-piperidin- 4-yl-methyl]-amino}-ethanol and dodecanoyl chloride.
The starting material used can be obtained from the compound of example 6b) by reaction with acrylonitrile analogously to example 21a) and subsequent hydrogenation analogously to example 21b).
Example 24 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(3amino-propyl)-piperidin-4-yl-methyl]-amino}-ethyl ester The title compound is obtained as an oil in a 38 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[1-(3-amino-propyl)-piperidin- 4-yl-methyl]-amino}-ethanol and tetradecanoyl chloride.
Example Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[3- (3,4,5,6-tetrahydro-2H-[1,4']bipyridinyl-4-ylamino)propyl]-amino}-ethyl ester The title compound is obtained as an oil in a 29 yield 26 in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[3-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-ylamino)-propyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[3-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-ylamino)-propyl]-amino}-ethanol used as a starting material can be obtained as follows: a) A solution of 46 g (0.4 mol) 4-chloropyridine and 123.5 g (0.86 mol) 4-piperidone ethylene ketal is refluxed for 48 h in 400 ml p-xylene. It is cooled, filtered, the filtrate is concentrated by evaporation and chromatographed on silica gel. 79.7 g (90 of theory) 8-pyridin-4-yl-l,4-dioxa-8-aza-spiro[4.5]decane with a melting point of 65 0 C is eluted with ethyl acetate/ ammoniacal methanol 9:1.
b) A solution of 79.7 g of the previously described ketal in 2 1 tetrahydrofuran is admixed with 1000 ml 6 N hydrochloric acid and stirred for 2 h at room temperature. It is concentrated by evaporation, made basic with semi-concentrated ammonia water and extracted with dichloromethane. After concentrating the extract by evaporation 64.2 g (quantitative) 2,3,5,6-tetrahydro- [1,4']bipyridin-4-one of melting point 102°C remains.
c) A mixture of 15 g (85 mmol) of the previously described ketone, 13.8 g (85 mmol) 2-[3-amino-propyl)- (2-hydroxy-ethyl)-amino]-ethanol Am. Chem. Soc. 66, 728 (1944)), 100 mg 4-toluene sulfonic acid and 200 ml toluene is heated for 3 h on a water separator and subsequently concentrated by evaporation. The residue is taken up in 200 ml methanol, 500 mg platinum dioxide is 27 added and it is hydrogenated for 10 h at 1 bar hydrogen pressure. After filtration and concentration by evaporation, it is chromatographed on silica gel and 22.4 g 2-{(2-hydroxy-ethyl)-[3-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-ylamino)-propyl]-amino}-ethanol is eluted as an oil with ethyl acetate/methanol 1:1.
Example 26 Dodecanoic acid-2-{(2-dodecanoyloxy-ethyl)-[3-(3,4,5,6tetrahydro-2H-[1,4']bipyridinyl-4-ylamino)-propyl]amino}-ethyl ester The title compound is obtained as an oil in a 34 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[3-(3,4,5,6-tetrahydro-2H- [1,4']bipyridinyl-4-ylamino)-propyl]-amino}-ethanol and dodecanoyl chloride.
Example 27 Oleic acid-2-{(2-oleoyloxy-ethyl)-[l'-(3-dimethylaminopropyl)-[1,4']bipiperidinyl-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 23 yield an analogous manner to that described in example 1 from 2-{(2-hydroxy-ethyl)-[l'-(3-dimethylamino-propyl)- [1,4']bipiperidinyl-4-yl]-amino}-ethanol and oleoyl chloride.
The 2-{(2-hydroxy-ethyl)-[1'-(3-dimethylamino-propyl)- [1,4']bipiperidinyl-4-yl]-amino}-ethanol used as the starting material can be obtained as follows: 28 A mixture of 4.05 g (15 mmol) of the 2-[(2-hydroxyethyl)-[1,4']bipiperidinyl-4-yl-amino]-ethanol described in example 17, 2.0 g potassium-carbonate, 2.2 g 3dimethylamino-propyl chloride and 25 ml n-propanol is refluxed for 5 h, cooled, filtered and the filtrated is concentrated by evaporation. It is chromatographed on silica gel and 2.0 g (37 of theory) of the desired compound is eluted as an oil with ethyl acetate/methanolic ammonia 1:1.
Example 28 Oleic acid-2-{[3-(4-dimethylamino-piperidin-l-yl)propyl]-(2-oleoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in a 65 yield in an analogous manner to that described in example 1 from 2-{[3-(4-dimethylamino-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol and oleoyl chloride.
The 2-{[3-(4-dimethylamino-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol used as a starting material can be obtained as follows: a) 4-Dimethylamino-piperidine is obtained as an oil in a yield by hydrogenation over ruthenium oxide from 4dimethylamino-pyridine analogously to the precursor described under example 12.
b) A mixture of 15.6 g (0.15 mol) diethanolamine, 30.9 g (0.3 mol) l-bromo-3-chloro-propane, 300 ml tetrahydrofuran and 12.6 g potassium carbonate is refluxed for 5 h, filtered, concentrated by evaporation 29 and chromatographed on silica gel. 16.7 g (62 of theory) N-(3-chloro-propyl)-diethanolamine is eluted as an oil with ethyl acetate/methanol 9:1.
c) A mixture of 1.92 (15 mmol) of the piperidine a), 2.72 g (15 mmol) of the halogenide 1.2 g potassium carbonate and 50 ml n-propanol is refluxed for 6h, filtered, concentrated by evaporation and chromatographed on silica gel. 2.7 g (66 of theory) 2- {[3-(4-dimethylamino-piperidin-l-yl)-propyl]-(2-hydroxyethyl)-amino}-ethanol is eluted as an oil with ethyl acetate/methanolic ammonia 1:1.
Example 29 Oleic acid-2-{(2-oleoyloxy-ethyl)-[l-(3-dimethylaminopropyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 24 yield in an analogous manner to that described in example 1 from 2-{(2-hydroxy-ethyl)-[1-(3-dimethylamino-propyl)piperidin-4-yl]-amino}-ethanol and oleoyl chloride.
The 2-{(2-hydroxy-ethyl)-[1-(3-dimethylamino-propyl)piperidin-4-yl]-amino}-ethanol used as the starting material can be obtained as follows: A mixture of 5.84 g (30 mmol) of the 2-[(2-hydroxyethyl)-(piperidin-4-yl)-amino]-ethanol described under 3b), 4.0 g (33 mmol) 3-dimethylamino-propyl chloride, g potassium carbonate and 20 ml n-propanol is refluxed for 5 h, filtered, concentrated by evaporation and chromatographed on silica gel. 4.4 g (54 of 30 theory) of the desired compound is eluted as an oil with ethyl acetate/methanolic ammonia 1:1.
Example Oleic acid-2-{[3-(4-amino-piperidin-l-yl)-propyl]-(2oleoyloxy-ethyl)-amino}-ethyl ester A suspension of 4.5 g (4 mmol) of the 2-{[3-(4-aminopiperidin-l-yl)-propyl]-(2-hydroxy-ethyl)-amino}ethanol-hydrochloride described in example 10 in 100 ml dichloromethane is admixed with 3.5 g N-ethyldiisopropylamine and 0.87 g (4 mmol) pyrocarbonic acid di-t-butyl ester, it is refluxed for 18 h, a solution of 2.4 g (8 mmol) oleoyl chloride in 40 ml dichloromethane is added dropwise, it is refluxed for 18 h, admixed with ml etheric hydrogen chloride solution and stirred for 6 h at room temperature. It is concentrated by evaporation, adjusted to pH 9 with N sodium hydroxide solution, extracted with dichloromethane and methanol, dried and concentrated by evaporation. After chromatography on silica gel (eluting agent ethyl acetate/methanol 1:1) 1.1 g (36 of theory) of the title compound is isolated as an oil.
Example 31 Oleic acid-2-{[3-(4-aminomethyl-piperidin-l-yl)-propyl]- (2-oleoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in a 28 yield in an analogous manner to that described in example from 2-{[3-(4-amino-methyl-piperidin-l-yl)-propyl]-(2- 31 hydroxy-ethyl)-amino}-ethanol and oleoyl chloride.
The 2-{[3-(4-aminomethyl-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol used as the starting material can be obtained from 4-aminomethyl-piperidine analogously to the compound described under 28c.
Example 32 Oleic acid-2-[(2-oleoyloxy-ethyl)-(l'-ethyl- [1,4']bipiperidinyl-4-yl)-amino]-ethyl ester The title compound is obtained as an oil in a 22 yield in an analogous manner to that described in example 1 from 2-[(2-hydroxy-ethyl)-(l'-ethyl-[l,4']bipiperidinyl- 4-yl)-amino]-ethanol and oleoyl chloride.
The 2-[(2-hydroxy-ethyl)-(l'-ethyl-[1,4']bipiperidinyl- 4-yl)-amino]-ethanol used as the starting material can be obtained as follows: a) 5.4 g (20 mmol) of the 2-[(2-hydroxy-ethyl)- [1,4']bipiperidinyl-4-yl-amino]-ethanol described in example 17 is stirred for 5 h at room temperature in ml dimethylformamide and 60 ml dichloromethane containing 1.6 ml acetyl chloride and 1.7 g sodium hydrogen carbonate. It is filtered, dried and concentrated by evaporation. 6.4 g (quantitative) hydroxy-ethyl)-(1'-acetyl-[1,4']bipiperidinyl-4-yl)amino]-ethanol remains as an oil.
b) 5.6 g (18 mmol) of the previously described compound is reduced analogously to example 20b). 2.1 g (39 of 32 theory) 2-[(2-hydroxy-ethyl)-(1'-ethyl- [1,4']bipiperidinyl-4-yl)-amino]-ethanol is obtained as an oil.
Example 33 Oleic acid-2-{(2-oleoyloxy-ethyl)-[l-(3-amino-propyl)piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 25 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(3-amino-propyl)-piperidin- 4-yl]-amino}-ethanol (example 21b) and oleoyl chloride.
Example 34 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(3dimethylamino-propyl)-piperidin-4-yl-methyl]-amino}ethyl ester The title compound is obtained as an oil in a 31 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[1-(3-dimethylamino-propyl)piperidin-4-yl-methyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[1-(3-dimethylamino-propyl)piperidin-4-yl-methyl]-amino}-ethanol used as the starting material can be obtained as follows: 2-{(2-Hydroxy-ethyl)-[l-(3-dimethylamino-propyl)piperidin-4-yl-methyl]-amino}-ethanol is obtained as an oil in a 29 yield analogously to the process described 33 in example 27 by alkylation of the compound described in example 6b) with 3-dimethylamino-propyl chloride.
Example Oleic acid-2-{(2-oleoyloxy-ethyl)-[l-(3-dimethylaminopropyl)-piperidin-4-yl-methyl]-amino}-ethyl ester The title compound is obtained as an oil in a 26 yield in an analogous manner to that described in example 1 from 2-{(2-hydroxy-ethyl)-[l-(3-dimethylamino-propyl)piperidin-4-yl-methyl]-amino}-ethanol and oleoyl chloride.
Example 36 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-2-[[1- (3-amino-propyl)-piperidin-4-yl]-ethyl]-amino}-ethyl ester The title compound is obtained as an oil in a 44 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-2-[[1-[3-amino-propyl)piperidin-4-yl]-ethyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-2-[[1-(3-amino-propyl)piperidin-4-yl]-ethyl]-amino}-ethanol used as the starting material can be obtained analogously to the reaction procedure described in examples 21a) and 21b) from acrylonitrile and the precursor of example 12 (yield 47 34 Example 37 Dodecanoic acid-2-{(2-dodecanoyloxy-ethyl)-2-[[l-(3amino-propyl)-piperidin-4-yl]-ethyl]-amino}-ethyl ester The title compound is obtained as an oil in a 61 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-2-[[l-(3-amino-propyl)piperidin-4-yl]-ethyl]-amino}-ethanol and dodecanoyl chloride.
Example 38 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-2-[[1- (3-dimethylamino-propyl)-piperidin-4-yl]-ethyl]-amino}ethyl ester The title compound is obtained as an oil in a 50 yield in an analogous manner to that described in example 1 from 2-{(2-hydroxy-ethyl)-2-[[l-(3-dimethylaminopropyl)-piperidin-4-yl]-ethyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-2-[[1-(3-dimethylamino-propyl)piperidin-4-yl]-ethyl]-amino}-ethanol used as the starting material can be obtained in a 66 yield from the precursor of example 12 and 3-dimethylamino-propyl chloride analogously to the precursor of example 27.
Example 39 Oleic acid-2-{(2-oleoyloxy-ethyl)-2-[[l-(3-dimethylamino-propyl)-piperidin-4-yl]-ethyl]-amino}-ethyl ester 35 The title compound is obtained as an oil in a 41 yield in an analogous manner to that described in example 1 from 2-{(2-hydroxy-ethyl)-2-[[J-(3-dimethylaminopropyl)-piperidin-4-yl]-ethyl]-amino}-ethanol and oleoyl chloride.
Example Tetradecanoic acid-2-{[3-(4-(2-amino-ethyl)-piperidin-lyl)-propyl]-(2-tetradecanoyloxy-ethyl)-amino}-ethyl ester 32 of the theoretical yield of the title compound is obtained as an oil in an analogous manner to that described in example 10 from 2-{[3-(4-(2-amino-ethyl)piperidin-l-yl)-propyl]-(2-hydroxy-ethyl)-amino}-ethanol and tetradecanoyl chloride.
The 2-{[3-(4-(2-amino-ethyl)-piperidin-l-yl]-propyl]-(2hydroxy-ethyl)-amino}-ethanol used as the starting material can be obtained as follows: a) Hydrogenation of 4-(2-amino-ethyl)-pyridine Am.
Chem. Soc. 78, 4129 (1956)) yields 4-(2-amino-ethyl)piperidine in a yield of 68 in an analogous procedure to that described in example 12.
b) 9.0 g (70 mmol) of the previous compound is heated for 1 h to 150 0 C with 6.4 g (35 mmol) of the compound from example 28b). It is allowed to cool, taken up in ml 2 N sodium hydroxide solution and made strongly alkaline with 10 N sodium hydroxide solution. After extraction with dichloromethane, drying and 36 concentrating the extract by evaporation it is chromatographed on silica gel. 6.0 g (63 of theory) (3-(4-(2-amino-ethyl) -piperidin-1-yl) -propyl]-(2hydroxy-ethyl)-amino}-ethanol is eluted with ethyl acetate/methanol 3:1.
Example 41 Dodecanoic acid-2-{[3-(4-(2-amino-ethyl)-piperidin-lyl)-propyl]-(2-dodecanoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in 35 of the theoretical yield in an analogous manner to that described in example 10 from 2-{[3-(4-(2-amino-ethyl)piperidin-1-yl)-propyl]-(2-hydroxy-ethyl)-amino}-ethanol and dodecanoyl chloride.
Example 42 Dodecanoic acid-2-{[3-(4-(3-amino-propylamino)piperidin-1-yl)-propyl]-(2-dodecanoyloxy-ethyl)-amino}ethyl ester The title compound is obtained as an oil in 18 of the theoretical yield in an analogous manner to that described in example 10 from 2-{[3-(4-(3-aminopropylamino)-piperidin-1-yl)-propyl]-(2-hydroxy-ethyl)amino}-ethanol and dodecanoyl chloride.
The 2-{[3-(4-(3-amino-propylamino)-piperidin-1-yl)propyl]-(2-hydroxy-ethyl)-amino}-ethanol used as the starting material can be obtained as follows: 37 Reaction of the 2-{[3-(4-amino-piperidin-l-yl)-propyl]- (2-hydroxy-ethyl)-amino}-ethanol described in example with acrylonitrile analogously-to example 21a) and subsequent hydrogenation analogously to example 21b) yields the desired compound as an oil.
Example 43 Tetradecanoic acid-2-{[3-(4-(3-amino-propylamino)piperidin-l-yl)-propyl]-(2-tetradecanoyloxy-ethyl)amino}-ethyl ester The title compound is obtained as an oil in 12 of the theoretical yield in an analogous manner to that described in example 10 from 2-{[3-(4-(3-aminopropylamino)-piperidin-l-yl)-propyl]-(2-hydroxy-ethyl)amino}-ethanol and tetradecanoyl chloride.
Example 44 4-<2-{[Bis-(2-tetradecanoyloxy-ethyl)]-amino}-ethyl>piperidine-1-carboxamidine A mixture of 1.92 g (3 mmol) of the compound from example 13, 0.25 g cyanamide and 5 ml n-butanol is heated for 2 h to 120 0 C, cooled, the residue is taken up in dichloromethane, washed with a small amount of water, dried and concentrated by evaporation. After chromatography on silica gel 0.96 g (47 of theory) of the title compound is eluted as a wax with ethyl acetate/methanol 1:1.
38 Example N-[3-(4-<2[Bis-(2-tetradecanoyToxy-ethyl)-amino]-ethyl>piperidin-1-yl)-propyl]-guanidine The title compound is obtained as an oil in a 64 yield in an analogous manner to that described in example 44 from the compound of example 36 and cyanamide.
Example 46 Oleic acid-2-[(2-ethylamino-ethyl)-(2-oleoyloxy-ethyl)amino]-ethyl ester-hydrochloride The title compound is obtained as an oil in a 36 yield in an analogous manner to that described in example 1 from 2-[(2-ethylamino-ethyl)-(2-hydroxy-ethyl)-amino]ethanol and oleoyl chloride.
The 2-[(2-ethylamino-ethyl)-(2-hydroxy-ethyl)-amino]ethanol used as the starting material can be obtained as follows: 11.0 g (58 mmol) N-{2-[bis-(2-hydroxy-ethyl)-amino]ethyl}-acetamide Med. Chem. 36, 1839 (1993)) is reduced analogously to example 20b). 8.3 g (81 of theory) of the desired compound is isolated as an oil.
Example 47 Oleic acid-2-[(2-diethylamino-ethyl)-(2-oleoyloxyethyl)-amino]-ethyl ester-hydrochloride 39 The title compound is obtained as an oil in a 44 yield in an analogous manner to that described in example 12 from 2-[(2-diethylamino-ethyl)-42-hydroxy-ethyl)-amino]ethanol and oleoyl chloride.
Example 48 Oleic acid-2-[(2-amino-ethyl)-(2-oleoyloxy-ethyl)amino]-ethyl ester-hydrochloride The title compound is obtained as an oil in a 25 yield in an analogous manner to that described in example 12 from 2-[(2-amino-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol Am. Chem. Soc. 81, 3984 (1959)) and oleoyl chloride.
Example 49 Oleic acid-2-{[3-(3-amino-propylamino)-propyl]-(2oleoyloxy-ethyl)-amino}-ethyl ester-hydrochloride The title compound is obtained as an oil in a 29 yield in an analogous manner to that described in example 12 from 2-{[3-(3-amino-propylamino)-propyl]-(2-hydroxyethyl)-amino}-ethanol and oleoyl chloride.
The 2-{[3-(3-amino-propylamino)-propyl]-(2-hydroxyethyl)-amino}-ethanol used as the starting material can be obtained by reaction of 2-[3-amino-propyl)-(2hydroxy-ethyl)-amino]-ethanol Am. Chem. Soc. 66, 728 (1944)) with acrylonitrile analogously to example 21a) and subsequentl hydrogenation analogously to example 21b). b.p.o.
0 6 176-177 0
C.
40 Example Oleic acid-2-[(3-dimethylaminoapropyl)-(2-oleoyloxyethyl)-amino]-ethyl ester-hydrochloride The title compound is obtained as an oil in a 65 yield in an analogous manner to that described in example 1 from 2-[(3-dimethylamino-propyl)-(2-hydroxy-ethyl)amino]-ethanol and oleoyl chloride.
The 2-[(3-dimethylamino-propyl)-(2-hydroxy-ethyl)amino]-ethanol used as the starting material can be obtained analogously to the procedure of example 27 from diethanolamine and 3-dimethylamino-propyl chloride.
b.p.1.
5 135-1360C.
Example 51 Oleic acid-2-[(3-diethylamino-propyl)-(2-oleoyloxyethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 65 yield in an analogous manner to that described in example 1 from 2-[(3-diethylamino-propyl)-(2-hydroxy-ethyl)amino]-ethanol (Chem. Pharm. Bull. 9, 313 (1961)) and oleoyl chloride.
Example 52 Tetradecanoic acid-2-[(3-dimethylamino-propyl)-(2tetradecanoyloxy-ethyl)-amino]-ethyl ester 41 The title compound is obtained as an oil in a 78 yield in an analogous manner to that described in example 1 from 2-[(3-dimethyl-amino-propyl)-(2-hydroxy-ethyl)amino]-ethanol and tetradecanoyl chloride.
Example 53 Dodecanoic acid-2-[(3-dimethylamino-propyl)-(2dodecanoyloxy-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 79 yield in an analogous manner to that described in example 1 from 2-[(3-dimethylamino-propyl)-(2-hydroxy-ethyl)amino]-ethanol and dodecanoyl chloride.
Example 54 Tetradecanoic acid-2-[(3-diethylamino-propyl)-(2tetradecanoyloxy-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 50 yield in an analogous manner to that described in example 1 from 2-[(3-diethylamino-propyl)-(2-hydroxy-ethyl)amino]-ethanol and tetradecanoyl chloride.
Example Dodecanoic acid-2-[(3-diethylamino-propyl)-(2dodecanoyloxy-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 60 yield in an analogous manner to that described in example 1 42 from 2-[(3-diethylamino-propyl)-(2-hydroxy-ethyl)amino]-ethanol and dodecanoyl chloride.
Example 56 Oleic acid-2-[{3-[(3-dimethylamino-propyl)-methylamino]-propyl}-(2-oleoyloxy-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 63 yield in an analogous manner to that described in example 1 from 2-[{3-[(3-dimethylamino-propyl)-methyl-amino]propyl}-(2-hydroxy-ethyl)-amino]-ethanol and oleoyl chloride.
The 2-[{3-[(3-dimethylamino-propyl)-methyl-amino]propyl}-(2-hydroxy-ethyl)-amino]-ethanol used as the starting material can be obtained analogously to example 28c) by alkylation of N,N,N'-trimethyl-propane-l,3diamine Chem. Soc. 1966, 527) with N-(3-chloropropyl)-diethanolamine.
Example 57 Oleic acid-2-[{3-[(3-diethylamino-propyl)-methyl-amino]propyl}-(2-oleoyloxy-ethyl)-amino]-ethyl ester The title compound is obtained as an oil in a 59 yield in an analogous manner to that described in example 1 from 2-[{3-[(3-diethylamino-propyl)-methyl-amino]propyl}-(2-hydroxy-ethyl)-amino]-ethanol and oleoyl chloride.
The 2-[{3-[(3-diethylamino-propyl)-methyl-amino]- 43 propyl}-(2-hydroxy-ethyl)-amino]-ethanol used as the starting material can be obtained analogously to the precursor described in example_56 by alkylation of N,Ndiethyl-N'-methyl-propane-l,3-diamine ("Monatsh. Chem.
112, 825 (1981)) with N-(3-chloro-propyl)diethanolamine.
Example 58 Dodecanoic acid-2-{[4-(3-amino-propylamino)-butyl]-(2dodecanoyloxy-ethyl)-amino}-ethyl ester-hydrochloride The title compound is obtained as a wax in a 31 yield in an analogous manner to that described in example from 2-{[4-(3-amino-propylamino)-butyl]-(2-hydroxyethyl)-amino}-ethanol and dodecanoyl chloride.
The 2-{[4-(3-amino-propylamino)-butyl]-(2-hydroxyethyl)-amino}-ethanol used as the starting material can be obtained 2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]ethanol Am. Chem. Soc. 81, 3984 (1959)) and acrylonitrile analogously to example 21a) and subsequent hydrogenation analogously to example 21b).
Example 59 Dodecanoic acid-2-{[3-(3-amino-propylamino)-propyl]-(2dodecanoyloxy-ethyl)-amino}-ethyl ester-hydrochloride The title compound with a melting point of 245-246 0 C is obtained in a 49 yield in an analogous manner to that described in example 10 from 2-{[3-(3-aminopropylamino)-propyl]-(2-hydroxy-ethyl)-amino}-ethanol 44 (see example 49) and dodecanoyl chloride.
Example Tetradecanoic acid-2-{[4-(3-amino-propylamino)-butyl]- (2-tetradecanoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in a 27 yield in an analogous manner to that described in example from 2-{[4-(3-amino-propylamino)-butyl]-(2-hydroxyethyl)-amino}-ethanol and tetradecanoyl chloride.
Example 61 Tetradecanoic acid-2-[{3-[(3-dimethylamino-propyl)methyl-amino]-propyl}-(2-tetradecanoyloxy-ethyl)-amino]ethyl ester The title compound is obtained as an oil in a 35 yield in an analogous manner to that described in example 1 from 2-[{3-[(3-dimethylamino-propyl)-methyl-amino]propyl}-(2-hydroxy-ethyl)-amino]-ethanol and tetradecanoyl chloride.
Example 62 Tetradecanoic acid-2-[{3-[(3-diethylamino-propyl)methyl-amino]-propyl}-(2-tetradecanoyloxy-ethyl)-amino]ethyl ester The title compound is obtained as an oil in a 61 yield in an analogous manner to that described in example 1 45 from 2-[{3-[(3-diethylamino-propyl)-methyl-amino]propyl}-(2-hydroxy-ethyl)-amino]-ethanol and tetradecanoyl chloride.
Example 63 N-<3-{4-[Bis-(2-tetradecanoyloxy-ethyl)-amino]piperidin-l-yl}-propyl>-guanidine The title compound is obtained as an oil in a 91 yield in an analogous manner to that described in example 44 from the compound of example 22 and cyanamide.
Example 64 N-[3-(4-<[Bis-(2-tetradecanoyloxy-ethyl)-amino]-methyl>piperidin-l-yl)-propyl]-guanidine The title compound is obtained as an oil in an 82 yield in an analogous manner to that described in example 44 from the compound of example 24 and cyanamide.
Example N-[2-(1-<3-[Bis-(2-tetradecanoyloxy-ethyl)-amino]propyl>-piperidin-4-yl)-ethyl]-guanidine.
The title compound is obtained as an oil in a 94 yield in an analogous manner to that described in example 44 from the compound of example 40 and cyanamide.
46 Example 66 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(2amino-ethyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 38 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(2-amino-ethyl)-piperidin- 4-yl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[l-(2-amino-ethyl)-piperidin-4yl]-amino}-ethanol used as the starting material can be obtained as follows: a) A mixture of 8.5 g (45 mmol) of the 2-[(2-hydroxyethyl)-(piperidin-4-yl)-amino]-ethanol described in example 3b), 150 ml dimethylformamide, 3.4 g (45 mmol) chloroacetonitrile, 14.5. g potassium carbonate and 100 mg potassium iodide is stirred for 2 h at 60 0 C. It is filtered and the filtrate is concentrated by evaporation in a vacuum. 10.5 g (quantitative) hydroxy-ethyl)-[l-cyanomethyl-piperidin-4-yl]-amino}ethanol remains as an oily crude product.
b) 4.1 g (18 mmol) of the previously described compound is hydrogenated in 175 ml methanolic ammonia over Raney nickel at 35 0 C and 100 bar hydrogen pressure. It is filtered, concentrated by evaporation and after chromatography on silica gel one obtains 2.3 g (55 of theory) 2{(2-hydroxy-ethyl)-[l-(2-amino-ethyl)piperidin-4-yl]-amino}-ethanol as an oil.
47 Example 67 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(2amino-ethyl)-piperidin-4-yl-methyl]-amino}-ethyl ester The title compound is obtained as an oil in a 29 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[1-(2-amino-ethyl)-piperidin- 4-yl-methyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[l-(2-amino-ethyl)-piperidin-4yl-methyl]-amino}-ethanol used as the starting material can be obtained as follows: a) The intermediate product described in example 6b) is reacted with chloroacetonitrile analogously to the method described in example 66a).
b) The crude product obtained above is hydrogenated as in example 66b). The desired 2-{(2-hydroxy-ethyl)-[1-(2amino-ethyl)-piperidin-4-yl-methyl]-amino}-ethanol is obtained in a yield of 47 of theory.
Example 68 Tetradecanoic acid-2-{[3-(4-(aminomethyl)-piperidin-lyl)-propyl]-(2-tetradecanoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in a 27 yield in an analogous manner to that described in example from 2-{[3-(4-(aminomethyl)-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol and tetradecanoyl 48 chloride.
The 2-{[3-(4-aminomethyl-piperlain-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol used as the starting material can be obtained analogously to the compound described in example 28c from 4-aminomethyl-piperidine.
Example 69 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(3dimethylamino-propyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 25 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(3-dimethylamino-propyl)piperidin-4-yl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[l-(3-dimethylamino-propyl)piperidin-4-yl]-amino}-ethanol used as the starting material is described in example 29.
Example Tetradecanoic acid-2-{[3-(4-dimethylamino-piperidin-1yl)-propyl]-(2-tetradecanoyloxy-ethyl)-amino}-ethyl ester The title compound is obtained as an oil in a 62 yield in an analogous manner to that described in example from 2-{[3-(4-dimethylamino-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol and tetradecanoyl chloride.
49 The 2-{[3-(4-dimethylamino-piperidin-l-yl)-propyl]-(2hydroxy-ethyl)-amino}-ethanol used as the starting material is described in example 28.
Example 71 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(4amino-butyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 22 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(4-amino-butyl)-piperidin- 4-yl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[1-(4-amino-butyl)-piperidin-4yl]-amino}-ethanol used as the starting material can be obtained as follows: a) A mixture of 18.8 g (100 mmol) of the 2-[(2-hydroxyethyl)-(piperidin-4-yl)-amino]-ethanol described in example 3b), 100 ml dimethyl-formamide, 11 ml (110 mmol) 4-bromo-butyronitrile, 18.9 ml N-ethyldiisopropylamine and 100 mg 4-dimethyl-amino-pyridine is stirred for 8 h at 90 0 C and subsequently concentrated by evaporation in a vacuum. It is taken up in dichloromethane, filtered and the filtrate is concentrated. 15.0 g (59 of theory) 2-{(2-hydroxy-ethyl)-[1-(3-cyano-propyl)piperidin-4-yl]-amino}-ethanol remains as an oil.
b) 15.0 g (59 mmol) of the previously described compound is hydrogenated in 300 ml methanolic ammonia over Raney nickel at 35 0 C and 100 bar hydrogen pressure. It is filtered, concentrated by evaporation and 10.9 g (71 50 of theory) 2-{(2-hydroxy-ethyl)-[l-(4-amino-butyl)piperidin-4-yl]-amino}-ethanol is obtained as an oil.
Example 72 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(4dimethylamino-butyl)-piperidin-4-yl]-amino}-ethyl ester The title compound is obtained as an oil in a 23 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(4-dimethylamino-butyl)piperidin-4-yl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[1-(4-dimethylamino-butyl)piperidin-4-yl]-amino}-ethanol used as the starting material can be obtained as follows: 4.7 ml formic acid and 5.6 ml saturated Formalin solution are added dropwise at 0 C to 6.5 g (25 mmol) 2- {(2-hydroxy-ethyl)-[l-(4-amino-butyl)-piperidin-4-yl]amino}-ethanol (example 71b) it is heated to 95 100 0
C
and stirred for a further 9 h. It is allowed to cool, admixed with 6.5 ml concentrated hydrochloric acid, refluxed for 3 h, made strongly alkaline with 10 N sodium hydroxide solution and extracted with dichloromethane. After drying and concentrating the extract by evaporation, 6.0 g (84 of theory) of the desired compound remain as an oil.
51 Example 73 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(4amino-butyl)-piperidin-4-yl-methyl]-amino}-ethyl ester The title compound is obtained as an oil in a 33 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[1-(4-amino-butyl)-piperidin- 4-yl-methyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[1-(4-amino-butyl)-piperidin-4yl-methyl]-amino}-ethanol used as the starting material can be obtained as follows: The desired compound is obtained as an oil by reacting 2-[(2-hydroxy-ethyl)-(piperidin-4-yl-methyl)-amino]ethanol (example 6b) with 4-bromo-butyronitrile analogously to example 71b) and subsequently hydrogenating analogously to example 71b).
Example 74 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-[1-(4dimethylamino-butyl)-piperidin-4-yl-methyl]-amino}-ethyl ester The title compound is obtained as an oil in a 43 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-[l-(4-dimethylamino-butyl)piperidin-4-yl-methyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-[l-(4-dimethylamino-butyl)- 52 piperidin-4-yl-methyl]-amino}-ethanol used as the starting material can be obtained (yield 69 of theory) from the 2-{(2-hydroxy-ethyl)-1--(4-amino-butyl)piperidin-4-yl-methyl]-amino}-ethanol described under example 73 by the method described in example 72 by reaction with formic acid and Formalin solution.
Example Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-2-[[1- (4-amino-butyl)-piperidin-4-yl]-ethyl]-amino}-ethyl ester The title compound is obtained as an oil in a 17 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-2-[[l-(4-amino-butyl)piperidin-4-yl]-ethyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-2-[[l-(4-amino-butyl)piperidin-4-yl]-ethyl]-amino}-ethanol used as the starting material can be obtained as follows: The desired compound is obtained as an oil by reacting the 2-[(2-hydroxy-ethyl)-(2-piperidin-4-yl-ethyl)amino]-ethanol described in example 12 with 4-bromobutyronitrile analogously to example 71a) and subsequently hydrogenating analogously to example 71b).
-N
53 Example 76 Tetradecanoic acid-2-{(2-tetradecanoyloxy-ethyl)-2-[[1- (4-dimethylamino-butyl)-piperidin-4-yl]-ethyl]-amino}ethyl ester The title compound is obtained as an oil in a 33 yield in an analogous manner to that described in example from 2-{(2-hydroxy-ethyl)-2-[[1-(4-dimethylamino-butyl)piperidin-4-yl]-ethyl]-amino}-ethanol and tetradecanoyl chloride.
The 2-{(2-hydroxy-ethyl)-2-[[l-(4-dimethylamino-butyl)piperidin-4-yl]-ethyl]-amino}-ethanol used as the starting material can be obtained (yield 72 of theory) from the 2-{(2-hydroxy-ethyl)-2-[[l-(4-amino-butyl)piperidin-4-yl]-ethyl]-amino}-ethanol described in example 75 by reaction with formic acid and Formalin solution according to the method described in example 72.
Example 77 Pharmacological testing 1. Test principle The testing of DOTAP or the compounds of the invention comprises transfection of the test cells, protein determination by means of the BCA method (Pierce) and carrying out a CAT Elisa and these are described here using DOTAP (Boehringer Mannheim) as an example. After ultrasonication the cationic lipid DOTAP forms unilamellar vesicles (liposomes) in aqueous solution which spontaneously form stable complexes with the DNA 54 (pCMV-CAT). These complexes adhere to the cell surface, fuse with the cell membrane and pCMV-CAT is released into the cytoplasm. The transigntly expressed CAT is detected in the cell lysate.
1.1 Test cells HeLa, human cancer epithelial cell line from the cervix, ATCC CCL 2 RPMI 1640, human cancer epithelial cell line from the nasal septum, ATCC CCL CALU 1, human cancer epithelial cell line from the lung, ECACC 93120818 or another suitable test cell line 1.2 Test medium The composition of the test medium used for the respective cell line corresponds with that of the respective culture medium, only the content of FCS is reduced by 50 (only 5 FCS instead of 10 2. Determination procedure 2.1 Feeding cells for the test 2.0 ml cell suspension (1.5 x 105 cells/ml) are placed into each well of a 6-well multiplate incubate for 24 h at 37 0 C, 5 CO 2 2.2 Transfection mixture The DOTAP/DNA complexes are mixed in a sterile 96-well round-bottom plate.
Example; gl HBS (Hank's buffered saline) buffer is added first, then 20 gl DOTAP is added. The DNA is diluted 1:20 with HBS. Then 40 1l 2 Ag DNA is added to the transfection mixtures and mixed thoroughly. The mixture 55 is allowed to stand for 15 min at room temperature.
Procedure for transfection: aspirate TM (transfection medium) from all wells add 2 ml TM/well rapidly add the transfection mixtures thoroughly mix the content of the wells by gentle swirling incubate the cells for 6 h at 37°C, 5 CO2 afterwards aspirate the DOTAP/DNA mixture add 2 ml TM/well incubate the cells for 40-44 h, 37°C, 5 CO 2 2.3 Lysing the cells aspirate the TM and wash the cells twice with 2 ml ice-cold PBS/well, aspirate completely add 0.5 ml lysis buffer (from the CAT-Elisa kit, Boehringer Mannheim Co.) to the washed cells and allow to stand for 30 min at room temperature after 30 min transfer the lysates into Eppendorf cups and centrifuge for 10 min at 13000 rpm using a Biofuge remove an aliquot from the supernatant for the protein assay according to the BCA method. The remainder is shock-frozen with liquid nitrogen and stored at -800C until the CAT-Elisa is carried out.
2.4 Protein determination of the lysates using the BCA (bicinchoninic acid) method the BSA (bovine serum albumin) solution contained in the kit (Boehringer Mannheim Co.) is used to prepare protein standards by dilution with lysis buffer 10 pil of the protein standard solution, the blank (lysis buffer) and the unknown sample are pipetted 56 into a microtitre plate. 200 'l working solution is added to each well and the plate is shaken for 30 min on a shaker. After incubating for 30 min at 37 0 C they are measured at 550 nm in an ELISA reader. The determination of the protein concentration is carried out using an evaluation program.
CAT-Elisa Principle: The CAT (chloroamphenicol acetyl transferase)-Elisa serves to quantitatively determine the CAT expression in eukaryotic cells after transfection with a plasmid that contains CAT as the reporter gene. The CAT-Elisa is a sandwich enzyme immunoassay. Anti-CAT antibodies are bound adsorptively to the walls of the modules. In the first step CAT from cell extracts specifically binds to the coated modules. In the second step the fixed CAT is bound by an ANTI-CAT antibody which is labelled with digoxigenin (anti-CAT-DIG). Anti-CAT-DIG is detected in the third step by a peroxidase-labelled antibody against digoxigenin (Anti-DIG-POD) and visualized in a subsequent substrate reaction.
Procedure: The working steps of the CAT-Elisa are carried out according to the working instructions contained in the kit.
The microtitre plate is measured at 405 nm and a reference wavelength of 492 nm with an Elisa reader.
57 The pharmacological data are shown as an example in the following table: relative transfection efficiency in a CAT-Assay (DOTAP=1) compound of example HeLa cells Calu cells 34 3.2 3.9 3.2 3.4

Claims (9)

1. Pharmaceutical preparation containing at least one compound of formula I 0 O (CH 2 O-C-Y D-N O (I) (CH 2 )0-0-C-Z in which A denotes hydrogen, a group NRiRq, a group NRI(CH 2 )pNR3R 4 or a pyridinyl residue, B and D are the same or different and each denotes a bond, a C 1 to C 6 alkylene residue or a group NR 5 -C 2 to C 6 -alkylene, S0. C denotes piperidinediyl, o Y and Z are the same or different and each denotes a saturated or unsaturated hydrocarbon residue with 7 to 24 carbon atoms, 59 R 1 to R 5 are the same or different and each represents hydrogen or a C 1 to C 6 alkyl residue, m is an integer 0, 1 or 2 and if m equals 2 both residues C can be the same.or different, n and o are the same or different and each denotes the integers 2, 3 or 4 and p denotes an integer from 2 to 6 as well as physiologically tolerated salts thereof, *"provided that hydrazine derivatives are not included and that m cannot be 0 if A denotes hydrogen and B ag and D being the same or different represent a bond or an alkylene residue.
2. Compounds of formula I (CH 2 )n O-C-Y A- II (CH 2 C-Z in which A denotes hydrogen, a group NR 1 R 2 a group NR 1 (CH 2 )pNR 3 R 4 or a pyridinyl residue, 60 S
9. OS S 4* S 0 a* S 0* S B and D are the same or different and each denotes a bond, a C 1 to C 6 alkylene residue or a group NR 5 -C 2 to Cg alkylene, C denotes piperidinediyl, Y and Z are the same or different and each denotes a saturated or unsaturated hydrocarbon residue with 7 to 24 carbon atoms, R 1 to R 5 are the same or different and each represents hydrogen or a C 1 to C 6 alkyl residue, m is an integer O, 1 or 2 and if m equals 2 both residues C can be the same or different, n and o are the same or different and each denotes the integers 2, 3 or 4 and p denotes an integer from 2 to 6 as well as physiologically tolerated salts thereof, provided that hydrazine derivatives are not included that m cannot be 0 if A denotes hydrogen or a group NR 1 R 2 and B and D being the same or different represent a bond or an alkylene residue 61 and in the case that m 1, the group A-B cannot be hydrogen or C,-C 4 alkyl and that they do not include the compounds octadecanoic acid-[ (3-diethylamino-propyl)iino]- bis (methyl-2, 1-ethanediyl) -ester-hydrochloride octadecanoic acid-[ (3-dixnethylaluino-propyl) iminojdi- 3, i-propanediyl ester-dihydrochioride octadecanoic acid- [(3-dimethylamino-propyl) imino] di- 3, i-propanediyl ester octadecanoic acid-[ (3-dimethylamino-propyl) imino]di- 2, l-ethanediyl ester-hydrochloride docosanoic acid-2-[ (3-dimethylaxnino-propyl) (1- o xododecyl) oxy]ethyl]amino]ethyl ester hexadecanoic acid-[ (ethylmethylamilo) ethyl] imino]di-2, i-ethanediyl ester octadecanoic acid- (dimethylamino) propyl] imino]di- 2, i-ethanediyl ester octadecanoic acid-[ (dimethylamino) propyl] imino]di- 2, i-ethanediyl ester-dihydrochioride octadecanoic acid-[ (dimethylamino) propyl] imino~di- 2, i-ethanediyl ester N,N-Bis (dodecyloxy) propyl] -l,2-ethanediamile octadecanoic acid-[ (2-aminoethyl) amino]ethyl) imino] -di-2, l-ethanediyl ester stearic acid-iminobis- (ethyleneiminoethylele) -ester- monoacetate. 3. Compounds as claimed in claim 1 or claim 2, in which Y denotes C 13 H 27 or C 17 H 33 P\US) OFICH P:\OPER\Kbm 43841-97 sp.doc-21 AS I -62- 4. Compounds as claimed in any one of claims 1-3, in which Z denotes Cz 1 H 2 or C, 7 H 33 Compounds as claimed in any one of claims 1-4, in which A denotes NH 2 or N(CH 3 2 6. Compounds as claimed in any one of claims 1-5, in which B and D are the same or different and denote a bond, a CI to C 3 -alkylene residue or, if m=0, an N(CH 3 )C 3 to C 4 -alkylene residue. 7. Compounds as claimed in any one of claims 1-6, in which m denotes 0 or 1. S 15 8. Compounds as claimed in any one of claims 1-7, in which n and o denote 2. 9. Pharmaceutical preparations as claimed in claim 1, which additionally contain a therapeutic agent.
10. Use of compounds as claimed in claim 2 for the S*production of pharmaceutical compositions for gene therapy.
11. Use of compounds as claimed in claim 2 for in vitro transfection.
12. Use of compounds as claimed in claim 2 for the production of in vivo transfection reagents. P:%OPERXom\43841-97 spc.doc 23510/I -63-
13. Use of compounds as claimed in claim 2 for the production of drug combinations in cancer therapy, antiviral therapy, infection therapy and in diseases caused by dysregulation.
14. A method of treating a mammal in need of cancer therapy, antiviral therapy, infection therapy or suffering diseases caused by dysregulation, by administering a drug combination containing a compound as claimed in claim 2, or a pharmaceutical preparation of claim 9. Pharmaceutical preparation according to claim 1, substantially as hereinbefore described with 15 reference to the Examples.
16. Compounds of formula I according to claim 2, substantially as hereinbefore described with reference to the Examples. DATED THIS 23rd day of May, 2001 Roche Diagnostics GmbH by DAVIES COLLISON CAVE 25 Patent Attorneys for the Applicants
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US10800635B2 (en) 2017-08-30 2020-10-13 Otis Elevator Company Elevator door wedge monitoring system
EP4077272B1 (en) * 2020-04-09 2024-09-18 Suzhou Abogen Biosciences Co., Ltd. Lipid nanoparticle composition
TW202204622A (en) 2020-04-09 2022-02-01 大陸商蘇州艾博生物科技有限公司 Nucleic acid vaccines for coronavirus
CN116710074A (en) * 2020-10-14 2023-09-05 乔治梅森研究基金会公司 Methods of making lipid nanoparticles and compositions derived therefrom
JP2023546175A (en) * 2020-10-14 2023-11-01 ジョージ・メイソン・リサーチ・ファウンデーション・インコーポレイテッド Method for producing lipid nanoparticles and compositions derived therefrom
CN115947672B (en) * 2023-01-04 2024-02-27 成都威斯津生物医药科技有限公司 Compounds, liposomes and drug carriers for drug delivery

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05331118A (en) * 1992-06-02 1993-12-14 Kao Corp Novel diaminodiester and process for producing the same
JPH06340598A (en) * 1993-05-28 1994-12-13 Lion Corp Novel diester diamine compound, intermediate thereof, production method thereof and softener

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3689494A (en) * 1971-03-31 1972-09-05 William R J Simpson N-pyridinealkyl-alkanolamine nitrates
US4158093A (en) * 1977-12-15 1979-06-12 Reilly Tar & Chemical Corporation Process for substituting and dequaternizing pyridylethyl quaternary salts of pyridine and bypyridine bases
JPS6325654A (en) * 1986-07-18 1988-02-03 Fuji Photo Film Co Ltd Color photographic developing solution composition and method for processing silver halide color photographic sensitive material
JPH05232660A (en) * 1992-02-19 1993-09-10 Konica Corp Treatment for silver halide color photographic sensitive material
US5334761A (en) * 1992-08-28 1994-08-02 Life Technologies, Inc. Cationic lipids
US5491263A (en) * 1993-12-21 1996-02-13 The Dow Chemical Company Aminoethylation process for production of substituted ethylene diamines
FR2717694B1 (en) * 1994-03-22 1996-05-03 Seppic Sa A composition comprising a recombinant plasmid and its uses as a vaccine and medicament.
FR2727679B1 (en) * 1994-12-05 1997-01-03 Rhone Poulenc Rorer Sa NEW TRANSFECTION AGENTS AND THEIR PHARMACEUTICAL APPLICATIONS
US5635487A (en) * 1994-12-29 1997-06-03 Wolff; Jon A. Amphipathic, micellar delivery systems for biologically active polyions
DE19521412A1 (en) * 1995-06-14 1996-12-19 Boehringer Mannheim Gmbh New cationic and polycationic amphiphiles, reagents containing them and their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05331118A (en) * 1992-06-02 1993-12-14 Kao Corp Novel diaminodiester and process for producing the same
JPH06340598A (en) * 1993-05-28 1994-12-13 Lion Corp Novel diester diamine compound, intermediate thereof, production method thereof and softener

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EP0927174B1 (en) 2007-12-12
BR9712818A (en) 1999-12-21
ATE380798T1 (en) 2007-12-15
CA2265765A1 (en) 1998-03-19
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AU4384197A (en) 1998-04-02
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TR199901200T2 (en) 1999-10-21
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ZA978170B (en) 1999-03-11
DE19637043A1 (en) 1998-03-19

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