Urea hydantoin derivatives as formyl peptide modulators

Abstract

The present invention relates to urea hydantoin compounds, processes for preparing them, pharmaceutical compositions containing them, and their use as pharmaceuticals as modulators of the FPR2 receptor, and to methods of treating inflammatory diseases or conditions in a subject in need thereof by administering the compound(s) or pharmaceutical composition to the subject.

Claims

1. A compound represented by Formula I: ##STR00010## wherein: R.sup.1 is optionally substituted C.sub.1-8 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted heterocycle; R.sup.2 is H, or optionally substituted C.sub.1-8alkyl; R.sup.3 is NR.sup.5; n is 1 or 2; m is 1 or 2; R.sup.4 is C(O)R.sup.6, R.sup.5 is H or optionally substituted C.sub.1-8alkyl; R.sup.6 is OC.sub.1-8alkyl or OH; R.sup.7 is H or optionally substituted C.sub.1-8alkyl; R.sup.8 is H or optionally substituted C.sub.1-8alkyl; R.sup.9 is H or optionally substituted C.sub.1-8alkyl; R.sup.10 is H or optionally substituted C.sub.1-8alkyl; R.sup.11 is H or optionally substituted C.sub.1-8alkyl; R.sup.12 is H, OH, NR.sup.14R.sup.15 or optionally substituted C.sub.1-8alkyl; R.sup.13 is H or optionally substituted C.sub.1-8alkyl; R.sup.14 is H or optionally substituted C.sub.1-8alkyl; and R.sup.15 is H or optionally substituted C.sub.1-8alkyl; or an enantiomer, diastereomer or tautomer thereof; or a zwitterion or pharmaceutically acceptable salt of the foregoing.

2. The compound according to claim 1, wherein R.sup.1 is substituted C.sub.6aryl.

3. The compound according to claim 1, wherein R.sup.1 is substituted phenyl.

4. The compound according to claim 1, wherein n is 2.

5. The compound according to claim 1, wherein m is 2.

6. The compound according to claim 1, wherein R.sup.3 is NR.sup.5, and R.sup.5 is H.

7. The compound according to claim 1, wherein R.sup.6 is OC.sub.1-8alkyl.

8. The compound according to claim 1, wherein R.sup.2 is selected from methyl, ethyl, n-propyl and isopropyl.

9. The compound according to claim 1, which is: Ethyl 3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.

10. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition according to claim 10 wherein the compound is: Ethyl 3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.

12. A method of treating a disease or condition associated with FPR2 modulation in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject, wherein the disease or condition is selected from dry eye, post-cataract surgical inflammation, post-surgical corneal inflammation, a post-surgical corneal wound, arthritis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, rosacea, a dermal wound, pain and inflammatory bowel disease.

13. The method of claim 12, wherein the compound is: Ethyl 3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.

14. The method of claim 12 or 13, wherein the subject is a human.

Description

DRAWINGS

(1) FIG. 1 shows the structure of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

(2) It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.

(3) It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. As will be evident to those skilled in the art, individual diasteroisomeric forms can be obtained by separation of mixtures thereof in conventional manner; chromatographic separation may be employed.

(4) Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.

(5) The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium .sup.2H (or D) in place of hydrogen .sup.1H (or H) or use of .sup.13C enriched material in place of .sup.12C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.

(6) The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

(7) Non-limiting embodiments of the invention are as follows.

(8) In embodiment (1), there is provided a compound represented by Formula I:

(9) ##STR00003##

(10) wherein: R.sup.1 is substituted or unsubstituted C.sub.1-8 alkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.6-C.sub.10 aryl, or substituted or unsubstituted heterocycle; R.sup.2 is H, or substituted or unsubstituted C.sub.1-8alkyl; R.sup.3 is O or NR.sup.5; n is 1 or 2; m is 1 or 2; R.sup.4 is C(O)R.sup.6, P(O)(OR.sup.7)(OR.sup.8), P(O)(OR.sup.9)(NR.sup.10R.sup.11), S(O)R.sup.12 or SO.sub.2R.sup.13; R.sup.5 is H or substituted or unsubstituted substituted C.sub.1-8alkyl; R.sup.6 is OC.sub.1-8alkyl or OH; R.sup.7 is H or substituted or unsubstituted C.sub.1-8alkyl; R.sup.8 is H or substituted or unsubstituted C.sub.1-8alkyl; R.sup.9 is H or substituted or unsubstituted C.sub.1-8alkyl; R.sup.10 is H or substituted or unsubstituted C.sub.1-8alkyl; R.sup.11 is H or substituted or unsubstituted C.sub.1-8alkyl; R.sup.12 is H, OH, NR.sup.14R.sup.15 or substituted or unsubstituted C.sub.1-8alkyl; R.sup.13 is H or substituted or unsubstituted C.sub.1-8alkyl; R.sup.14 is H or substituted or unsubstituted C.sub.1-8alkyl; and R.sup.15 is H or substituted or unsubstituted C.sub.1-8alkyl;

(11) or an enantiomer, diastereomer or tautomer thereof;

(12) or a zwitterion or pharmaceutically acceptable salt of the foregoing;

(13) wherein:

(14) each substituted C.sub.1-8alkyl is independently substituted with one or more halogen, hydroxyl, C.sub.3-8cycloalkyl, amino, heterocyclyl, substituted or unsubstituted C.sub.6-C.sub.10aryl, carboxylic acid, phosphonic acid, phosphonate, phosphoric acid, sulphonic acid, sulfonamide, nitro, amide, ester, ether or ketone;

(15) each substituted C.sub.3-8cycloalkyl is independently substituted with one or more halogen, hydroxyl, sulfonyl C.sub.1-8alkyl, sulfoxide C.sub.1-8alkyl, sulfonamide, nitro, cyano, OC.sub.1-8 alkyl, amide, ester, ether, SH, SC.sub.1-8 alkyl, C.sub.1-8 alkyl, ketone, alkylamino, amino, C.sub.6-C.sub.10aryl or C.sub.3-8 cycloalkyl;

(16) each substituted C.sub.6-C.sub.10aryl is independently substituted with one or more halogen, hydroxyl, sulfonyl C.sub.1-8alkyl, sulfoxide C.sub.1-8alkyl, sulfonamide, carboxylic acid, C.sub.1-8 alkyl carboxylate (ester), amide, nitro, cyano, OC.sub.1-6 alkyl, SH, SC.sub.1-8alkyl, C.sub.1-8 alkyl, ether, ketone, aldehyde, C.sub.1-8alkylamino, amino, C.sub.3-8cycloalkyl or C.sub.6-C.sub.10aryl; and

(17) each substituted heterocycle is independently substituted with one or more halogen, hydroxyl, sulfonyl, sulfoxide, sulfonamide, nitro, cyano, OC.sub.1-8alkyl, SH, SC.sub.1-8 alkyl, C.sub.1-8alkyl, carboxylic acid, ketone, amide, ester, ether, C.sub.1-8alkylamino, amino, C.sub.6-C.sub.10aryl or C.sub.3-8cycloalkyl.

(18) In embodiment (2), there is provided a compound of embodiment (1), wherein R.sup.1 is substituted or unsubstituted C.sub.6aryl.

(19) In embodiment (3), there is provided a compound of embodiment (1) or (2), wherein R.sup.1 is C.sub.6aryl substituted with at least one halogen.

(20) In embodiment (4), there is provided a compound of any one of embodiments (1), (2) or (3), wherein R.sup.1 is substituted phenyl.

(21) In embodiment (5), there is provided a compound of any one of embodiments (1) through (4), wherein R.sup.1 is phenyl substituted with at least one halogen.

(22) In embodiment (6), there is provided a compound of any one of embodiments (1) through (5), wherein R.sup.1 is 4-bromo-phenyl.

(23) In embodiment (7), there is provided a compound of any one of embodiments (1) through (6), wherein R.sup.4 is C(O)R.sup.6.

(24) In embodiment (8), there is provided a compound of any one of embodiments (1) through (7), wherein R.sup.6 is OC.sub.1-8alkyl.

(25) In embodiment (9), there is provided a compound of any one of embodiments (1) through (8), wherein R.sup.6 is OEt.

(26) In embodiment (10), there is provided a compound of any one of embodiments (1) through (9), wherein R.sup.3 is NR.sup.5.

(27) In embodiment (11), there is provided a compound of any one of embodiments (1) through (10), wherein R.sup.5 is H.

(28) In embodiment (12), there is provided a compound of any one of embodiments (1) through (11), wherein n is 2.

(29) In embodiment (13), there is provided a compound of any one of embodiments (1) through (12), wherein m is 2.

(30) In embodiment (14), there is provided a compound of any one of embodiments (1) through (13), wherein R.sup.2 is selected from methyl, ethyl, n-propyl and isopropyl.

(31) In embodiment (15), there is provided a compound of any one of embodiments (1) through (14), wherein each C.sub.1-8 alkyl is independently optionally replaced with C.sub.1-4alkyl.

(32) In embodiment (16), there is provided a compound of embodiment (15), wherein each C.sub.1-4alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, isobutyl and sec-butyl.

(33) In embodiment (17), there is provided a compound which is ethyl 3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.

(34) In embodiment (18), there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of embodiments (1) through (17), and a pharmaceutically acceptable carrier.

(35) In embodiment (19), there is provided a compound or pharmaceutical composition according to any one of embodiments (1) through (18) for use in treating an inflammatory disease condition.

(36) In embodiment (20), there is provided a compound or pharmaceutical composition according to any one of embodiments (1) through (18) for use in treating an inflammatory disease or condition, wherein the disease or condition is an ocular inflammatory disease or condition or a dermal inflammatory disease or condition.

(37) In embodiment (21), there is provided method of treating an inflammatory disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition according to any one of embodiments (1) through (18) to the subject, thereby treating the condition.

(38) In embodiment (22), there is provided the method of embodiment (21), wherein the disease or condition is an ocular inflammatory disease or condition or a dermal inflammatory disease or condition.

(39) Compound names were generated with ACDLabs version 12.5. Some of the intermediate and reagent names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.

(40) In general, characterization of the compounds was performed according to the following methods. NMR spectra were recorded on a 300 or 600 MHz Varian NMR spectrometer and acquired at room temperature. Chemical shifts are given in ppm referenced either to internal TMS or to the solvent signal. Optical rotations were recorded on Perkin Elmer Polarimeter 341, 589 nm at 20 C., Na/Hal lamp.

(41) All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures.

(42) Usually the compounds of the invention were purified by column chromatography (Auto-column) on Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise.

(43) The following abbreviations are used in the examples:

(44) THF tetrahydrofuran

(45) CD.sub.3OD deuterated methanol

(46) RT room temperature

(47) CH.sub.2Cl.sub.2 dichloromethane

(48) NH.sub.4Cl ammonium chloride

(49) EtOAc ethyl acetate

(50) KCN potassium cyanide

(51) (NH.sub.4).sub.2CO.sub.3 ammonium carbonate

(52) NaHSO.sub.3 sodium hydrogen sulfite

(53) EtOH ethanol

(54) CF.sub.3CO.sub.2H trifluoroacetic acid

(55) Et.sub.3N triethylamine

(56) MeOH methanol

Example 1

Intermediate 1

tert-Butyl (3-oxopentyl)carbamate

(57) ##STR00004##

(58) To a cold (78 C.) solution of N-[(1,1-dimethylethoxy)carbonyl]--Alanine [CAS #3303-84-2] (2 g, 10.6 mmol) in THF (50 mL) was added a solution of ethyl lithium in cyclohexane (0.5 M solution, 64 mL, 32 mmol). The reaction was warmed to 0 C. and stirred at 0 C. for 90 min. The reaction was quenched with aq. NH.sub.4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried and the solvent removed under reduced pressure. Intermediate 1 was isolated as colorless oil.

(59) .sup.1HNMR (CD.sub.3OD) : 1.05 (t, J=7.3 Hz, 3H), 1.40 (s, 9H), 2.42 (q, J=7.3 Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 3.35 (q, J=5.6 Hz, 2H).

Example 2

Intermediate 2

tert-Butyl (2-(4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl)carbamate

(60) ##STR00005##

(61) A mixture of Intermediate 1 (350 mg, 1.74 mmol), KCN (230 mg, 3.48 mmol), (NH.sub.4).sub.2CO.sub.3 (1.12 g, 12.2 mmol), NaHSO.sub.3 (220 mg, 2.1 mmol) and EtOH (10 mL) was heated in a sealed tube for 18 h. The crude reaction was filtered through a celite column. The solvent was removed under reduced pressure, the crude product was purified by silicagel chromatography using EtOAc in hexane as eluent. Intermediate 2 was isolated as a white solid.

(62) .sup.1HNMR (CD.sub.3OD) : 0.85 (t, J=7.3 Hz, 3H), 1.42 (br s, 9H), 1.60-1.82 (m, 2H), 1.83-2.00 (m, 2H), 2.90-3.04 (m, 1H), 3.05-3.19 (m, 1H).

Example 3

Intermediate 3

tert-Butyl (2-(1-amino-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl)carbamate

(63) ##STR00006##

(64) A solution of Intermediate 2 (132 mg, 0.46 mmol) and hydrazine hydrate (2 mL) was stirred at 120 C. in a sealed tube for 10 h. The reaction mixture was then diluted with water, extracted with EtOAc, the organic layers were washed with brine, dried and the solvent was removed under reduced pressure. Intermediate 3 was isolated as a clear oil.

(65) .sup.1HNMR (CD.sub.3OD) : 0.85 (t, J=7.3 Hz, 3H), 1.41 (s, 9H), 1.61-1.85 (m, 2H), 1.91-2.04 (m, 2H), 2.85-3.03 (m, 1H), 3.04-3.17 (m, 1H).

Example 4

Intermediate 4

tert-Butyl (2-(1-(3-(4-bromophenyl)ureido)-4-ethyl-2,5-dioxoimidazolidin-4-yl) ethyl)carbamate

(66) ##STR00007##

(67) A solution of Intermediate 3 (64 mg, 0.23 mmol), 4-bromophenyl isocyanate (50 mg, 0.25 mmol) in dioxane (5 mL) was stirred at RT for 1 h. The solvent was removed under reduced pressure and the crude product was purified by silicagel chromatography using EtOAc in hexane as eluent. Intermediate 4 was isolated as a white solid.

(68) .sup.1HNMR (CD.sub.3OD) : 0.81-1.00 (m, 3H), 1.40 (br s, 9H), 1.64-1.92 (m, 3H), 2.00-2.17 (m, 1H), 2.90-3.12 (m, 1H), 3.17-3.32 (m, 1H), 7.24-7.47 (m, 4H).

Example 5

Intermediate 5

1-(4-(2-Aminoethyl)-4-ethyl-2,5-dioxoimidazolidin-1-yl)-3-(4-bromophenyl)urea

(69) ##STR00008##

(70) A solution of Intermediate 4 (60 mg, 0.12 mmol), CF.sub.3CO.sub.2H (1 mL) and CH.sub.2Cl.sub.2 (5 mL) was stirred at ambient temperature for 2 h. Solvent was removed under reduced pressure, the crude Intermediate 5 was used as it is in the next step.

Example 6

Compound 1

Ethyl 3-{[2-(1-{[(4-Bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate

(71) ##STR00009##

(72) A mixture of crude intermediate 5 (47 mg, 0.12 mmol), ethyl acrylate (1 mL, excess), Et.sub.3N (1 mL) and EtOH (7 mL) was heated to 50 C. for 2 days. The solvent was removed under reduced pressure, and the crude reaction mixture was purified by silicagel chromatography using MeOH in CH.sub.2Cl.sub.2. Compound 1 was isolated as thick yellow oil.

(73) .sup.1HNMR (CD.sub.3OD) : 0.93 (t, J=7.3 Hz, 3H), 1.20 (t, J=6.9 Hz, 3H), 1.62-1.81 (m, 2H), 2.09-2.24 (m, 1H), 2.35-2.51 (m, 1H), 2.60 (t, J=6.9 Hz, 2H), 3.39-3.52 (m, 3H), 3.57-3.73 (m, 1H), 4.11 (q, J=6.9 Hz, 2H), 7.40 (s, 4H).

Biological Data

(74) Biological activity of compounds according to Formula I is set forth in Table 1 below. CHO-G16 cells stably expressing FPR2 were cultured in F12 media (10% FBS, 1% PSA, 400 g/ml geneticin and 50 g/ml hygromycin). In general, the day before the experiment, 18,000 cells/well were plated in a 384-well clear bottom poly-D-lysine coated plate. The following day the screening compound-induced calcium activity was assayed on a FLIPR.sup.Tetra. The drug plates were prepared in 384-well microplates using EP3 and MultiPROBE robotic liquid handling systems. Compounds were tested at concentrations ranging from 0.61 to 10,000 nM. Results are expressed as EC.sub.50 (nM) and % efficacy values.

(75) TABLE-US-00001 TABLE 1 FPR2 G16-CHO Com- EC.sub.50 nM pound Compound IUPAC name (% eff) 1 Ethyl 3-{[2-(1-{[(4-Bromo- 49 phenyl)carbamoyl]amino}-4-ethyl-2,5- (0.97) dioxoimidazolidin-4-yl)ethyl]amino}propanoate