Carbamoyl hydrazine derivatives as formyl peptide modulators
09868700 ยท 2018-01-16
Assignee
Inventors
- Vidyasagar Vuligonda (Irvine, CA)
- Thong Vu (Garden Grove, CA)
- Veena Viswanath (Irvine, CA)
- John E. Donello (Dana Point, CA)
- Richard L. Beard (Newport Beach, CA)
Cpc classification
C07C275/30
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to carbamoyl hydrazine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of the FPR receptor.
Claims
1. A compound of Formula I: ##STR00037## R.sup.1 is H, optionally substituted C.sub.1-6alkyl, C.sub.1-6haloalkyl, optionally substituted C.sub.3-8cycloalkyl, optionally substituted C.sub.6-10aryl, optionally substituted heterocycle, halogen, OR.sup.10, C.sub.2-6alkenyl, C.sub.2-6alkynyl, CN, C(O)R.sup.11, amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R.sup.2 is H, C.sub.1-6alkyl, optionally substituted C.sub.3-8cycloalkyl, optionally substituted C.sub.6-10aryl, optionally substituted heterocycle, C.sub.2-6alkenyl, C.sub.2-6 alkynyl, CN, C(O)R.sup.11, amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R.sup.3 is optionally substituted C.sub.1-6alkyl, C.sub.1-6haloalkyl, optionally substituted C.sub.3-8cycloalkyl, optionally substituted C.sub.6-10aryl, optionally substituted heterocycle, halogen, OR.sup.10, C.sub.2-6alkenyl, C.sub.2-6alkynyl, CN, C(O)R.sup.11, amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R.sup.4 is H, C.sub.1-6alkyl, optionally substituted C.sub.3-8cycloalkyl, optionally substituted C.sub.6-10aryl, optionally substituted heterocycle, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, CN, C(O)R.sup.11, amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R.sup.5 is H, optionally substituted C.sub.1-6alkyl, C.sub.1-6haloalkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10aryl, optionally substituted heterocycle, halogen, OR.sup.10, C.sub.2-6alkenyl, C.sub.2-6alkynyl, CN, C(O)R.sup.11, amine, amide, urea, sulfonamide, sulfone, sulfoxide, sulfide, sulfonic acid, nitro, phosphate or phosphonic acid; R.sup.6 is H or optionally substituted C.sub.1-6alkyl; R.sup.7 is H or optionally substituted C.sub.1-6alkyl; R.sup.8 is H or optionally substituted C.sub.1-6alkyl; R.sup.9 is H or optionally substituted C.sub.1-6alkyl; a is 0, 1, 2 or 3; R.sup.10 is optionally substituted C.sub.1-6alkyl; R.sup.11 is OH, OC.sub.1-6alkyl or optionally substituted C.sub.1-6alkyl; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl or halogen; R.sup.4 is H; R.sup.5 is H or halogen; and R.sup.9 is H or optionally substituted C.sub.1-6alkyl.
3. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl; R.sup.4 is H; R.sup.5 is H or halogen; and R.sup.9 is H or optionally substituted C.sub.1-6alkyl.
4. The compound according to claim 2, wherein R.sup.3 is halogen.
5. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl or halogen; R.sup.4 is H; R.sup.5 is H or halogen; and R.sup.9 is H.
6. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl or halogen; R.sup.4 is H; R.sup.5 is H or halogen; R.sup.9 is H; and a is 0 or 1.
7. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl; R.sup.4 is H; R.sup.5 is H or halogen; and R.sup.9 is H.
8. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl; R.sup.4 is H; R.sup.5 is H or halogen; and R.sup.9 is optionally substituted C.sub.1-6alkyl.
9. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is halogen; R.sup.4 is H; R.sup.5 is H or halogen; and R.sup.9 is H.
10. The compound according to claim 2, wherein R.sup.3 is halogen, R.sup.3 is halogen; and R.sup.9 is optionally substituted C.sub.1-6 alkyl.
11. The compound according to claim 1, wherein: R.sup.1 is H or halogen; R.sup.2 is H; R.sup.3 is C.sub.1-6haloalkyl or halogen; R.sup.4 is H; R.sup.5 is H or halogen; R.sup.6 is optionally substituted C.sub.1-6alkyl; R.sup.7 is H; R.sup.8 is H; R.sup.9 is H or optionally substituted C.sub.1-6 alkyl; and a is 0 or 1.
12. The compound according to claim 1, wherein R.sup.7 is C.sub.1-6 alkyl, R.sup.8 is C.sub.1-6 alkyl, and a is 0 or 1.
13. The compound according to claim 12, selected from the group consisting of: ##STR00038## and pharmaceutically acceptable salts thereof.
14. The compound according to claim 1, which is: ##STR00039## or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.
16. The pharmaceutical composition according to claim 15 comprising as active ingredient a therapeutically effective amount of a compound of claim 13.
17. The pharmaceutical composition according to claim 15 comprising as active ingredient a therapeutically effective amount of a compound of claim 14.
Description
DETAILED DESCRIPTION OF THE INVENTION
(1) 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.
(2) 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 mixtures thereof, including racemic mixtures. 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.
(3) 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.
(4) 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.
(5) As will be evident to those skilled in the art, individual diastereoisomeric forms can be obtained by separation of mixtures thereof in a conventional manner. For example, chromatographic separation may be employed; chiral chromatography may be performed to separate individual enantiomers.
(6) Compound names were generated with ACDLab version 12.5; some intermediates' and reagents' names used in the examples were generated with softwares such as Chem Bio Draw Ultra version 12.0, ACDLab version 12.5 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1.
(7) In general, characterization of the compounds was performed using NMR spectra, which 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. 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.
(8) Usually the compounds of the invention were purified by column chromatography (Auto-column) on Teledyne-ISCO CombiFlash with a silica column, unless noted otherwise.
(9) The following abbreviations are used in the examples:
(10) THF tetrahydrofuran
(11) CD.sub.3OD deuterated methanol
(12) RT room temperature
(13) CH.sub.2Cl.sub.2 dichloromethane
(14) EtOAc ethyl acetate
(15) EtOH ethanol
(16) Et.sub.3N triethylamine
(17) DMSO-D6 deuterated dimethylsulfonamide
(18) K.sub.2CO.sub.3 potassium carbonate
(19) HCl hydrochloric acid
(20) CD.sub.3CN deuterated acetonitrile
(21) NaCNBH.sub.3 sodium borohydride
(22) EtOAc ethyl acetate
(23) NaHCO.sub.3 sodium bicarbonate
(24) AcOH acetic acid
(25) CDCl.sub.3 deuterated chloroform
(26) TLC thin layer chromatography
(27) EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
(28) HOBT 1H-benzotriazol-1-ol
(29) LiOH lithium hydroxide
(30) H.sub.2O water
(31) KOH potassium hydroxide
Example 1
Intermediate 1
(E)-N-(4-Bromophenyl)-2-(2-methylpropylidene)hydrazinecarboxamide
(32) ##STR00009##
(33) A mixture of N-(4-bromophenyl)-hydrazinecarboxamide CAS#2646-26-6 (231 mg, 1 mmol), isobutyraldehyde CAS#78-84-2 (86 mg, 1.2 mmol), K.sub.2CO.sub.3 (304 mg, 1.2 mmol) in THF (5 mL) was stirred for 2 h. The reaction mixture was diluted with EtOAc (15 mL), washed with dilute aq. HCl (0.5% solution, 5 mL). The EtOAc layer was dried and the solvent was removed. Intermediate 1 was isolated as a white solid.
(34) .sup.1HNMR (CD.sub.3CN) : 1.12 (d, J=7.0 Hz, 6H), 2.48-2.59 (m, 1H), 7.18 (d, J=4.98 Hz, 1H), 7.42-7.53 (m, 4H).
(35) Intermediates 3, 5, 7 and 9 were prepared from the corresponding hydrazinecarboxamides and aldehydes, in a similar manner to the procedure described in Example 1 for Intermediate 1. The results are described below in Table 1.
(36) TABLE-US-00002 TABLE 1 Interme- diate IUPAC name Hydrazine No. Structure carboxamide Aldehyde 3
Example 2
Intermediate 2
N-(4-Bromophenyl)-2-isobutylhydrazinecarboxamide
(37) ##STR00014##
(38) To a mixture of Intermediate 1 (580 mg, 2.05 mmol) and NaCNBH.sub.3 (196 mg, 3.1 mmol) in THF (8 mL) was added AcOH (326 mg, 4.1 mmol) and stirred at RT for 6 h. All of the solvent was removed and the crude mixture was dissolved in EtOAc (50 mL), washed with aq. NaHCO.sub.3 (10% solution, 10 mL), brine, dried and the solvent was removed. The crude mixture was purified by silica gel chromatography, using EtOAc in hexane as eluent. Intermediate 2 was isolated as a white solid.
(39) .sup.1HNMR (CD.sub.3CN) : 0.97 (d, J=6.7 Hz, 6H), 1.75-1.87 (m, 1H), 2.61 (d, J=6.7 Hz, 2H), 7.38 (s, 4H).
(40) Intermediates 4, 6, 8 and 10 were prepared from in a similar manner to the procedure described in Example 2 for Intermediate 2. The results are described below in Table 2.
(41) TABLE-US-00003 TABLE 2 From Interm. IUPAC name Interm. No. Structure No. .sup.1H NMR (ppm) 4
Example 3
Compound 1
Ethyl 3-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-3-oxopropanoate
(42) ##STR00020##
(43) To a solution of N-(4-bromophenyl)hydrazinecarboxamide (CAS#2646-26-6; 100 mg, 0.44 mmol), and Et.sub.3N (88 mg, 0.88 mmol) in CH.sub.2Cl.sub.2 (3 mL) and DMF (1 mL) was added 3-chloro-3-oxo-propanoic acid ethyl ester (CAS#36239-09-5; 75 mg, 0.5 mmol). The mixture was stirred at RT for 18 h; then the solvent was removed, and the crude mixture was purified by preparative TLC. Compound 1 was isolated as a white solid.
(44) .sup.1HNMR (CD.sub.3OD) : 1.35 (t, J=7.5 Hz, 3H), 3.31 (s, 2H), 4.25 (q, J=7.5 Hz, 2H), 7.40 (s, 4H).
Example 4
Compound 2
3-{2-[(4-Bromophenyl)carbamoyl]hydrazinyl}-2,2-dimethyl-3-oxopropanoic acid
(45) ##STR00021##
(46) A mixture of N-(4-bromophenyl)hydrazinecarboxamide (CAS#2646-26-6; 100 mg, 0.44 mmol), EDC (130 mg, 0.66 mmol), HOBT (90 mg, 0.66 mmol), 4-methyl morpholine (131 mg, 1.32 mmol) and dimethylmalonic acid (58 mg, 0.44 mmol) in CH.sub.2Cl.sub.2 (5 mL) was stirred at RT for 18 h. The solvent was removed and the crude mixture was purified by preparative TLC. Compound 2 was isolated as a white solid.
(47) .sup.1HNMR (CD.sub.3OD) : 1.31 (s, 6H), 7.42 (brs, 4H).
(48) Compounds 3, 4 and 6 were prepared in a similar manner to the procedure described in Example 4 for Compound 2. The results are shown below in Table 3.
(49) TABLE-US-00004 TABLE 3 Cmpd. IUPAC name Starting .sup.1H NMR No. Structure materials (ppm) 3
Example 5
Compound 5
2-[2-(2-{[(4-Bromophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-2-propylpentanoic Acid
(50) ##STR00025##
(51) A mixture of Compound 4 (280 mg, 0.65 mmol) LiOHH.sub.2O (1 M solution, 2, mL) and methanol (5 mL) was stirred for 5 h at RT. The reaction was quenched with 10% HCl solution (2 mL), extracted with EtOAC, the organic layer was washed with brine, dried and solvent removed. The crude product was purified by preparative TLC. Compound 5 was isolated as a light yellow solid.
(52) .sup.1HNMR (CD.sub.3OD) : 0.93 (br s, 6H), 1.29 (br s, 4H), 1.65 (br s, 4H), 2.70 (br s, 2H), 7.23-7.51 (m, 4H).
Example 6
Compound 7
Ethyl 4-{2-[(4-Bromophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoate
(53) ##STR00026##
(54) To a cold (0 C.) mixture of Intermediate 2 (183 mg, 0.63 mmol), Et.sub.3N (77 mg, 0.77 mmol) in dioxane (4 mL) was added 4-chloro-4-oxo-butanoic acid ethyl ester (CAS#14794-31-1; 115 mg, 0.69 mmol). The mixture was stirred at RT for 2 h. The reaction was diluted with EtOAc (50 mL), washed with aq. NaHCO.sub.3 (10 mL), dried and solvent removed. The crude product was recrystallized from hot methanol. Compound 7 was isolated as a white solid.
(55) .sup.1HNMR (CD.sub.3CN): 0.93 (br d, 6H), 1.23 (t, J=7.3 Hz, 3H), 1.82-1.95 (m, 1H), 2.54 (t, J=6.1 Hz, 2H), 2.62 (br. d, 2H), 2.78 (t, J=6.1 Hz, 2H), 4.12 (q, J=7.3 Hz, 2H), 7.37-7.49 (m, 4H).
(56) Compounds 9, 11, 13, 15 and 16 were prepared in a similar manner to the procedure described in Example 6 for Compound 7. The results are described below in Table 4.
(57) TABLE-US-00005 TABLE 4 Compound IUPAC name Interm. .sup.1H NMR No. Structure No (ppm) 9
Example 7
Compound 8
4-{2-[(4-Bromophenyl)carbamoyl]-1-(2-methylpropyl)hydrazinyl}-4-oxobutanoic Acid
(58) ##STR00032##
(59) A mixture of Compound 7 (90 mg, 0.22 mmol), KOHH.sub.2O (1 M solution, 1 mL), EtOH (1 mL) and dioxane (1 mL) was stirred at RT for 3 h. About 80% of the solvent was removed, the crude mixture cooled to 78 C. and acidified with aq. HCl. Compound 8 was collected as a white solid.
(60) .sup.1HNMR (DMSO-D.sub.6): 0.93 (br s, 6H), 1.82-1.99 (m, 1H), 2.53 (br. s, 2H), 2.85 (br. s, 2H), 2.30 (br. s, 2H), 7.55 (s, 4H).
(61) Compounds 10, 12, 14 and 17 were prepared in a similar manner to the procedure described in Example 7 for Compound 8. The results are described below in Table 5.
(62) TABLE-US-00006 TABLE 5 Compound IUPAC name Starting .sup.1H NMR No. Structure Compound (ppm) 10
Biological Data
(63) Compounds of Formula I modulate FPR activity. For example, the data set forth in Table 6 below show that compounds of Formula I modulate FPR2 activity. HEK-G16 and CHO-G16 cells stably expressing FPR2 were cultured in (F12, 10% FBS, 1% PSA, 400 g/ml geneticin and 50 g/ml hygromycin) and HEK-Gqi5 cells stable expressing FPR2 were cultured in (DMEM high glucose, 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 the FLIPR Tetra. The drug plates were prepared in 384-well microplates using the EP3 and the MuItiPROBE 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.
(64) TABLE-US-00007 TABLE 6 EC.sub.50 nM Compound IUPAC name (% Efficacy) ethyl 3-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-3- 750 (100) oxopropanoate 3-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2,2- 5212 (73) dimethyl-3-oxopropanoic acid 4-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2,2- 602 (86) dimethyl-4-oxobutanoic acid methyl 2-(2-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}- 46 (89) 2-oxoethyl)-2-propylpentanoate 2-(2-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2- 215 (87) oxoethyl)-2-propylpentanoic acid 4-{2-[(4-bromophenyl)carbamoyl]hydrazinyl}-2,2- 421 (73) diethyl-4-oxobutanoic acid ethyl 4-{2-[(4-bromophenyl)carbamoyl]-1-(2- 31 (100) methylpropyl)hydrazinyl}-4-oxobutanoate 4-{2-[(4-bromophenyl)carbamoyl]-1-(2- 12 (100) methylpropyl)hydrazinyl}-4-oxobutanoic acid ethyl 4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1-(2- 3659 (76) methylpropyl)hydrazinyl}-4-oxobutanoate 4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1-(2- 339 (99) methylpropyl)hydrazinyl}-4-oxobutanoic acid ethyl 4-[1-(2-methylpropyl)-2-{[4- 57 (94) (trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4- oxobutanoate 4-[1-(2-methylpropyl)-2-{[4- 21 (98) (trifluoromethyl)phenyl]carbamoyl}hydrazinyl]-4- oxobutanoic acid ethyl 4-oxo-4-(1-propyl-2-{[4- 35 (98) (trifluoromethyl)phenyl]carbamoyl}hydrazinyl)butanoate 4-oxo-4-(1-propyl-2-{[4- 28 (97) (trifluoromethyl)phenyl]carbamoyl}hydrazinyl)butanoic acid ethyl 4-{2-[(4-bromophenyl)carbamoyl]-1- 34 (100) butylhydrazinyl}-4-oxobutanoate ethyl 4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1- 34 (100) propylhydrazinyl}-4-oxobutanoate 4-{2-[(4-bromo-2-fluorophenyl)carbamoyl]-1- 29 (100) propylhydrazinyl}-4-oxobutanoic acid