ISSN 0012-5008, Doklady Chemistry, 2009, Vol. 425, Part 2, pp. 88–90. © Pleiades Publishing, Ltd., 2009.Original Russian Text © I.V. Serkov, V.V. Bezuglov, 2009, published in Doklady Akademii Nauk, 2009, Vol. 425, No. 6, pp. 777–779.

88

Nonsteroidal anti-inflammatory drugs (NSAIDs)(Aspirin, Indomethacin, Naproxen, Ibuprofen, and oth-ers) are used for many years as antipyretic and anti-inflammatory agents. Moreover, Aspirin is used for thetreatment of ischemia in patients with acute cardiacinsufficiency and as a prophylactic for cardiovasculardiseases [1]. However, the long-term use of these phar-maceuticals increases the risk of gastrointestinal disor-ders [2, 3]. The pharmacological properties and sideeffects of Aspirin and other NSAIDs arise immediatelyfrom the mechanism of their action, the inhibition ofcyclooxygenases (COX-1 and COX-2), key enzymes inthe synthesis of prostaglandins and thromboxanes [4].The inhibition of biosynthesis of anti-inflammatoryprostaglandins, first of all prostaglandin E

2

, leads toanti-inflammatory, antipyretic, and analgesic effectstypical of NSAIDs. However, a decrease in the releaseof cytoprotective prostaglandins in the mucosa of thegastrointestinal tract under the action of these agentsprovides their gastrotoxicity and confines the clinicaluse of NSAIDs. The attachment of a fragment thatproduces nitric oxide (NO) to the NSAID core made itpossible to design a new class of anti-inflammatoryagents, so-called NO-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs). These hybridcompounds retain the anti-inflammatory activity ofthe parent compound but show a much lower negativeimpact on the gastrointestinal tract [5]. These hybridNO-NSAIDs are supposed to protect the gastrointesti-nal tract by the local release of NO resulting in theenhancement of blood circulation in the mucous coat[6]. At present, the nitroxyalkyl esters of Aspirin,

Paracetamol, Indomethacin, Ibuprofen, and otherpharmaceuticals are at the different stages of clinicaltrial [7].

To expand the library of NO-donating NSAIDs, weprepared a number of compounds containing, as theNO donor, a nitroxy group bound to the core moleculevia the aminoalcohol linker. We obtained the amides ofIndomethacin, Ibuprofen, Aspirin, and salicylic acidderived from O-nitrates of ethanolamine (

Ia

), methyle-thanolamine (

Ib

), 2-(2-aminoethylamino)ethanol (

Ic

),and 3-aminopropanediol-1,2-dinitrate (

Id

). TheO-nitrates of aminoalcohols were obtained by the nitra-tion of aminoalcohol with 100% nitric acid in methyl-ene chloride [8]. Indomethacin amides (

IIa

–

IIc

) weresynthesized by the “mixed anhydride” method throughthe reaction with isobutyl chloroformate followed bycondensation with the O-nitrates of aminoalcohols. Theyields of the target compounds were 65–85%. The useof this method for the synthesis of Ibuprofen and sali-cylic acid derivatives failed. The amidation reactioneither proceeded in a yield not higher than 40% with therecovery of the initial acid or resulted in isobutyl ester.The application of highly reactive imidazolides, whichare widely used for the synthesis of amides [9], alsofailed. A synthesis through intermediate acid chloridesproved to be the best method. The acid chlorides wereobtained by refluxing in chloroform with thionyl chlo-ride. The reaction mixture was concentrated and theresulting acid chloride was reacted with nitroxyalky-lamine to produce final amides (

IIIa

,

IIIb

,

IV

,

V

).

EXPERIMENTAL

1

H NMR spectra were recorded on a Bruker CXP-200 spectrometer (Germany), chemical shifts arereported on the

δ

scale relative to Me

4

Si. Melting pointswere determined on a Boetius hot-stage apparatus andwere uncorrected. Solutions were concentrated using arotary evaporator in a water-jet pump vacuum.

Synthesis of New Nitroxyalkylamides as Potential Prototypes of Hybrid Nonsteroidal

Anti-Inflammatory Drugs Containing NO-Donating Fragment

I. V. Serkov

a

and V. V. Bezuglov

b

Presented by Academician A.I. Miroshnikov October 21, 2008

Received October 21, 2008

DOI:

10.1134/S0012500809040065

a

Institute of Physiologically Active Substances, Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka, Moscow oblast, 142432 Russia

b

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997 Russia

CHEMISTRY

DOKLADY CHEMISTRY

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Part 2

2009

SYNTHESIS OF NEW NITROXYALKYLAMIDES AS POTENTIAL PROTOTYPES 89

Synthesis of nitroxyalkylamides via mixed anhy-drides with isobutyl chloroformate. General proce-dure.

Triethylamine (2 mmol) and isobutyl chlorofor-mate (1.2 mmol) were added sequentially to a solutionof 1 mmol of the acid in 5 mL of acetone at 5

°

C. A pre-cipitate of triethylamine hydrochloride began to formafter 1.5–2 min. The reaction mixture was stirred for40 min and concentrated. The residue was dissolved in5 mL of chloroform, a solution of 1.2 mmol of nitroxy-alkylamine hydronitrate

Ia

–

Id

and 300

µ

L of triethy-lamine in 2 mL of chloroform were added, and the mix-ture was stirred for 10 h at ambient temperature. Thereaction mixture was washed with a 1 M aqueous solu-tion of hydrochloric acid, water, and a saturated aque-ous solution of NaCl and dried over anhydrous Na

2

SO

4

.The drying agent was filtered off, the filtrate was con-centrated. The residue was purified by column chroma-tography or crystallization.

Synthesis of nitroxyalkylamides via acid chlo-rides. General procedure.

Thionyl chloride (500

µ

L)was added to a solution of 1 mmol of the acid in 2 mLof chloroform, and the resulting mixture was heatedunder reflux for 4 h. The reaction mixture was cooled,filtered, and evaporated. The residual oil was dissolved

in 1 mL of chloroform, a solution of 1.2 mmol ofnitroxyalkylamine hydronitrate

Ia

–

Id

and 300

µ

L oftriethylamine in 1 mL of chloroform were added, andthe mixture was stirred for 10 h at ambient temperature.The reaction mixture was diluted with 5 mL of waterand extracted with ethyl acetate (3

×

5 mL). The com-bined organic extracts were washed with a 1 M aqueoussolution of hydrochloric acid, water, and a saturatedaqueous solution of NaCl and dried over anhydrousNa

2

SO

4

. The drying agent was filtered off, the filtratewas concentrated in vacuum, and the residue was puri-fied by column chromatography on silica gel L (100–250

µ

m) in a benzene–acetone gradient system. Frac-tions containing the product (monitoring by TLC) werecombined, and the solvent was removed in vacuum.

Indomethacin

N-

(2-nitroxyethyl)amide (IIa).

Yellowish crystals, mp 124–126

°

C (decomp.).

1

HNMR (CDCl

3

,

δ

, ppm): 7.63 (d, 2H,

J

= 8.4 Hz, H

arom

),7.45 (d, 2H,

J

= 8.4 Hz, H

arom

), 6.74 (m, 3H, H

arom

), 5.87(m, 1H, NH), 4.49 (t, 2H,

J

= 5.2 Hz, CH

2

ONO

2

), 3.81(s, 3H, OCH

3

), 3.64 (s, 2H, COCH

2

), 3.53 (m, 2H,

CH

2

NH

), 2.38 (s, 3H, CH

3

).

H2NONO2

NH

ONO2

H2N

HN ONO2

H2N ONO2

ONO2

N

R

O

O

MeO

Cl

O

R

NH

ONO2

O

O

O

NH

ONO2

O

OH

Ia I

b

I

c

I

d

II III

IV V

R = NHCH

2

CH

2

ONO

2

(

a

); N(Me)CH

2

CH

2

ONO

2

(

b

),

NHCH

2

CH

2

NHCH

2

CH

2

ONO

2

(

c

)

R = NHCH

2

CH

2

ONO

2

(

a

),

NHCH

2

CH(ONO

2

)CH

2

ONO

2

(

b

)

Structure of the prepared compounds.

90

DOKLADY CHEMISTRY

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SERKOV, BEZUGLOV

Indomethacin

N-

methyl-

N-

(2-nitroxyethyl)amide(IIb).

Yellowish crystals, mp 118–119

°

C (decomp.).

1

HNMR (CDCl

3

,

δ

, ppm): 7.59 (d, 2H,

J

= 8.4 Hz, H

arom

),7.39 (d, 2H,

J

= 8.4 Hz, H

arom

), 6.95 (d, 1H,

J

= 2.2 Hz,H

arom

), 6.74 (d, 1H,

J

= 8.8 Hz, H

arom

), 6.55 (dd, 1H,

J

= 8.8 Hz,

J

= 2.2 Hz, H

arom

), 4.36 (m, 2H, CH

2

ONO

2

),3.76 (s, 3H, OCH

3

), 3.73 (s, 2H, COCH

2

), 3.21 (m, 2H,CH2N), 2.67 (s, 3H, NCH3), 2.31 (s, 3H, CCH3).

Indomethacin N-[2-(2-nitroxyethylamino)ethyl]ami-de (IIc). Yellowish crystals, mp 167–171°C (decomp.).1H NMR (DMSO-d6 + CF3CO2H, δ, ppm): 9.28 (m,2H, NH2), 8.20 (m, 1H, CONH), 7.65 (d, 2H, J =8.4 Hz, Harom), 7.48 (d, 2H, J = 8.4 Hz, Harom), 7.05 (m,1H, Harom), 6.92 (d, 1H, J = 8.8 Hz, Harom), 6.64 (d, 1H,J = 8.8 Hz, Harom), 4.79 (m, 2H, CH2ONO2), 3.80 (s,3H, OCH3), 3.59 (s, 2H, COCH2), 3.48 (m, 2H, CH2),3.35 (m, 2H, CH2), 3.10 (m, 2H, CH2), 2.32 (s, 3H,CCH3).

Ibuprofen N-(2-nitroxyethyl)amide (IIIa). A yel-lowish crystallizing oil. 1H NMR (CDCl3, δ, ppm):7.12 (m, 4H, Harom), 5.81 (m, 1H, NH), 4.45 (t, 2H, J =5.2 Hz, CH2ONO2), 3.51 (m, 3H, CH2NH, CH3CH),2.44 (d, 2H, J = 7.0 Hz, CH2CH), 1.83 (m, 1H,CH2CH), 1.49 (d, 3H, J = 7.2 Hz, CH3CH), 0.89 (d, 6H,J = 6.4 Hz, CH3)2CH).

Ibuprofen N-(2,3-dinitroxypropyl)amide (IIIb).A yellowish crystallizing oil. 1H NMR (CDCl3, δ,ppm): 7.11 (m, 4H, Harom), 5.96 (m, 1H, NH), 5.28 (m,1H, CHONO2), 4.74 (m, 1H, CHHONO2), 4.39 (m, 1H,J = 5.2 Hz, CHHONO2), 3.61 (m, 3H, CH2NH,CH3CH), 2.42 (d + d, 2H, J = 7.0 Hz, CH2CH), 1.83 (m,1H, CH2CH), 1.47 (d, 3H, J = 7.2 Hz, CH3CH), 0.89 (d,6H, J = 6.4 Hz, (CH3)2CH).

N-(2-Nitroxyethyl)-O-acetylsalicylamide (Aspi-rin N-(2-nitroxyethyl)amide) (IV). White crystals,mp 76–78°C (decomp.). 1H NMR (CDCl3, δ, ppm):7.69 (dd, 1H, J = 1.6 Hz, J = 7.6 Hz, Harom), 7.42 (m,1H, Harom), 7.24 (m, 1H, Harom), 7.04 (dd, 1H, J =8.0 Hz, Harom), 6.60 (m, 1H, NH), 4.57 (t, 2H, J =5.0 Hz, CH2ONO2), 3.71 (q, 2H, J = 5.4 Hz, CH2NH).

N-(2-Nitroxyethyl)salicylamide (V). A colorlesscrystallizing oil. 1H NMR (CDCl3, δ, ppm): 8.07 (d,1H, J = 7.8 Hz, Harom), 7.71 (t, 1H, J = 8.4 Hz, Harom),7.32 (m, 2H, Harom), 7.23 (s, 1H, NH), 4.75 (t, 2H, J =5.1 Hz, CH2ONO2), 3.43 (t, 2H, J = 5.1 Hz, CH2NH),1.59 (s, 1H, OH).

Thus, we have synthesized the new nitroxyalkyla-mides of Indomethacin, Ibuprofen, and salicylic andacetylsalicylic acids. These compounds containingNO-donating group can be the prototypes of new anti-inflammatory pharmaceuticals.

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