WO1989008098A2 - Lipophilic polyamines useful for treating hypercholesterolemia - Google Patents
Lipophilic polyamines useful for treating hypercholesterolemia Download PDFInfo
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- WO1989008098A2 WO1989008098A2 PCT/US1989/000490 US8900490W WO8908098A2 WO 1989008098 A2 WO1989008098 A2 WO 1989008098A2 US 8900490 W US8900490 W US 8900490W WO 8908098 A2 WO8908098 A2 WO 8908098A2
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- ethanediamine
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- aminoethyl
- ethyl
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- 0 C**CCN(CCN)CNC1CCCCCCCCCCC1 Chemical compound C**CCN(CCN)CNC1CCCCCCCCCCC1 0.000 description 3
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
- C07C225/06—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and acyclic
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
- C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
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- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
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- C07C2601/20—Systems containing only non-condensed rings with a ring being at least seven-membered the ring being twelve-membered
Definitions
- This invention includes novel lipophilic polyamines which are useful for treating hypercholesterolemia and intermediates thereto.
- Cholesterol is probably the sole precursor of bile acids.
- bile acids are secreted into the intestines. A major portion of the bile acid is absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation system. Only very small amounts of bile acids are found in normal serum.
- Polymeric anion exchange resins are known to combine with the bile acids in the intestine to form an insoluble complex which is excreted in the feces. This results in partial removal of bile acids from the enterohepatic circulation by preventing their reabsorption.
- the increased fecal loss of bile acids leads to an increased oxidation of cholesterol to bile acids, a decrease in beta lipoprotein or low density lipoprotein plasma levels and a decrease in plasma cholesterol levels.
- excretion of bile acids produces an increase in hepatic synthesis of cholesterol, plasma cholesterol falls.
- These anion exchange resins are not systemically absorbed or digested although large quantities, up to 54 grams of the formulated resin per day for cholestyramine resin powder, are needed. These resins are not water soluble but are typically administered as an aqueous suspension. Colestipol-niacin therapy has recently been shown to significantly increase the regression of atherosclerosis in drug-treated subjects. D.H.
- CA 88:106267Z discloses 1,2-Ethanedicimine, N-[2-(dimethylamino)ethyl]-N',N'-bis[2-[[2-(dimethylamino)-ethyl]methylamino]ethyl]-N-methyl-, useful as polyurethane foam materials.
- CA 105:197229X Japanese Patent, J61146265 discloses Ethanaminium, N,N-bis(2-amino-ethyl)-N-(carboxymethyl)-2-(dodecylamino)-chloride, useful as an antimicrobial agent.
- CA 74:99664g disclose Isophthalamic acid, N,N',N"-(nitrilotriethylene)-tris[5-nitro-, trimethyl ester, useful as a radiopaque agent.
- CA87 :22564k U.S. Patent 4,003,934 discloses 1,2-Ethanediamine, N,N-bis(2-aminoethyl)-N'[2-(3,3-dimethylbicyclo[2.2.1]hept-2-yl)-1- [2-(3,3-dimethylbicyclo[2.2.1]hept-2-yl)ethyl]propyl]tetrahydrochloride, useful as an antimicrobial agent.
- CA67:21731n U.S. Patent 3,291,808 discloses N-(dialkylaminoalkyl)-1,4-naphthalenediamines having useful antiparasitic properties.
- CAl07:40601f (U.S. Patent 4,631,337) discloses hydrolyticallystable dense star polyamines, which are useful as calibration standards, high efficiency proton scavengers and in making size selective membranes.
- CA54:26191g U.S. Patent 2,874,174 discloses alkyl amides of N,N,N-tris(aminoalkyl)amines which are useful as binding agents for asphalt pavements. Summary of the Invention
- R 2 is (a) -H, (b) -C 1 -C 6 alkyl, (c) -(CH 2 ) m -N(R 4 )(R 5 ), (d) -(CH 2 ) m -N(R 4 )-Y 1 -R 5 , (e) -(CH 2 ) m -O-(CH 2 ) m -N(R 4 )(R 5 ), or (f) -(CH 2 ) m -NH-C(NH)-NH 2 ; or when X 1 is -NR 2 -, wherein R 1 and R 2 taken together cab be -(CH 2 ) q - X 3 -(CH 2 ) q -; wherein R 3 is
- -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to three of the following:
- Z 1 is C 8 -C 20 cycloalkyl, then one of the following must occur: a) R 1 is other than -H, C 1 -C 4 alkyl, or benzyl; b) R 2 is other than -H, -C 1 -C 6 alkyl or - (CH 2 ) m -NH-C(NH) - NH 2 ; c) when R 1 is - (CH 2 ) p -N(R 4 ) (R 5 ) or when R 2 is -(CH 2 ) m - N(R 4 )(R 5 ) or -(CH 2 ) m -O-(CH 2 ) m -N(R 4 )(R 5 ), then R 4 is other than -H,- C 1 -C 6 alkyl, -benzyl, or -phenyl and R 5 is other than -H or -C 1 -C 6 alkyl; d) when R 4 is other than
- 1,2-Ethanediamine N,N-bis(2-aminoethyl)-N'-cyclododecyl
- 1,2-Ethanediamine N-(2-aminoethyl)-N'-cyclododecyl-
- 1 ,2-Ethanediamine N,N-bis(2-aminoethyl)-N'-cyclohexyl-
- 1,3-Propanediamine N,N''-[2-(cyclododecylamino)ethylimino-di-2,1-ethanediyl]-bis-;
- 1,2-Ethanediamine N-cyclododecyl-N',N'-bis-2-(dimethylamino)-ethyl-N-methyl-; Octadecanamide, N-[2[bis(2-aminoethyl)amino]ethyl]-; and
- Octadecacamide N,N'-[[(2-aminoethyl)imino]di-2,1-ethanediyl]- bis-.
- a method of treating hypercholesterolemia in an affected patient which comprises administering to said patient an effective amount for reducing serum cholesterol in said patient of a member selected from the group consisting of the free bases and pharmaceutically acceptable salts of a compound of formula I wherein Z 1 is
- -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to three of the following:
- 1,2-Ethanediamine N,N-bis(2-aminoethyl)-N'-cyclohexyl-; 1,2-Ethanediamine, N,N-bis(2-aminoethyl)-N'-1,4-dioxaspiro-4.5-dec-8-yl-; 1,2-Ethanediamine, N,N-bis-2-(1,4-dioxaspiro-4.5-dec-8-ylamino)-ethyl-;
- amino acid residue is meant the naturally-occurring amino acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof. These compounds may be in L or D configuration and are well known and readily available to those skilled in the art.
- Acid salts are formed by reacting the compounds described herein with the appropriate acid in a suitable solvent.
- Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, hydrobromic, hydroiodic, acetic, lactic, citric, succinic, benzoic, salicylic, palmoic, cyclohexansulfamic, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, maleic, fumaric, or oxalic.
- Charts A, G, H, & I (Generic Charts)
- the compounds A-3, A-4 and A-5 are made from commercially available ketones or aldehydes A-1 (or readily synthesized ketones or aldehydes) and commercially available amines, by reductive amination methods (See R.F. Borch, M.D. Berstein, H.D. Durst, JACS , 93:2897-2904, 1971; and J.H. Billman, and A.O. Diesing, J.O.C, 22:1068-1070, 1957).
- the compounds G-3, G-5 and G-7 are made from esters or activated esters G-1, G-4 and G-6, and amines G-2, using the procedures set forth in A.L.J. Bechmith, in "The Chemistry of Amides”; J. Zuhicky, Ed., Interscience, New York, Chapter 2, 1970.
- the compound A-5 is elaborated by reacting free amines 1-1 (A-5) and H-1 (A-5) with unsaturated esters J-2 or nitriles H-2 for chain extended compounds 1-3 and H-3, respectively.
- the intermediate H-3 is then reduced to the corresponding final amine H-4.
- the intermediate 1-3 is further reacted with amine 1-4 to yield the final product 1-5.
- 1-5 is reduced to yield another final product 1-6.
- Chart B For the formation of compounds B-6, 2 equivalents of amine (B-2) to ketone (B-5) is optimum for the formation of mono-adducts. When 2 equivalents of amine B-2 are reacted with one equivalent of ketone B-5, a statistical 1:2:1 ratio of B-6:B-7:B-8 are formed. Further treatment of amine B-2 with 4 equivalents of ketone B-5 affords the tris-adduct B-8, with no trace of mono-adduct B-6.
- Chart B (Scheme 3) For the formation of compound B-10, 2 equivalents of amine to ketone is optimum for the formation of mono-adducts.
- Chart B (Schemes 4, 5 and 6) Additional analogs B-12, B-13, B-15, B-16, and B-18 are also synthesized by this method.
- the compound B-14 and B-17 are commercially available.
- Chart B Two open-chain analogs, B-20 and B-22, also are produced by this method.
- Chart C Reductive amination of aldehydes
- the compound C-3, wherein R is pentadecyl is formed by hydrogenating the imine derived from hexadecyl aldehyde and the amine C-2.
- imines see, S. Dayagi and Y. Degani, "The Chemistry of Carbon-Nitrogen Double Bond", S. Patai, Ed., Interscience: New York, 1970: Chapter 2.
- Other adducts as listed in the Table for Chart C are synthesized by the same method.
- Chart D Amide derivatives of simple amines are readily available by a number of methods. A.L.J. Beckwith, in "The Chemistry of Amides”; J. Zubicky, Ed., Interscience: New York, 1970: Chapter 2. Treatment of ester D-1 on a steam bath with amine D-2 yields the amide D-3 and the diamide D-4, that are separated by column chromatography. Chart D (Schemes 2 and 3)
- acylating agents such as acid chlorides D-5 and D-7 when treated with amine D-2, afford none of the monoacylated material.
- Chart D (Schemes 4 and 5) A method found to produce at least a statistical product distribution from polyamines consists of increasing the reaction dilution and decreasing the reactivity of the acylating agent.
- the compound D-9 and diamine D-10 yield mainly D-11 and some diacylated D-12.
- Anhydride D-9 and amine D-2 form the monoacylated compound D-13 and diacylated D-14.
- Chart E [Amine portion modification] [Amine chain extension] Selective Michael addition of 2 equivalents of acrylonitrile of E-2 to the primary amines of E-1, prepared as the compound B-16 In Chart B, form the compound E-3. Reduction of the nitriles with lithium aluminum hydride (LAH) produces the hexamine E-4. In a similar fashion, methyl acrylate E-5 and amine E-1 produce the diester E-6. Following chemistry developed to produce starburst or arborol compounds (D.A. Tomalia, et al., Polymer Journal 1985, 17, 117-132; G.R. Newkome, et al., J. Am. Chem. Soc. 1986, 108, 849-850.), the diester E-6 is treated with excess ethylenediamine to yield the amine extended analog E-7. Chart F (Schemes 1, 2 and 3)
- the Eschweiler-Clark reaction affords penta-alkylated amine F-3.
- the two less hindered amines of F-3 are selectively alkylated with 2 equivalents of methyl iodide to form F-4.
- the Eschweiler-Clark reaction is also employed to produce analog F-6.
- Control groups received diet D1 alone, and positive control groups received diet D1 mixed with colestipol hydrochloride) at an amount to provide a dose of 750 mg/kg/day. After two weeks on the diets, each bird was bled from the right jugular vein and serum samples were obtained after low speed centrifugation. Food intake was determined for each group by subtracting the weight of diet remaining at the end of the experiment from the weight of the starting diet.
- Beta- and alpha-lipoproteins were isolated from individual serum samples using PEG- 8000 and glycine buffer, pH 9. Three hundred microliters of serum were mixed with 300 microliters of solution A (20 gram of PEG- 8000 + 100 ml of glycine buffer, pH 9) using a Micromedic automatic pipette. Samples were allowed to stand at room temperature for 10 minutes and were then centrifuged for 20 minutes at 2000 ⁇ g at 4oC. The beta-lipoprotein pellet was dissolved in 300 microliters of solution B (10 ml Triton X-100 + 1000 ml Milli Q water).
- Cholesterol, triglycerides and total protein in alpha- and beta-lipoproteins were measured using the Demand Autoanalyzer Aystem Model AU 500 (Cooper Biomedical Inc.) and Worthington Demand Enzymatic reagents.
- the results of studies performed using SEA quail are shown in Table 1.
- the compound, N,N-bis(2-aminoethyl)-N'-cyclopentadecyl-1,2-ethanediamine administered at 150 mg/kg/day is about fifteen times more potent than colestipol hydrochloride; the effect of 150 mg/kg/-day of N,N-bis(2-aminoethyl)-N'-cyclopentadecyl-1,2-ethanediamine was similar to the effect of 2250 mg/kg/day colestipol hydrochloride.
- the results of studies performed in cholesterol-fed rats are shown in Table 2.
- the compound N,N-bis(2-aminoethyl)-N'-cyclopentadecyl-1,2-ethanediamine administered at 150 mg/kg/day is about five times more potent than colestipol hydrochloride; the effect of 150 mg/kg/day of N,N-bis(2-aminoethyl)-N'-cyclopentadecyl-1,2-ethanediamine was about half-way between the effects of 500 and 1000 mg/kg/day of colestipol hydrochloride.
- Table 2 are the results using N,N-bis[2-(cyclododecylamino)ethyl]-1,2-ethanediamine.
- This compound is about eight times more potent than colestipol hydrochloride; the effect of 60 mg/kg/day of N,N-bis[2-(cyclododecylamino)ethyl]-1,2-ethanediamine is very similar to the effect of 500 mg/kg/day of colestipol hydrochloride.
- the compounds used to practice the present invention lower cholesterol levels when the dose of the active ingredient varies from about 0.5 to about 5 gm, administered from one to three times daily.
- the preferred compounds of the present invention are:
- N,N-bis(2-cyclododecylamino)ethyl-1,2-ethanediamine are prepared from the following ingredients: N,N-bis(2-cyclododecylamino)ethyl- 1,2-ethanediamine 500 gm
- Ten thousand powder packets, each containing 1.25 gm of N,N-bis(2-cyclododecylamino)ethyl-1,2-ethanediamine hydrochloride are prepared from the following:
- Oil base qs 1,000 ml
- the oil base consists of equal parts of soybean oil and purified linseed oil gelled with 1% aluminum monostearate. Each 5 ml of base supplies 1.1 ml of linolenic acid. One or two teaspoonsful (5 or 10 ml) is administered three times a day with meals.
- Example 4 Aqueous dispersion
- N,N-bis(2-cyclododecylamino)ethyl-1,2-ethanediamine is prepared from the following materials: N,N-bis(2-cyclododecylamino)ethyl- 1,2-ethanediamine 1,000 gm
- Amine B-2 (39.1 g), methanol (800 ml), acetic acid (62 ml, and cyclopentadecanone B-1 (50.0 g) are combined. After 1.5 h, sodium cyano-borohydride (14.7 g) is added via Gooch tubing and the reaction is continued at room temperature. After 18 h the reaction is evacuated in vacuo. A solution of 10% sodium hydroxide (200 ml) is added to the solid. The aqueous portion is extracted with methylene chloride (3 ⁇ 400 ml). The combined organic fractions are dried, and concentrated in vacuo to 80.71 g.
- fraction A is chromato graphed on silicon dioxide (2.5 kg) and eluted with chloroform/-methanol/ammonium hydroxide (10/4/1) to yield fraction A (23.84 g) and the first title product (38.0 g), which is similar by NMR to material prepared previously. Fraction A is rechromatographed in the same solvent system to yield the second title product (8.0 g).
- Amine B-2 (18.28 g), methanol (900 ml), acetic acid (60 ml), and ketone B-5 (91.15 g) are combined. After 0.5 h, sodium cyanoborohydride (31.4 g) is added via Gooch tubing over several hours.
- the reaction is continued at room temperature for 18 h.
- the mixture is concentrated in vacuo and 20% sodium hydroxide (200 m) is added.
- the aqueous portion is extracted with hexane (3 ⁇ 200 ml) and the organic portions are combined and concentrated to 40.9 g.
- the aqueous portion is then extracted with chloroform (3 ⁇ 200 ml) and the organic fractions are combined and concentrated to 69.4 g. Since the TLC of both organic fractions shows a mixture of compounds, the material is combined and chromatographed on 2.5 kg of silicon dioxide eluting first with chloroform/methanol followed by chloroform/-methanol/ammonium hydroxide (10/4/1).
- the first compound eluted is identified as cyclododecanol (21.98 g).
- the second compound eluted is B-8 (66.9 g).
- the material is heated in a Kugelrohr oven (up to
- IR mineral oil mull: 3298, 2970, 1475, 1445, 1377, 1348, 1125, 1120, 1061, 793, 774, 741, 721 cm -1 .
- Example 17 12-[N',N'-bis(2-aminoethyl)-N-l,2-ethanediaminyl]octadecylamide (Formula B-20). Refer to Chart
- the amide B-19 (4.9 g) is added to a stirred solution of the amine B-2 (5.0 ml) and acetic acid (15.8 ml) in methanol (60 ml).
- the ketone B-21 (5.0 g) is added to a stirred solution of the amine B-2 (4.4 ml) and acetic acid (13.8 ml) in methanol (52.5 ml).
- the resulting yellow suspens ion is stirred at room temperature for 1 h.
- Sodium cyano-borohydride (0.925 g) is added portionwise and the solution is stirred overnight at room temperature.
- the solution is concentrated in vacuo.
- the residue is taken up in water (a small amount of chloroform is added to dissolve material that does not dissolve in water) and adjusted to pH 12 with 20% sodium hydroxide.
- the organic layer is removed, and the aqueous layer is extracted with chloroform (3 X 125 ml) .
- the organic layers are combined, dried with magnesium sulfate, filtered and concentrated in vacuo.
- the residue is chromatographed (silicon dioxide) eluting with chloroform/-methanol/ammonium hydroxide (10/4/1). The appropriate fractions are combined and concentrated in vacuo.
- Solvent traces are removed under high vacuum producing the very viscous, green oily title product (3.38 g).
- reaction mixture is filtered through a celite pad, and the pad is washed several times with diethyl ether.
- the filtrate is concentrated in vacuo producing a yellow oil (5.86 g).
- the residue is chromatographed eluting with chloroform/methanol/ammonium hydroxide, 10/4/1. The appropriate fractions are combined and concentrated in vacuo yielding the product as an off-white foam. Solvent traces are removed under high vacuum affording the title product (1.13 g).
- Octanal C-1 (wherein R 1 is CH 3 -(CH 2 ) 6 -) (5.0 g), amine C-2 (11.7 ml) and p-toluenesulfonic acid (0.5 g) are dissolved in toluene (400 ml) and heated to reflux with azeotropic removal of water for 18 h. The solution is cooled to room temperature and concentrated in vacuo.
- the residue is dissolved in absolute ethanol (200 ml) and hydrogenated over 10% Pd/C at 50 psi for 48 h.
- the reaction mixture is filtered through a Celite pad, and the pad is washed with diethyl ether.
- the filtrated is concentrated in vacuo producing a yellow residue.
- the residue is chromatographed eluting with chloroform/-methanol/ammonium hydroxide, 10/4/1. The appropriate fractions are combined and concentrated in vacuo yielding a yellow-green oil.
- Example 22 N,N-bis(2-aminoethyl)-N'-(2-trifluoromethyl)- phenylmethyl)-1,2-ethanediamine (Formula C-3: wherein R 1 is O-CF 3 -C 6 H 4 -).
- the amine C-2 (8.6 ml) is added to a solution of 2-trifluoromethylbenzaldehyde C-1 (wherein R 1 is O-CF 3 -C 6 H 4 -) (5.0 g) in toluene (290 ml).
- p-Toluenesulfonic acid (0.50 g) is added to the resulting solution.
- the solution is stirred and heated at reflux with azeotropic removal of water overnight.
- the solution is concentrated in vacuo producing a yellow-orange residue.
- the residue is dissolved in absolute ethanol (95 ml) and hydrogenated over 10% Pd/C (1.3 g) at 50 psi overnight.
- the reaction mixture is filtered though a celite pad, the pad is washed with diethyl ether and the filtrate is concentrated in vacuo.
- the residue was chromatographed eluting with chloroform/-methanol/ammonium hydroxide, 10/4/1. The appropriate fractions are combined and concentrated in vacuo producing a yellow oil. Solvent traces are removed under high vacuum from the title product (5.95 g).
- the amine D-2 (2.92 g) and methyl octadecanoate D-1 (2.98 g) are heated on a steam bath, under nitrogen, for 24 h.
- the resulting solid is heated in water and is then filtered to remove excess amine.
- the solid is chromatographed on silicon dioxide (40 g), eluting first with methanol/chloroform, followed by chloroform/methanol/ammonium hydroxide, 10/4/1.
- the diamide D-4 (0.66 g) elutes first followed by the amide D-3 (1.89 g).
- Example 26 N[2-[-bis(2-aminoethyl)amino]ethyl]benzamide (Formula D-13); and N,N'-(((2-aminoethyl)imino)- di-2,1-ethanediyl)bis-benzamide (Formula D-14).
- Benzoic anhydride 5.0 g
- methylene chloride 250 ml
- methylene chloride 850 ml
- the solution is allowed to warm to room temperature and is stirred overnight.
- N,N'-1,8-octanediylbis-benzamide (Formula D-12). Refer to Chart D (Scheme 4). A solution of benzoic anhydride D-9 (1.00 g) In methylene chloride (110 ml) is added dropwise to a vigorously stirred solution of the amine D-10 (1.27 g) in methylene chloride (330 ml) at -78oC over a period of 45 min. The resulting suspension is allowed to stir at room temperature overnight. The reaction mixture is extracted with 5% aqueous hydrochloric acid (2 X 300 ml). The organic layers are combined and concentrated in vacuo producing a white solid which cannot be further purified due to its insolubility.
- the HCl layer is adjusted to pH 11 with ammonium hydroxide and extracted with methylene chloride (3 X 300 ml).
- the organic layers are combined and concentrated in vacuo producing an off-white solid which is chromatographed eluting with chloroform/methanol/ammonium hydroxide, 20/8/1.
- a small amount of the second title product (0.068 g) is isolated off the column.
- Ammonium chloride (20 ml) is used to quench the reaction and 20% sodium hydroxide is used to bring the mixture to pH 12.
- the aluminum salts are removed by filtration and the filtrate is extracted with chloroform (3 x 150 ml) .
- the organic layers are combined, dried, and concentrated to provide the title product (3.3 g).
- Ethylene diamine (49.4 g) is added to a solution of the title product of Example 30 (5.0 g) in methanol (105 ml). The reaction is stirred at room temperature for 4 days. The solution is concentrated in vacuo and solvent traces are removed under high vacuum producing the title product as a green oil (4.39 g).
- Example 33 2,2'-[2-(Cyclododecylmethylamino)ethyl-imino]- bis-N,N,N-trimethylethanaminium diiodide (Formula F-4). Refer to Chart F (Scheme 2). The title product of Example 32 (1.0 g) and acetonitrile (250 ml) are combined. Methyl iodide (740 mg) in acetonitrile (1 ml) is added to the reaction. After 14 hr, a white solid is present In the flask. The contents of the flask are concentrated in vacuo to yield 1.67 g of the title product.
- Serum lipoprotein cholesterol in SEA quail fed 0.5% cholesterol-1% peanut oil Effect of bile acid binding compounds
- Example 7 150 10 162 77** 243** (1st cpd.) 10 10 239 299 567 30 10 243 325 590 100 10 280* 191 481 300 10 194 60** 256** 150 10 179 80** 264**
- Example 8 150 10 209 166 415 30 10 273 332 638 100 10 279 166 455 300 10 219 65** 289** 200 10 205 116** 326
- Serum lipoprotein cholesterol in SEA quail fed 0.5% cholesterol-1% peanut oil Effect of bile acid binding compounds
- Example 22 50 10 222 212 455
- Example 18 50 10 223 251 490
- Example 23 100 10 206 173 398
- Priority Country US Upjohn Company, Kalamazoo, MI 49001 (US).
- This invention relates to novel lipophilic polyamides of the formula Z]-(CH ) n -Y ⁇ -X ⁇ -R], the method of using the compounds to treat hypercholesterolemia, and intermediates thereto.
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019890701908A KR900700433A (ko) | 1988-02-19 | 1989-10-18 | 과 콜레스테롤 혈증 치료에 유용한 친지성 폴리아민 |
DK196990A DK196990D0 (da) | 1988-02-19 | 1990-08-17 | Lipofile polyaminer, der er anvendelige til behandling af hypercholesterolaemia |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US15821388A | 1988-02-19 | 1988-02-19 | |
US158,213 | 1988-02-19 |
Publications (2)
Publication Number | Publication Date |
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WO1989008098A2 true WO1989008098A2 (en) | 1989-09-08 |
WO1989008098A3 WO1989008098A3 (en) | 1989-11-02 |
Family
ID=22567128
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1989/000490 WO1989008098A2 (en) | 1988-02-19 | 1989-02-13 | Lipophilic polyamines useful for treating hypercholesterolemia |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0424385A1 (da) |
JP (1) | JPH03502796A (da) |
KR (1) | KR900700433A (da) |
AU (1) | AU3203489A (da) |
DK (1) | DK196990D0 (da) |
WO (1) | WO1989008098A2 (da) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997030024A2 (de) * | 1996-02-13 | 1997-08-21 | Andrej Sourovoi | Lipidverbindungen und deren verwendung z.b. in liposomen |
US5693769A (en) * | 1991-12-13 | 1997-12-02 | Transcell Technologies, Inc. | Glycosylated steroid derivatives for transport across biological membranes and process for making and using same |
US5795870A (en) * | 1991-12-13 | 1998-08-18 | Trustees Of Princeton University | Compositions and methods for cell transformation |
FR2802817A1 (fr) * | 1999-12-23 | 2001-06-29 | Centre Nat Rech Scient | Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete |
WO2006090289A3 (en) * | 2005-02-28 | 2006-12-07 | Alphabeta Ab | Compounds for reducing aggregation of amyloid beta-peptide |
WO2010108108A3 (en) * | 2009-03-20 | 2011-04-07 | Egen, Inc. | Polyamine derivatives |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1065248A (fr) * | 1951-04-16 | 1954-05-21 | Ciba Geigy | Procédé pour la préparation de nouvelles trialcoylamines |
WO1987002367A2 (en) * | 1985-10-18 | 1987-04-23 | The Upjohn Company | Cyclic hydrocarbons with an aminoalkyl sidechain |
-
1989
- 1989-02-13 WO PCT/US1989/000490 patent/WO1989008098A2/en not_active Application Discontinuation
- 1989-02-13 JP JP1502873A patent/JPH03502796A/ja active Pending
- 1989-02-13 AU AU32034/89A patent/AU3203489A/en not_active Abandoned
- 1989-02-13 EP EP89903382A patent/EP0424385A1/en not_active Withdrawn
- 1989-10-18 KR KR1019890701908A patent/KR900700433A/ko not_active Application Discontinuation
-
1990
- 1990-08-17 DK DK196990A patent/DK196990D0/da not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1065248A (fr) * | 1951-04-16 | 1954-05-21 | Ciba Geigy | Procédé pour la préparation de nouvelles trialcoylamines |
WO1987002367A2 (en) * | 1985-10-18 | 1987-04-23 | The Upjohn Company | Cyclic hydrocarbons with an aminoalkyl sidechain |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5693769A (en) * | 1991-12-13 | 1997-12-02 | Transcell Technologies, Inc. | Glycosylated steroid derivatives for transport across biological membranes and process for making and using same |
US5795870A (en) * | 1991-12-13 | 1998-08-18 | Trustees Of Princeton University | Compositions and methods for cell transformation |
WO1997030024A2 (de) * | 1996-02-13 | 1997-08-21 | Andrej Sourovoi | Lipidverbindungen und deren verwendung z.b. in liposomen |
WO1997030024A3 (de) * | 1996-02-13 | 1997-09-25 | Andrej Sourovoi | Lipidverbindungen und deren verwendung z.b. in liposomen |
US6458381B1 (en) | 1996-02-13 | 2002-10-01 | Andrej Sourovoi | Lipids and their use, for example, in liposomes |
WO2001047528A3 (fr) * | 1999-12-23 | 2002-06-20 | Centre Nat Rech Scient | Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete |
WO2001047528A2 (fr) * | 1999-12-23 | 2001-07-05 | Centre National De La Recherche Scientifique | Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete |
FR2802817A1 (fr) * | 1999-12-23 | 2001-06-29 | Centre Nat Rech Scient | Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete |
WO2006090289A3 (en) * | 2005-02-28 | 2006-12-07 | Alphabeta Ab | Compounds for reducing aggregation of amyloid beta-peptide |
WO2010108108A3 (en) * | 2009-03-20 | 2011-04-07 | Egen, Inc. | Polyamine derivatives |
US8460696B2 (en) | 2009-03-20 | 2013-06-11 | Egen, Inc. | Polyamine derivatives |
US8900621B2 (en) | 2009-03-20 | 2014-12-02 | Clsn Laboratories, Inc. | Polyamine derivatives |
US8932638B2 (en) | 2009-03-20 | 2015-01-13 | Clsn Laboratories, Inc. | Polyamine derivatives |
US9254334B2 (en) | 2009-03-20 | 2016-02-09 | Clsn Laboratories, Inc. | Polyamine derivatives |
Also Published As
Publication number | Publication date |
---|---|
WO1989008098A3 (en) | 1989-11-02 |
DK196990A (da) | 1990-08-17 |
DK196990D0 (da) | 1990-08-17 |
JPH03502796A (ja) | 1991-06-27 |
AU3203489A (en) | 1989-09-22 |
EP0424385A1 (en) | 1991-05-02 |
KR900700433A (ko) | 1990-08-13 |
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