WO2005014528A1 - Straight-chain and branched-chain lipid compounds as selective inhibitors of cyclooxygenase-2, anti-inflammatory agents, and anti-cancer agents - Google Patents

Straight-chain and branched-chain lipid compounds as selective inhibitors of cyclooxygenase-2, anti-inflammatory agents, and anti-cancer agents Download PDF

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WO2005014528A1
WO2005014528A1 PCT/US2004/019101 US2004019101W WO2005014528A1 WO 2005014528 A1 WO2005014528 A1 WO 2005014528A1 US 2004019101 W US2004019101 W US 2004019101W WO 2005014528 A1 WO2005014528 A1 WO 2005014528A1
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Zhenhua Yang
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Zhenhua Yang
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • 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
    • C07C211/13—Amines containing three or more amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—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
    • 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
    • C07C229/24—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 more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/14—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine

Definitions

  • This invention is directed to a group of selective cyclooxygenase-2 (COX-2) inhibitors, which are unique straight-chain or branched-chain lipid compounds. Those selective COX-2 inhibitors can be used as anti-inflammatory agents and cancer treatment and prevention drugs.
  • COX-2 selective cyclooxygenase-2
  • Such compounds were further illustrated by 9 typical structure formulae in Applicant's application PCT/US02/24296, filed on August 2, 2002 and published as WO 03/014296 on February 20, 2003.
  • COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins (such as PGE ) and other eicosanoids. This enzyme is expressed in a number of tumor cells.
  • PGE prostaglandins
  • U.S. patent No. 6,486,204 disclosed treatment or prevention of prostate cancer using rofecoxib, a COX-2 selective inhibiting drug. This patent is hereby incorporated by reference.
  • COX-2 selective cyclooxygenase-2
  • COX-2 inhibitors which are unique lipid compounds and expressed as the derivatives of branched or straight-chain, fatty amines or fatty amides, or pharmaceutically acceptable salts thereof.
  • COX-2 inhibitors as anti-inflammatory agents and cancer treatment and prevention drugs.
  • the invention encompasses a unique branched-chain lipid compound as selective COX-2 inhibitor. It is a derivative compound from a branched-chain fatty amine or a branched-chain fatty amide, or a pharmaceutically acceptable salt thereof.
  • the invention will now be illustrated by the following non-limiting formula (1) - (12), where CH 3 C n H 2n-2 m- is defined as branched saturated or unsaturated alkyl chain with any branched terminal type like those listed in WO 03/014296, including isopropyl, sec-butyl, tert.
  • n 3 - 25
  • m 0 - n/2, preferably 0 - 4, and any -H in the alkyl chain can be replaced by -OH, -Cl, -Br, F, or -I.
  • the invention includes all the isomers and pharmaceutically acceptable salts of the compounds above, including geometrical isomers and their racemates.
  • the derivatives from a branched-chain fatty amine or a branched-chain fatty amide have other configurations, not limited to the formulae (1) - (12) above.
  • the inventor also found that straight chain analogs of the branched-chain fatty amine and branched-chain fatty amide derivatives had selective COX-2 inhibition effects and/or anti-cancer effects.
  • branched-chain compounds of the present invention can be prepared according to the following synthetic methods, which have been well understood by skilled chemical technicians.
  • Method 1 the compounds of the formula (1) can be prepared synthetically through the reaction of isoaliphatic acyl chloride and diethanolamine, amino-of which had been protected with benzaldehyde, then acylation reaction, and finally hydrolysis with acid. This method is demonstrated in Example 1.
  • Method 2 the compounds of the formula (2) can be prepared synthetically through the reaction of chloroiso fatty hydrocarbon and diethylenetriamine amino-of which had been protected with benzaldehyde, then acylation reaction, and finally hydrolysis with acid. This method is demonstrated in Example 2.
  • Method 3 the compounds of the formula (3) can be prepared synthetically through the reaction of p-nitrophenyl iso aliphatatate and guanidine. This method is demonstrated in Example 3.
  • Method 4 the compounds of the formula (4) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and guanidine. This method is demonstrated in Example 4.
  • Method 5 the compounds of the formula (5) can be prepared synthetically through the reaction of p-nitrophenyl iso aliphatatate and guanamine. This method is demonstrated in Example 5.
  • Method 6 the compounds of the formula (6) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and guanamine. This method is demonstrated in Example 6.
  • Method 7 the compounds of the formula (7) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and hydrazine acetic acid. This method is demonstrated in Example 7.
  • Method 8 the compounds of the formula (8) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and hydrazine hydrate. This method is demonstrated in Example 8.
  • Method 9 the compounds of the formula (9) can be prepared synthetically through the reaction of the product of the formula(l) and chloroacotic acid. This method is demonstrated in Example 9.
  • Method 10 the compounds of the formula (10) can be prepared synthetically through the reaction of isoaliphaticacyl chloride and diethanolamine, then chlorinated with thionyl chloride, and finally reacted with diethanolamine again. This method is demonstrated in Example 10.
  • Method 11 the compounds of the formula (11) can be prepared synthetically through the reaction of the product of the formula (2) and chloroacetic acid. This method is demonstrated in Example 11.
  • Method 12 the compounds of the formula (12) can be prepared synthetically through the reaction of the product of the formula (2) and chloroethanol. This method is demonstrated in Example 12.
  • Example 1 preparation of 13-Methyl tetradecanoyl-N,N-di(2-amino ethyl) amine dihydrochloride
  • 13-methyltetradecanoyl chloride was added dropwise into a 500 ml flask containing 11.4 g (0.082 mol) of 3-nitrophenol and 100 ml of benzene while stirring for 4 hours. After filtrating, washing the filter cake, and crystallizing, 13.0 g (0.036 mol) of 3-nitrophenyl-13-methyltetradecanoate was produced. A mixture of 13.0g of 3-nitrophenyl-13-methyltetradecanoate obtained above and 11.9 g (0.108 mol) of guanamine hydrochloride was heated and refluxed with 100 ml of 95% alcohol for 5 hours.
  • Example 7 preparation of lN-(ll-m ethyl lauryl)-2N-carboxym ethyl hydrazine NH 2 -NH 2 + CI-CHXOOH NH 2 -NH-CH 2 COOH
  • Example 9 preparation of 13-Methyl tetradecanoyl -N,N-di-[ dicarboxymethyl amino ethyl] amine
  • 13-methyltetradecanoyl chloride was added dropwise into a solution of 108.15 g (1.03 mol) of diethanolamine in benzene. Removing benzene by distilling under reduced pressure (water aspirator), cooling, the solid product was obtained through filtrating under reduced pressure. After dissolving those products in 95%) alcohol, decoloring with activated charcoal, crystallizing and drying, 72.70 g (0.22 mol) of 13-methyltetradecanoyl diethanolamine was produced. 78.89g of thionyl chloride was added dropwise into those 13-methyltetradecanoyl diethanolamine while stirring, and then refluxed for another 1 hour.
  • Example 11 preparation of N-(ll-methyl lauryl) -N,N-di-[ dicarboxymethyl amino ethyl] amine
  • Example 12 preparation of N-(ll-methyl lauryl) -N,N-di-[ di(hydroxyl ethyl) amino ethyl] amine
  • COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins (such as PGE 2 ) and other eicosanoids. In the present application, the measurement of changes of PGE 2 production will be used to indicate the inhibition effects. This enzyme is expressed in a number of tumor cells.
  • the invention encompasses a method of treating a patient for a cyclooxygenase mediated disease comprising administering to a patient in need of such treatment the present unique branched-chain lipid compounds in an amount which is effective for treating said cyclooxygenase mediated disease, such as osteoarthritis, or rheumatoid arthritis.
  • the invention also encompasses a method of treating inflammation in a patient in need of such treatment comprising administering to said patient the present unique branched-chain lipid compounds in an amount effective for treating inflammation.
  • the invention also encompasses a pharmaceutical composition comprising a compound according to the invention in combination with a pharmaceutically acceptable carrier.
  • Example 13 Present compounds selectively inhibited COX-2 activity measured by PGE 2 production in human prostate cancer PC3 cells
  • Sample #1 N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride
  • Sample #2 N-(l 1-methyl lauryl)hydrazine dihydrochloride
  • Sample #3 13-Methyl tetradecanoyl -N,N-di (2-amino ethyl) amine dihydrochloride
  • Sample #4 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine
  • Sample #5 13-Methyl tetradecanoyl guanidine hydrochloride.
  • the PC3 cells (1 x 10 6 ) were plated in 100-mm tissue culture dishes overnight. On day 2, cells were treated with arachidonic acid (AA, 10 ⁇ M) as control or a combination of one of the samples above in different concentrations and AA for 2 hrs at 37°C. After 2 hrs, aliquots of the culture medium were taken, and eicosanoids were extracted.
  • PGE 2 prostaglandin E 2
  • RP-HPLC reversed-phase high-performance liquid chromatography
  • Example 14 Present compounds selectively inhibited COX-2 activity measured by PGE 2 production in human hepatoma Hep3B cells
  • Example 13 The compounds in Example 13 above were also tested to measure their effect on the formation of eicosanoids PGE 2 in the human hepatoma Hep3B cells.
  • the tested compounds were listed as following: Sample #1: N,N-di(2-amino ethyl)- 11-methyl -lauryl amine trihydrochloride
  • Sample #2 N-(l 1-methyl lauryl)hydrazine dihydrochloride
  • Sample #3 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride
  • Sample #4 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine
  • Sample #5 13-Methyl tetradecanoyl guanidine hydrochloride.
  • Example 15 N-(ll-methyl lauryl)hydrazine dihydrochloride selectively inhibited COX-2 activity, but not COX-1 activity measured by PGE 2 production
  • ovine COX-1 and human recombinant COX-2 (5 units, Cayman Chemicals, MI) were tested.
  • the enzymes were pre-incubated with the sample at concentrations 2.5, 5.0, 10.0 and 20.0 ⁇ g/ml, for 10 min. followed by further incubation with 50 ⁇ M of arachidonic acid (AA) for 5 min at 37°C.
  • the reaction was stopped by adding 1 N citric acid.
  • 0.1 % BHT and PGE 2 -d4 were added and PGE 2 was extracted and analyzed.
  • the other compounds of the present invention have also shown selective COX-2 inhibition effects in measurements.
  • Arachidonate metabolism and cancer elevated COX-2 and PGE 2 levels have been reported in a number of human malignancies including colon, lung, head and neck, breast, pancreatic, bladder and prostate tumors.
  • the present compounds as selective COX-2 inhibitors have significant inhibitory effects on the growth of mouse and human tumor cells in vitro and in vivo shown in the following examples. The compounds and the types of cancer will not been limited to those below.
  • Example 16 In vivo test on the anticancer effects of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride in mouse sarcoma Siso model
  • mice 50 male mice, weighing 18-22 g, were randomized into 5 groups of 10 each.
  • S 18 o sarcoma mass (about 2 mm 3 each) was transplanted subcutaneously (s.c.) into the right armpits of all animals following standard procedure.
  • 3 test groups were given 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (sample) at 0.12, 0.24, and 0.36 g/kg intragastrically (i.g.) and the negative control group was given water 0.3 ml/lOg daily for 10 days.
  • the positive control group was given a single dose of cyclophosphamide (CTX) i.g.
  • Example 17 In vivo test on the anticancer effects of N,N-di(2-amino ethyl)-ll-methyl-lauryl amine trihydrochloride in mouse sarcoma Siso model
  • mice 50 male mice, weighing 18-21 g, were randomized into 5 groups of 10 each.
  • S 180 sarcoma mass (about 2 mm 3 each) was transplanted subcutaneously (s.c) into the right armpits of all animals following standard procedure.
  • 3 test groups were given N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride (sample) at 20, 30, and 40 mg/kg intragastrically (i.g.) and the negative control group was given water 0.3 ml/lOg daily for 13 days.
  • the positive control group was given a single dose of cyclophosphamide (CTX) i.g. (30 mg/kg) on day 1, day 3 and day 5.
  • CTX cyclophosphamide
  • Example 18 In vivo test on the anticancer effects of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride in mouse cervical carcinoma U 14 model
  • mice 50 female mice, weighing 18-22 g, were randomized into 5 groups of 10 each.
  • U 14 cervical carcinoma suspension 0.2 ml (about 10 7 /mm 3 ) was transplanted subcutaneously (s.c.) into the right armpits of all animals following standard procedure.
  • 3 test groups were given 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (sample) at 120, 240, and 360 mg/kg intragastrically (i.g.) and the negative control group was given water 0.3 ml/lOg daily for 10 days.
  • the positive control group was given a single dose of cyclophosphamide (CTX) i.g.
  • Example 19 In vitro test on the anticancer effects of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride against the growth of various human and mouse cancer cell lines
  • All human and mouse cancer cell cultures and subcultures were established according to standard procedures.
  • the adherent cells were incubated in sealed culture flask at 37°C.
  • the suspension cells in culture flask with a screwed cap were incubated in 5% CO 2 atmosphere at 37°C.
  • the culture medium was RPMI 1640 supplemented with 15%> deactivated fetal bovine serum, and was refreshed every three days.
  • the subcultures were established by treating the cells with 0.25% trypsin every week for adherent cells, and by centrifugation for suspension cells, respectively. Log-phase growing cells after 24 ⁇ 48 hours subculturing were used in this test, at a density of 1 x 10 5 cells/ml.
  • Suspension cells were seeded in triplication onto 40-well plates at 0.18 ml/well. After incubation at 37°C with 5% CO 2 in atmosphere for 12 hours, cells were treated with a series of 5-6 different concentrations of 13-Methyl tetradecanoyl -N,N-di (2-amino ethyl) amine dihydrochloride (sample) (20 ⁇ l/well). Same volume of normal saline (NS) only was used in control groups. After 24 hours of incubation, numbers of live cells in each well were counted by trypan blue dye exclusion. Rates of inhibition at different drug concentrations were calculated by linear regression analysis.
  • Adherent cells were diluted into 1 x 10 5 /ml and seeded in triplication onto 96-well plates at 0.18 ml/well.
  • the cells in test groups were treated with a series of 5 ⁇ 6 different concentrations of the sample (20 ⁇ l/well), and the cells in control group were added with same volume of NS. In the blank wells, there were no cells but medium.
  • 20 ⁇ l of 5 mg fresh MTT solution was added to each well.
  • 150 ⁇ l DMSO was added into each well and shaken for 10 minutes to fully dissolve the precipitate.
  • Example 20 Comparison of in vitro anticancer effects of N,N-di(2-amino ethyl)-ll-methyl-lauryl amine trihydrochloride, N-(ll-methyl lauryl)hydrazine dihydrochloride and 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride against the growth of various human cancer cell lines
  • Example 3 To compare the in vitro anticancer effects of N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride (sample 1), N-(l 1-methyl lauryl)hydrazine dihydrochloride (sample 2), and 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (sample 3) against the growth of various human cancer cell lines, the same test procedure was used as in Example 19 above. The results were shown in Table 8 below.
  • N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride Use the same method in Example 2 above for preparation of N, N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride except that 11 -methyl lauryl chloride, a material used in second step, is replaced by tetradecyl chloride. N,N-di(2-amino ethyl)- tetradecyl amine trihydrochloride was obtained.

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Abstract

Unique branched-chain lipid compounds are disclosed as selective COX-2 inhibitors, which are derivatives of a branched-chain fatty amine or a branched-chain fatty amide, or a pharmaceutically acceptable salt thereof. The compounds can be used for osteoarthritis and rheumatoid arthritis as anti-inflammatory agents, in addition to treating and preventing cancer. Straight-chain analogs of the branched-chain lipid compounds provide similar uses.

Description

STRAIGHT-CHAIN AND BRANCHED-CHAIN LIPID COMPOUNDS AS SELECTIVE INHIBITORS OF CYCLOOXYGENASE-2, ANTI-INFLAMMATORY AGENTS, AND ANTI-CANCER AGENTS
This application claims the benefit of U.S. Provisional Application 60/488,807, filed July 22, 2003, which application is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
Field of the Invention:
This invention is directed to a group of selective cyclooxygenase-2 (COX-2) inhibitors, which are unique straight-chain or branched-chain lipid compounds. Those selective COX-2 inhibitors can be used as anti-inflammatory agents and cancer treatment and prevention drugs.
Description of the Background: A group of branched-chain lipids, which are specific iso- and anteiso- branched-chain fatty acids with significant anti-cancer effects, has been described in Applicant's U.S. patent No. 6,214,875. Such compounds as described in the above Applicant's U.S. patent, and derivatives thereof obtained by reacting the acid moiety thereof, are described in Applicant's U.S. Application 09/647,918, which is the application of PCT/US99/06525, filed on April 14, 1999, and which was published as WO 99/53086 on October 21, 1999, which WO 99/53086 is hereby incorporated by reference. Applicant's application PCT/USOl/00683, filed on February 7, 2001 and published as WO 01/59067 on August 16, 2001, described a group of anti-cancer compounds which are comprised of three parts: an end-terminal group, which is isopropyl, sec-butyl, or tert. -butyl group; a leading group; and a long-chain aliphatic, non-cyclic, saturated or unsaturated, hydrocarbon group that links the end-terminal group and the leading group. Such compounds were further illustrated by 9 typical structure formulae in Applicant's application PCT/US02/24296, filed on August 2, 2002 and published as WO 03/014296 on February 20, 2003. Both WO 01/59067 and WO 03/014296 are hereby incorporated by references. However, none of Applicant's previous patent and applications disclosed the present discovery that the derivatives of a branched-chain fatty amine or a branched-chain fatty amide selectively inhibit cyclooxygenase-2 (COX-2) activity, in addition to inhibit the growth of cancer cells. For about two years, selective inhibitors of COX-2 have been hailed as powerful additions to the armamentarium of non-steroidal anti-inflammatory drugs (NSAIDs). Two so-called coxibs are now widely utilized clinically: rofecoxib (Vioxx, Merck) and celeoxib (Celebrex, Pfizer). Either old NSAID such as aspirin or new coxibs have some side effects, especially due to inhibition of COX-1. COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins (such as PGE ) and other eicosanoids. This enzyme is expressed in a number of tumor cells. U.S. patent No. 6,486,204 (Waldstreicher, et al., Merck) disclosed treatment or prevention of prostate cancer using rofecoxib, a COX-2 selective inhibiting drug. This patent is hereby incorporated by reference. However, none of the above prior art recognizes the unique lipids chemically described as the derivatives of a branched-chain fatty amine or a branched-chain fatty amide, or their corresponding straight-chain analogs, as selective COX-2 inhibitors.
SUMMARY OF THE INVENTION
A group of selective cyclooxygenase-2 (COX-2) inhibitors, which are unique lipid compounds and expressed as the derivatives of branched or straight-chain, fatty amines or fatty amides, or pharmaceutically acceptable salts thereof. The use of those selective COX-2 inhibitors as anti-inflammatory agents and cancer treatment and prevention drugs. DETAILED DESCRIPTION OF THE INVENTION
It should be presumed below that any differences between a chemical structure and its chemical name be resolved in favor of the chemical structure. The invention encompasses a unique branched-chain lipid compound as selective COX-2 inhibitor. It is a derivative compound from a branched-chain fatty amine or a branched-chain fatty amide, or a pharmaceutically acceptable salt thereof. The invention will now be illustrated by the following non-limiting formula (1) - (12), where CH3CnH2n-2m- is defined as branched saturated or unsaturated alkyl chain with any branched terminal type like those listed in WO 03/014296, including isopropyl, sec-butyl, tert. -butyl, and the like, n = 3 - 25, m = 0 - n/2, preferably 0 - 4, and any -H in the alkyl chain can be replaced by -OH, -Cl, -Br, F, or -I.
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000004_0004
Figure imgf000005_0001
CH3
Figure imgf000005_0002
CH3CnH2n.2m NH-NH-CH2COOH (7)
CH Z,Cn nH* "2.1-2™ NH-NH- (8)
Figure imgf000005_0003
Figure imgf000005_0004
CHXOOH CHXH2N< N CH2COOH
CH3 CnH2n.2m N rnnw XCH2CH2N<CH2COOH CH2COOH (11) CH2CH2OH CH2CH2N < CH2CH2OH CH, Cn nH' '2n-2m N \ XH2CH2OH CHXH2N < CH2CH2OH (12)
The invention includes all the isomers and pharmaceutically acceptable salts of the compounds above, including geometrical isomers and their racemates. The derivatives from a branched-chain fatty amine or a branched-chain fatty amide have other configurations, not limited to the formulae (1) - (12) above. The inventor also found that straight chain analogs of the branched-chain fatty amine and branched-chain fatty amide derivatives had selective COX-2 inhibition effects and/or anti-cancer effects. Thus, CH3CnH2n- m- may be defined as saturated or unsaturated alkyl chain, n = 3 - 25, m = 0 - n/2, preferably 0 - 4, and any -H in the alkyl chain can be replaced by -OH, -Cl, -Br, F, or -I.
Exemplifying the invention are examples hereinunder which include: (1'): 13 -Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride
Figure imgf000006_0001
(2'): N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride
Figure imgf000006_0002
(3'): 13 -Methyl tetradecanoyl guanidine hydrochloride
Figure imgf000007_0001
(4'): N-(l 1 -methyl lauryl) guanidine hydrochloride
Figure imgf000007_0002
(5'): 13 -Methyl tetradecanoyl guanamine hydrochloride
Figure imgf000007_0003
(6'): N-(l 1 -methyl lauryl) guanamine hydrochloride
Figure imgf000007_0004
(7'): 1N-(11 -methyl lauryl)-2N-carboxymethyl hydrazine
Figure imgf000007_0005
(81): N-(l 1 -methyl lauryl)hydrazine dihydrochloride
Figure imgf000007_0006
(9'): 13 -Methyl tetradecanoyl -N,N-di-[ dicarboxymethyl a ino ethyl] amine
Figure imgf000008_0001
(10'): 13-Methyl tetradecanoyl -N,N-di-[N,N-di(hydroxyl ethyl)amino ethyl] amine
Figure imgf000008_0002
(I V): N-(l 1 -methyl lauryl) -N,N-di-[ dicarboxymethyl amino ethyl] amine
Figure imgf000008_0003
(12'): N-(l 1 -methyl lauryl) -N,N-di-[ di(hydroxyl ethyl)amino ethyl] amine
Figure imgf000008_0004
The branched-chain compounds of the present invention can be prepared according to the following synthetic methods, which have been well understood by skilled chemical technicians.
Method 1 : the compounds of the formula (1) can be prepared synthetically through the reaction of isoaliphatic acyl chloride and diethanolamine, amino-of which had been protected with benzaldehyde, then acylation reaction, and finally hydrolysis with acid. This method is demonstrated in Example 1. Method 2: the compounds of the formula (2) can be prepared synthetically through the reaction of chloroiso fatty hydrocarbon and diethylenetriamine amino-of which had been protected with benzaldehyde, then acylation reaction, and finally hydrolysis with acid. This method is demonstrated in Example 2. Method 3: the compounds of the formula (3) can be prepared synthetically through the reaction of p-nitrophenyl iso aliphatatate and guanidine. This method is demonstrated in Example 3. Method 4: the compounds of the formula (4) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and guanidine. This method is demonstrated in Example 4. Method 5: the compounds of the formula (5) can be prepared synthetically through the reaction of p-nitrophenyl iso aliphatatate and guanamine. This method is demonstrated in Example 5. Method 6: the compounds of the formula (6) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and guanamine. This method is demonstrated in Example 6. Method 7: the compounds of the formula (7) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and hydrazine acetic acid. This method is demonstrated in Example 7. Method 8: the compounds of the formula (8) can be prepared synthetically through the reaction of chloro iso fatty hydrocarbon and hydrazine hydrate. This method is demonstrated in Example 8. Method 9: the compounds of the formula (9) can be prepared synthetically through the reaction of the product of the formula(l) and chloroacotic acid. This method is demonstrated in Example 9. Method 10: the compounds of the formula (10) can be prepared synthetically through the reaction of isoaliphaticacyl chloride and diethanolamine, then chlorinated with thionyl chloride, and finally reacted with diethanolamine again. This method is demonstrated in Example 10. Method 11: the compounds of the formula (11) can be prepared synthetically through the reaction of the product of the formula (2) and chloroacetic acid. This method is demonstrated in Example 11. Method 12: the compounds of the formula (12) can be prepared synthetically through the reaction of the product of the formula (2) and chloroethanol. This method is demonstrated in Example 12.
Example 1: preparation of 13-Methyl tetradecanoyl-N,N-di(2-amino ethyl) amine dihydrochloride
Figure imgf000010_0001
309.0 g (3.0 mol) of diethylenetriamine was added into a 2000-ml three-necked flask fitted with a sealed mechanical stirrer, a dropping funnel and a reflux condenser, while stirring. 667.8 g (6.3 mol) of benzaldehyde was added slowly from the dropping funnel for about an hour. Then 781.5 g (3.0 mol) of 13-methyltetradecanoyl chloride was added dropwise to the reaction mixture in a ice-bath for about 2 hours. Reaction was continued while stirring for 4 hours. The reacted mixture was poured into a big beaker, acidified to pH=l by using 36% hydrochloric acid. Now the mass of solid was separated. Filtrate and wash the filter cake with absolute alcohol till pH=7, and then dissolve it in 2000 ml of 50% alcohol under warming. After decoloring with activated charcoal, filtrating and crystallizing, 627.0 g of 13-methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride was obtained. Furthermore, adding 1000 ml of absolute alcohol into the original mother solution and cooling down to 10°C, additional 233.0 g of 13-methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride was recovered for a total yield of 11.6%. (C: 57.12%; H: 10.87%; N: 10.21%; O: 4.12%; OC1: 17.53%.) MS: 350.66, 327.54, 311.64, 268.67, 87.27.
Example 2: preparation of N, N-di(2-amino ethyl)-ll-methyl-lauryl amine trihydrochloride
Figure imgf000011_0001
30.9 g (0.3 mol) of diethylenetriamine was added into a 200-ml three-necked flask, fitted with a sealed mechanical stirrer, a dropping funned and a reflux condenser, while stirring. 66.8 g (0.63 mol) of benzaldehyde was added from the dropping funnel for an hour, and then 100ml of 95% alcohol was added. While stirring, 65.6 g (0.30 mol) of 11 -methyl lauryl chloride was added dropwise for about an hour. Then the solution was refluxed for 4 hours, and alcohol was removed by distilling under reduced pressure. The reaction mixture was basified to basicity using 10% sodium hydroxide. The mixture arose organic and aqueous layers. Then the organic layer was separated from aqueous layer and was acidified to pH=l using 36% hydrochloric acid. After filtrating, washing the filter cake with absolute alcohol until pH=7, dissolving the filter cake in 200ml of 50% alcohol under warming, decoloring, cooling and filtrating, 79.6 g of N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride was obtained. Yield: 64.7%. (C: 51.67%; H: 10.68%; N: 10.72%; Cl: 27.05%.) MS : 285.52, 127.25, 76.88, 44.08, 43.09.
Example 3: preparation of 13-Methyl tetradecanoyl guanidine hydrochloride
Figure imgf000012_0001
Figure imgf000012_0002
10.0 g (0.041 mol) of 13-methyltetradecanoic acid and 20.0 ml thionyl chloride were added into a 100 ml flask, then were heated and refluxed for 4 hours. The excess of thionyl chloride was removed by distilling under reduced pressure (water aspirator). In order to further clean the residual thionyl chloride, 100ml of petroleum ether was added, and then 13-methyltetradecanoyl chloride was obtained. Put 11.4 g (0.082 mol) of 3-nitrophenol and 100 ml of benzene into a 500 ml flask, and then drop the obtained 13-methyltetradecanoyl chloride and stir for 4 hours. After washing and crystallizing, 13.0 g (0.036 mol) of 3-nitrophenyl-13-methyltetradecanoate was produced. Those 13.0 g (0.036 mol) of 3-nitrophenyl-13-methyltetradecanoate and 10.3g(0.108mol) guanidine hydrochloride were reacted in 100ml of 95% alcohol, as a solvent, and then heated and refluxed for 5 hours. Finally, after decoloring with activated charcoal, cooling, filtrating and crystallizing, 7.0 g of 13-methyltetradecanoyl guanidine hydrochloride was obtained. A total yield: 53.7% (C: 59.73%; H: 10.78%; N: 13.02%; O: 5.12%; Cl: 11.70%.) MS: 283.45, 169.33, 86.07, 43.08, 30.05.
Example 4: preparation of N-(ll -methyl lauryl) guanidine hydrochloride
Figure imgf000013_0001
Put 19.1 g (0.20 mol) of guanidine hydrochloride and 120ml of 95% alcohol into a 100-ml flask, and stir to dissolve it. Then add 21.9 g (0.10 mol) of 11 -methyl lauryl chloride, and heat and reflux them for 14 hours. Finally, after decoloring with activated charcoal, cooling, filtrating and crystallizing, 19.4 g (0.062mol) of N-( 11 -methyl lauryl) guanidine hydrochloride was obtained. A yield: 62%. (C: 53.72%; H: 10.38%; N: 13.42%; Cl: 22.83%.) MS: 241.42, 127.25, 72.09, 43.08, 30.05. Example 5: preparation of 13-Methyl tetradecanoyl guanamine hydrochloride
Figure imgf000014_0001
Figure imgf000014_0002
The mixture of 10.0 g (0.041 mol) 13-methyltetradecanoic acid and 20 ml of thionyl chloride was heated and refluxed in a 100-ml flask for 4 hours. The excess of thionyl chloride was removed by distilling under reduced pressure(water aspirator). The residual thionyl chloride was cleaned by adding 100 ml of petroleum ether, and removed in the same way, obtaining 13-methyltetradecanoyl chloride. Those obtained
13-methyltetradecanoyl chloride was added dropwise into a 500 ml flask containing 11.4 g (0.082 mol) of 3-nitrophenol and 100 ml of benzene while stirring for 4 hours. After filtrating, washing the filter cake, and crystallizing, 13.0 g (0.036 mol) of 3-nitrophenyl-13-methyltetradecanoate was produced. A mixture of 13.0g of 3-nitrophenyl-13-methyltetradecanoate obtained above and 11.9 g (0.108 mol) of guanamine hydrochloride was heated and refluxed with 100 ml of 95% alcohol for 5 hours. After decoloring, cooling, filtrating and crystallizing, 6.7 g (0.020 mol) of 13-methyltetradecanoyl guanamine hydrochloride was obtained. A total yield: 48.8%0 (C: 57.23%; H: 10.58%; N: 16.82%; O: 4.72%; Cl: 10.71%.) MS: 298.47, 155.30, 101.09, 43.08, 30.05. Example 6: preparation of N-(ll-methyl lauryl) guanamine hydrochloride
Figure imgf000015_0001
Figure imgf000015_0002
21.9 g (0.10 mol) of 11 -methyl lauryl chloride was added into a 100-ml flask containing a solution of 22.1 g (0.20 mol) of guanamine hydrochloride in 120 ml of 95% alcohol, and then refluxed for 14 hours. The product was decolored with activated charcoal, cooled, filtrated and crystallized. 22.0 g (0.067 mol) of N-( 11 -methyl lauryl) guanamine hydrochloride was obtained. Yield: 67% (C: 51.12%; H: 10.37%; N: 17.10%; Cl: 21.63%.) MS: 256.43, 127.25, 120.30, 43.08, 30.05.
Example 7: preparation of lN-(ll-m ethyl lauryl)-2N-carboxym ethyl hydrazine NH2-NH2 + CI-CHXOOH NH2-NH-CH2COOH
NH--NH-CHXOOH
Figure imgf000015_0003
Figure imgf000015_0004
Put 187.5 g (3.0 mol) of 80% hydrazine hydrate into a 1000-ml flask containing a solution of 94.5 g (1.0 mol) of chloroacetic acid in 100 ml of water. Setting for 24 hours, acidifying to pH = 6, cooling and filtrating the crystallization, 61.2 g (0.68 mol) of hydrazine acetic acid was produced. Those hydrazine acetic acid was added into a mixture of 74.3 g (0.34 mol) of 11 -methyl lauryl chloride, 28.6 g (0.34 mol) of sodium bicarbonate, and 340 ml of 95%) alcohol, stirring and refluxing for 10 hours. Finally, after decoloring with activated charcoal, acidifying to pH=6, cooling, filtrating and crystallizing, 68.0g of 1N-(11 -methyl lauryl) -2N-carboxymethyl hydrazine was obtained. A total yield: 25.0%. (C: 66.03%; H: 11.64%; N: 10.52%; O: 11.73%.) MS: 272.43, 254.41, 169 .33, 127.25, 43.08.
Example 8: preparation of N-(ll-methyl lauryl)hydrazine dihydrochloride
Figure imgf000016_0001
13 ml (0.3 mol) of 80% hydrazine hydrate was added into a 250-ml flask containing 21.9 g (0.10 mol) of 11 -methyl lauryl chloride, refluxed for 3 hours and then acidified to pH=2 by using 10% hydrochloric acid. After cooling, filtrating and washing the filter cake with a little amount of water, dissolving the filter cake in 95% alcohol, decoloring with activated charcoal, and crystallizing, 14.6 g of N- (11 -methyl lauryl) hydrazine dihydrochloride was obtained. Yield: 48.5%. (C: 54.32%; H: 11.19%; N: 9.80%; Cl: 24.79%.) MS: 228.42, 141.28, 99.20, 57.07, 43.0.
Example 9: preparation of 13-Methyl tetradecanoyl -N,N-di-[ dicarboxymethyl amino ethyl] amine
Figure imgf000017_0001
Figure imgf000017_0002
200.0 g (0.50 mol) of 13-methyltetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride was added into a 3000-ml three-necked flask containing a mixture of 1000 ml of 95%o alcohol and 40.0g (1.0 mol) of sodium hydroxide, which had been dissolved in 100 ml of water. Stirring commenced after dissolving completely. A solution containing 429.3 g (5.11 mol) of sodium bicarbonate was added dropwise into a 1000-ml beaker containing 480.3 g (5.11 mol) of chloroacetic acid. Then the reaction mixture was condensed to an amount of 500 ml, which then was added into the 3000-ml three-necked flask mentioned above and refluxed for 24 hours. After cooling, the filter residue was discarded, and the filtrate was acidified to pH=5. Then the excess of alcohol was removed by distilling. Cooled, the reaction mixture was filtrated, and the filter cake was dissolved in 200ml of 95% alcohol under warming condition. Decoloring with activated charcoal, filtrating and crystallizing, finally 55.9 g of 13-Methyl tetradecanoyl -N, N-di-(dicarboxymethyl amino ethyl) amine was obtained. Yield: 20.0%.( C: 57.82%; H: 8.79%; N: 7.48%; O: 25.84%. )MS: 559.69, 487.63, 362.31, 169.33, 70.07, 45.01. Example 10: preparation of 13-Methyl tetradecanoyl -N, N-di-[N,N-di(hydroxyl ethyl)amino ethyl] amine
Figure imgf000018_0001
The mixture of 265.0 g (1.1 mol) 13-methyltetradecanoic acid and 530 ml of thionyl chloride was heated and refluxed for 4 hours. Removing the excess of thionyl chloride by distilling under reduced pressure (water aspirator), 260.5 g (1.0 mol) of 13-methyltetradecanoyl chloride was produced. While stirring, those
13-methyltetradecanoyl chloride was added dropwise into a solution of 108.15 g (1.03 mol) of diethanolamine in benzene. Removing benzene by distilling under reduced pressure (water aspirator), cooling, the solid product was obtained through filtrating under reduced pressure. After dissolving those products in 95%) alcohol, decoloring with activated charcoal, crystallizing and drying, 72.70 g (0.22 mol) of 13-methyltetradecanoyl diethanolamine was produced. 78.89g of thionyl chloride was added dropwise into those 13-methyltetradecanoyl diethanolamine while stirring, and then refluxed for another 1 hour. Removing the excess of thionyl chloride by distilling under reduced pressure, filtrating, washing with water, dissolving the filter cake with 95%) alcohol, decoloring with activated charcoal, crystallizing and drying, 41.38g (O.l lmol) of 13-methyltetradecanoyl N, N-dichloethyl amine was produced. The mixture of those 13-methyltetradecanoyl N, N-dichloethyl amine with 23.8 g of diethanolamine and 19.05 g of sodium bicarbonate in 95% alcohol as a solvent was refluxed for 6 hours. After cooling, filtrate and remove the residue. Removing the alcohol from the filtrate by distilling under reduced pressure, cooling, filtrating and dissolving the filter cake in 95% alcohol, decoloring with activated charcoal, and crystallizing, 21.56g (0.04mol) of
13-methyltetradecanoyl-N,N-di-[N,N-di(hydroxyl ethyl) amino ethyl] amine was obtained. Mp.: 172~175°C (C: 64.53%; H: 11.24%; N: 8.42%; O: 16.13%.) MS: 503.76, 306.38, 279.37, 155.30, 118.15, 43.08, 31.03.
Example 11: preparation of N-(ll-methyl lauryl) -N,N-di-[ dicarboxymethyl amino ethyl] amine
,N/CH2CH2NH2 CICH2COOH CH^CHgN^
39.2 g (0.10 mol) of N, N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride was added into a 500-ml three-necked flask, containing a mixture of 200 ml of 95% alcohol and 12.0 g (0.3 mol) of sodium hydroxide, which had been dissolved in 20 ml of water. Stirring was commencing when dissolving completely. A solution which contained 50.4 g (0.6 mol) of sodium bicarbonate was added dropwise into a 500-ml beaker containing 56.7g (0.6mol) of chloroacetic acid. After dropping, the reaction mixture was condensed to an amount of 50 ml, which was added into the previous stated 500-ml three-necked flask, and refluxed for 24 hours. Cooled, the filter residue was discarded, and the filtrate was acidified to pH=5. Then the excess of alcohol was removed by distilling. Cooled, the reaction mixture was filtrated, and the filter cake was dissolved in 50 ml of 95% alcohol under warming condition. After decoloring with activated charcoal, filtrating and crystallizing, finally 24.1 g of N-(l l -methyl lauryl)-N,N-di-(dicarboxymethyl amino ethyl) amine was obtained. Yield: 46.6%.( C: 58.12%; H: 9.01%; N: 8.18%; O: 24.74%. ) MS :517.65, 445.60, 348.32, 146.12, 56.09, 43.09.
Example 12: preparation of N-(ll-methyl lauryl) -N,N-di-[ di(hydroxyl ethyl) amino ethyl] amine
.N/CH2CH2NH2 CICH2CH2OH CH2CH2NH2
Figure imgf000020_0001
39.2 g (0.10 mol) of N, N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride was added into a 500-ml flask containing a mixture of 200 ml of 95%> alcohol and 12.0 g (0.3mol) of sodium hydroxide which had been dissolved in 20ml of water. Stirring commenced after dissolving completely. 48.3 g (0.6 mol) of 2-chloroethanol was introduced to the solution, and refluxed for 24 hours. Cooled, the filter residue was discarded and the filtrate was acidified to pH=5. Then the excess of alcohol was removed by distilling. Cooled, the reaction mixture was filtrated, and the filter cake was dissolved in 50 ml of 95% alcohol under warming condition. After decoloring with activated charcoal, filtrating and crystallizing, 23.6 g of N-( 11 -methyl lauryl) -N,N-di-[ di(hydroxyl ethyl) amino ethyl] amine was obtained. Yield: 51.2%. ( C: 65.04%; H: 11.97%; N: 9.14%; O: 13.81%. ) MS: 461.72,
389.66, 292.39, 127.25, 56.09, 31.03. The inventor discovered that the compounds of the formula (1) - (12), which are the derivatives from branched-chain fatty amine or from branched-chain fatty amide, not only inhibit the growth of cancer cell lines, but also selectively inhibit cyclooxygenase-2 activity. COX-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins (such as PGE2) and other eicosanoids. In the present application, the measurement of changes of PGE2 production will be used to indicate the inhibition effects. This enzyme is expressed in a number of tumor cells. This enzymatic pathway for the metabolism of arachidonic acid is known to play important roles in inflammation, as well as the development of several types of cancers. Therefore, the present compounds as selective inhibitors of COX-2 can be used as anti-inflammatory agents, as well as to treat and prevent cancer, and can be present in pharmaceutical compositions in combination with a pharmaceutically acceptable carrier will be used. Since the compound selectively inhibits cycloxygenase-2, the invention encompasses a method of treating a patient for a cyclooxygenase mediated disease comprising administering to a patient in need of such treatment the present unique branched-chain lipid compounds in an amount which is effective for treating said cyclooxygenase mediated disease, such as osteoarthritis, or rheumatoid arthritis. The invention also encompasses a method of treating inflammation in a patient in need of such treatment comprising administering to said patient the present unique branched-chain lipid compounds in an amount effective for treating inflammation. The invention also encompasses a pharmaceutical composition comprising a compound according to the invention in combination with a pharmaceutically acceptable carrier. It is well known that either old NSAID such as aspirin or new coxibs have some side effects, especially due to inhibition of COX-1. The inventor found that the present compounds selectively inhibit COX-2, but do not inhibit COX-1 as shown in the Example below. A further understanding this invention can be obtained by reference to certain specific examples, which are provided herein for purpose of illustration only and not intended to be limiting unless otherwise specified. Since COX-2 as a key enzyme to convert arachidonic acid to PGE2, the inhibition effect of selective COX-2 inhibitor is measured through the metabolism product PGE2 in following examples.
Example 13: Present compounds selectively inhibited COX-2 activity measured by PGE2 production in human prostate cancer PC3 cells
Several compounds from among formulae (1) - (12) were tested to measure their effect on the formation of eicosanoids PGE2 in the human prostate cancer PC3 cells. In this example the tested compounds were listed as following: Sample #1 : N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride Sample #2: N-(l 1-methyl lauryl)hydrazine dihydrochloride Sample #3: 13-Methyl tetradecanoyl -N,N-di (2-amino ethyl) amine dihydrochloride Sample #4: 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine Sample #5: 13-Methyl tetradecanoyl guanidine hydrochloride. The PC3 cells (1 x 106) were plated in 100-mm tissue culture dishes overnight. On day 2, cells were treated with arachidonic acid (AA, 10 μM) as control or a combination of one of the samples above in different concentrations and AA for 2 hrs at 37°C. After 2 hrs, aliquots of the culture medium were taken, and eicosanoids were extracted. To quantify the prostaglandin E2 (PGE2) products in cells, the traditional method of analysis with reversed-phase high-performance liquid chromatography (RP-HPLC) was used, using PGE2 as internal standard. The formation of PGE2 in PC3 cells treated with every sample was compared with that in untreated control cells separately, as shown in the Table 1 below.
Table 1, the inhibition effects of the compounds on formation of PGE2 (ng/ml) in PC3 cells
Figure imgf000022_0001
As seen in the Table 1, exposure of cells to compounds of the present invention reduced PGE concentrations, showing that N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride, N-(l 1-methyl lauryl)hydrazine dihydrochloride, 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride, 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine, and 13-Methyl tetradecanoyl guanidine hydrochloride selectively inhibited COX-2 activity. This selective effect of the compounds on formation of PGE2 was concentration dependent in PC3 cells.
Example 14: Present compounds selectively inhibited COX-2 activity measured by PGE2 production in human hepatoma Hep3B cells
The compounds in Example 13 above were also tested to measure their effect on the formation of eicosanoids PGE2 in the human hepatoma Hep3B cells. In this example the tested compounds were listed as following: Sample #1: N,N-di(2-amino ethyl)- 11-methyl -lauryl amine trihydrochloride Sample #2: N-(l 1-methyl lauryl)hydrazine dihydrochloride Sample #3: 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride Sample #4: 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine Sample #5: 13-Methyl tetradecanoyl guanidine hydrochloride. The Hep3B cells (1 x 106) were seeded in 6-well plates overnight. On day 2, cells were treated with arachidonic acid (AA, 10 μM) as control or a combination of one of the samples above in different concentrations and AA for 6 hrs at 37°C. After 2 hrs, aliquots of the culture medium were taken, and eicosanoids were extracted. To quantify the prostaglandin E2 (PGE2) products in cells, the traditional method of analysis with reversed-phase high-performance liquid chromatography (RP-HPLC) was used, using PGE2 as internal standard. The formation of PGE2 in Hep3B cells treated with every sample was compared with that in untreated control cells separately, as shown in the Table 2 below. Table 2, the inhibition effects of the compounds on formation of PGE2 (ng/ml) in Hep3B cells
Figure imgf000024_0001
As seen in the Table 2, exposure of cells to compounds of the present invention reduced PGE2 concentrations, showing that N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride, N-(l 1-methyl lauryl)hydrazine dihydrochloride, 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride, 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine, and 13-Methyl tetradecanoyl guanidine hydrochloride selectively inhibited COX-2 activity. This selective effect of the compounds on formation of PGE2 was concentration dependent in Hep3B.
Example 15: N-(ll-methyl lauryl)hydrazine dihydrochloride selectively inhibited COX-2 activity, but not COX-1 activity measured by PGE2 production
To compare the inhibition effects of N-(l 1-methyl lauryl)hydrazine dihydrochloride (sample) compound on two cycloxygenase enzymes, ovine COX-1 and human recombinant COX-2 (5 units, Cayman Chemicals, MI) were tested. The enzymes were pre-incubated with the sample at concentrations 2.5, 5.0, 10.0 and 20.0 μg/ml, for 10 min. followed by further incubation with 50 μM of arachidonic acid (AA) for 5 min at 37°C. The reaction was stopped by adding 1 N citric acid. Prior to extraction, 0.1 % BHT and PGE2-d4 were added and PGE2 was extracted and analyzed. The result shown in Table 3 below indicated that N-(l 1-methyl lauryl)hydrazine dihydrochloride selectively inhibited COX-2 activity, but not COX-1 activity measured by PGE2 production. It has been desirable to have new pharmaceutical anti-inflammatory drugs with selective inhibition of COX-2 in preference to COX-1. Those drugs with similar anti-inflammatory property to conventional non-steroidal anti-inflammatory drugs will have a remarkable decrease of non-desired side effects.
Table 3, The effects of N-(l 1-methyl lauryl)hydrazine dihydrochloride On the activity of COX-1 and COX-2 measured by PGE2
Figure imgf000025_0001
The other compounds of the present invention have also shown selective COX-2 inhibition effects in measurements. Arachidonate metabolism and cancer elevated COX-2 and PGE2 levels have been reported in a number of human malignancies including colon, lung, head and neck, breast, pancreatic, bladder and prostate tumors. The present compounds as selective COX-2 inhibitors have significant inhibitory effects on the growth of mouse and human tumor cells in vitro and in vivo shown in the following examples. The compounds and the types of cancer will not been limited to those below.
Example 16: In vivo test on the anticancer effects of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride in mouse sarcoma Siso model
50 male mice, weighing 18-22 g, were randomized into 5 groups of 10 each. S18o sarcoma mass (about 2 mm3 each) was transplanted subcutaneously (s.c.) into the right armpits of all animals following standard procedure. 3 test groups were given 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (sample) at 0.12, 0.24, and 0.36 g/kg intragastrically (i.g.) and the negative control group was given water 0.3 ml/lOg daily for 10 days. The positive control group was given a single dose of cyclophosphamide (CTX) i.g. (25 mg/kg) on day 1 and day 3. On the 11th day, all mice were sacrificed and the tumors were isolated and weighed. The inhibition rates (IR) of solid tumor weight were calculated by the following formula and subject to t test. Inhibition rate (%) = 1 - (mean tumor weight in the group / mean tumor weight in negative control group) The result in Table 4 below showed that the compound 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride significantly inhibits the tumor growth in mouse sarcoma S 180 model.
Table 4, Inhibition effect of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride on mouse sarcoma S180
Figure imgf000026_0001
Example 17: In vivo test on the anticancer effects of N,N-di(2-amino ethyl)-ll-methyl-lauryl amine trihydrochloride in mouse sarcoma Siso model
50 male mice, weighing 18-21 g, were randomized into 5 groups of 10 each. S180 sarcoma mass (about 2 mm3 each) was transplanted subcutaneously (s.c) into the right armpits of all animals following standard procedure. 3 test groups were given N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride (sample) at 20, 30, and 40 mg/kg intragastrically (i.g.) and the negative control group was given water 0.3 ml/lOg daily for 13 days. The positive control group was given a single dose of cyclophosphamide (CTX) i.g. (30 mg/kg) on day 1, day 3 and day 5. On the 14th day, all mice were sacrificed and the tumors were isolated and weighed. The inhibition rates (IR) of solid tumor weight were calculated by the following formula and subject to t test. Inhibition rate (%) = 1 - (mean tumor weight in the group / mean tumor weight in negative control group) The result in Table 5 below showed that the compound N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride significantly inhibits the tumor growth in mouse sarcoma S180 model. Table 5, Inhibition effect ofN,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride on mouse sarcoma S180
Figure imgf000027_0001
Example 18: In vivo test on the anticancer effects of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride in mouse cervical carcinoma U14 model
50 female mice, weighing 18-22 g, were randomized into 5 groups of 10 each. U14 cervical carcinoma suspension 0.2 ml (about 107/mm3) was transplanted subcutaneously (s.c.) into the right armpits of all animals following standard procedure. 3 test groups were given 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (sample) at 120, 240, and 360 mg/kg intragastrically (i.g.) and the negative control group was given water 0.3 ml/lOg daily for 10 days. The positive control group was given a single dose of cyclophosphamide (CTX) i.g. (25 mg/kg) on day 1 and day 3. On the 11th day, all mice were sacrificed and the tumors were isolated and weighed. The inhibition rates (IR) of solid tumor weight were calculated by the following formula and subject to t test. Inhibition rate (%) = 1 - (mean tumor weight in the group / mean tumor weight in negative control group) The result in Table 6 below showed that the compound 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride significantly inhibits the tumor growth in U_4 cervical carcinoma model. Table 6, Inhibition effect of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride on mouse cervical tumor U14
Figure imgf000028_0001
Example 19: In vitro test on the anticancer effects of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride against the growth of various human and mouse cancer cell lines
All human and mouse cancer cell cultures and subcultures were established according to standard procedures. The adherent cells were incubated in sealed culture flask at 37°C. The suspension cells in culture flask with a screwed cap were incubated in 5% CO2 atmosphere at 37°C. The culture medium was RPMI 1640 supplemented with 15%> deactivated fetal bovine serum, and was refreshed every three days. The subcultures were established by treating the cells with 0.25% trypsin every week for adherent cells, and by centrifugation for suspension cells, respectively. Log-phase growing cells after 24~48 hours subculturing were used in this test, at a density of 1 x 105 cells/ml. Suspension cells were seeded in triplication onto 40-well plates at 0.18 ml/well. After incubation at 37°C with 5% CO2 in atmosphere for 12 hours, cells were treated with a series of 5-6 different concentrations of 13-Methyl tetradecanoyl -N,N-di (2-amino ethyl) amine dihydrochloride (sample) (20 μl/well). Same volume of normal saline (NS) only was used in control groups. After 24 hours of incubation, numbers of live cells in each well were counted by trypan blue dye exclusion. Rates of inhibition at different drug concentrations were calculated by linear regression analysis. Adherent cells were diluted into 1 x 105 /ml and seeded in triplication onto 96-well plates at 0.18 ml/well. The cells in test groups were treated with a series of 5~6 different concentrations of the sample (20 μl/well), and the cells in control group were added with same volume of NS. In the blank wells, there were no cells but medium. After incubation at 37°C with 5% CO2 in atmosphere for 48-72 hours, 20 μl of 5 mg fresh MTT solution was added to each well. After another 4 hours of incubation and removal of supernatant, 150 μl DMSO was added into each well and shaken for 10 minutes to fully dissolve the precipitate. OD490 was measured on Immunoreader Bio-TEK EL311 and normalized by the controls. The inhibition rate was calculated by the following formula and IC50 was determined. Inhibition rate (%) = 1 - (OD4 0 in test well / OD 90 in control well).
The results in Table 7 below showed that compound 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride significantly inhibited the growth of various human and mouse cancer cell lines.
Table 7, The effect of 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride against the growth of various human and mouse cancer cell lines
Figure imgf000029_0001
Example 20: Comparison of in vitro anticancer effects of N,N-di(2-amino ethyl)-ll-methyl-lauryl amine trihydrochloride, N-(ll-methyl lauryl)hydrazine dihydrochloride and 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride against the growth of various human cancer cell lines
To compare the in vitro anticancer effects of N,N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride (sample 1), N-(l 1-methyl lauryl)hydrazine dihydrochloride (sample 2), and 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (sample 3) against the growth of various human cancer cell lines, the same test procedure was used as in Example 19 above. The results were shown in Table 8 below.
Table 8, Comparison of in vitro anticancer effects of present compounds
Figure imgf000030_0001
The inventor has also found that some derivatives from a straight-chain fatty amine or a straight-chain fatty amide with similar formula as those (1) - (12) above but when CH3CnH2n-m- is a straight chain, or a pharmaceutically acceptable salt thereof, had similar COX-2 and cancer cell inhibition effects. The preparation methods are similar as the method 1 to method 12, which are easily understood by skilled chemical technicians. Following is an example, which corresponds to formula (2) above: N,N-di(2-amino ethyl)- tetradecyl amine trihydrochloride
Figure imgf000031_0001
Example 21: Preparation of N,N-di(2-amino ethyl)- tetradecyl amine trihydrochloride
Use the same method in Example 2 above for preparation of N, N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride except that 11 -methyl lauryl chloride, a material used in second step, is replaced by tetradecyl chloride. N,N-di(2-amino ethyl)- tetradecyl amine trihydrochloride was obtained.
Example 22: Comparison of in vitro anticancer effects of N,N-di(2-amino ethyl)- tetradecyl amine trihydrochloride and N, N-di(2-amino ethyl)-ll-methyl-lauryl amine trihydrochloride against the growth of cancer cell lines
To compare the in vitro anticancer effects of N,N-di(2-amino ethyl)- tetradecyl amine trihydrochloride (sample 1) and N, N-di(2-amino ethyl)- 11-methyl-lauryl amine trihydrochloride (sample 2) against the growth of cancer cell lines, the same test procedure was used as in Example 19 above. The results are shown in Table 9 below.
Table 9, Comparison of in vitro anticancer effects of two compounds
Figure imgf000031_0002
Derivatives of straight-chain fatty amine and amide according to the present invention are not limited to those above. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

CLAIMS:
1. A compound selected from the group consisting of the following formulae (1) - (12):
Figure imgf000033_0001
/CH HaNHa CH3CnH2n.2rn N ^ CH2CH2NH2 (2)
Figure imgf000033_0002
Figure imgf000033_0003
Figure imgf000033_0004
Figure imgf000033_0005
CH3CnH2n.2m NH-NH-CH2COOH
CH3CnH2n.2m NH-NH2 (8)
Figure imgf000034_0001
Figure imgf000034_0002
CHXOOH CHXH2N< / CH2COOH
CH3 CnH2n.2m N m w XCH2CH2N<CH2COOH CH2COOH (11)
Figure imgf000034_0003
or a pharmaceutically acceptable salt thereof, wherein CH3CnH2n-m- is defined as a saturated or unsaturated alkyl chain, n = 3 - 25, m = 0 - n/2, and any -H in the alkyl chain can be replaced by -OH, -Cl, -Br, F, or -I.
2. The compound of Claim 1 wherein CH3CnH2n-m- is defined as a branched saturated or unsaturated alkyl chain.
3. The compound of Claim 2 selected from the group consisting of the following compounds (1*) - (12'): (1'): 13-Methyl tetradecanoyl-N,N-di (2-amino ethyl) amine dihydrochloride (2'): N,N-di(2 -amino ethyl)- 11-methyl-lauryl amine trihydrochloride (3'): 13-Methyl tetradecanoyl guanidine hydrochloride (41): N-(l 1-methyl lauryl) guanidine hydrochloride (5'): 13-Methyl tetradecanoyl guanamine hydrochloride (6'): N-(l 1-methyl lauryl) guanamine hydrochloride (7'): 1N-(11-methyl lauryl)-2N-carboxymethyl hydrazine (8'): N-(l 1-methyl lauryl)hydrazine dihydrochloride (9'): 13-Methyl tetradecanoyl -N,N-di-[ dicarboxymethyl amino ethyl] amine (10'): 13-Methyl tetradecanoyl -N,N-di-[N,N-di(hydroxyl ethyl)amino ethyl] amine (11'): N-(l 1-methyl lauryl) -N,N-di-[ dicarboxymethyl amino ethyl] amine (12'): N-(l 1-methyl lauryl) -N,N-di-[ di(hydroxyl ethyl)amino ethyl] amine
4. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising a compound according to claim 2 in combination with a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising a compound according to claim 3 in combination with a pharmaceutically acceptable carrier.
7. A method of treating inflammation in a patient in need of such treatment comprising administering to said patient a compound according to claim 1 in an amount effective for treating inflammation.
8. A method of treating inflammation in a patient in need of such treatment comprising administering to said patient a compound according to claim 2 in an amount effective for treating inflammation.
9. A method of treating inflammation in a patient in need of such treatment comprising administering to said patient a compound according to claim 3 in an amount effective for treating inflammation.
10. A method of treating a patient for a cyclooxygenase mediated disease comprising administering to the patient in need of such treatment a compound according to claim 1 in an amount which is effective for treating said cyclooxygenase mediated disease.
11. A method of treating a patient for a cyclooxygenase mediated disease comprising administering to the patient in need of such treatment a compound according to claim 2 in an amount which is effective for treating said cyclooxygenase mediated disease.
12. A method of treating a patient for a cyclooxygenase mediated disease comprising administering to the patient in need of such treatment a compound according to claim 3 in an amount which is effective for treating said cyclooxygenase mediated disease.
13. A method in accordance with claim 10 wherein the cyclooxygenase mediated disease is osteoarthritis or rheumatoid arthritis.
14. A method in accordance with claim 11 wherein the cyclooxygenase mediated disease is osteoarthritis or rheumatoid arthritis.
15. A method in accordance with claim 12 wherein the cyclooxygenase mediated disease is osteoarthritis or rheumatoid arthritis.
16. A method of treating or preventing cancer in a patient in need thereof, comprising administering to said patient a COX-2 selective inhibiting compound in an amount that is effective to treat or prevent cancer, wherein the COX-2 selective inhibiting compound is a compound according to claim 1.
17. A method of treating or preventing cancer in a patient in need thereof, comprising administering to said patient a COX-2 selective inhibiting compound in an amount that is effective to treat or prevent cancer, wherein the COX-2 selective inhibiting compound is a compound according to claim 2.
18. A method of treating or preventing cancer in a patient in need thereof, comprising administering to said patient a COX-2 selective inhibiting compound in an amount that is effective to treat or prevent cancer, wherein the COX-2 selective inhibiting compound is a compound according to claim 3.
19. The compound of Claim 1 wherein CH3CnH2n.m- is defined as a straight saturated or unsaturated alkyl chain.
20. A pharmaceutical composition comprising a compound according to claim 19 in combination with a pharmaceutically acceptable carrier.
21. A method of treating inflammation in a patient in need of such treatment comprising administering to said patient a compound according to claim 19 in an amount effective for treating inflammation.
22. A method of treating a patient for a cyclooxygenase mediated disease comprising administering to the patient in need of such treatment a compound according to claim 19 in an amount which is effective for treating said cyclooxygenase mediated disease.
23. A method in accordance with claim 22 wherein the cyclooxygenase mediated disease is osteoarthritis or rheumatoid arthritis.
24. A method of treating or preventing cancer in a patient in need thereof, comprising administering to said patient a COX-2 selective inhibiting compound in an amount that is effective to treat or prevent cancer, wherein the COX-2 selective inhibiting compound is a compound according to claim 19.
PCT/US2004/019101 2003-07-22 2004-07-22 Straight-chain and branched-chain lipid compounds as selective inhibitors of cyclooxygenase-2, anti-inflammatory agents, and anti-cancer agents WO2005014528A1 (en)

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CN107304175A (en) * 2016-04-21 2017-10-31 上海生农生化制品有限公司 A kind of synthetic method of dodine
CN110229655A (en) * 2019-08-07 2019-09-13 山东新港化工有限公司 Polyhydroxy nonionic surfactant and its preparation method and application

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107304175A (en) * 2016-04-21 2017-10-31 上海生农生化制品有限公司 A kind of synthetic method of dodine
CN110229655A (en) * 2019-08-07 2019-09-13 山东新港化工有限公司 Polyhydroxy nonionic surfactant and its preparation method and application

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