Opioid agonists and uses thereof

Abstract

Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.

Claims

1. A compound selected from the formula: ##STR00128## wherein: R.sup.2 is an substituted alkyl; (i) R.sup.1 and R.sup.3 are taken together with their intervening atoms to form a fused, substituted thiazole and R.sup.5 is hydrogen, where R.sup.1 and R.sup.3 are positions 4 and 5 of the thiazole, wherein the thiazole is substituted with X-POLY at position 2 of the thiazole; or (ii) R.sup.3 and R.sup.5 are taken together with their intervening atoms to form a fused, substituted thiazole and R.sup.1 is hydrogen, where R.sup.1 and R.sup.3 are positions 4 and 5 of the thiazole, wherein the thiazole is substituted with X-POLY at position 2 of the thiazole; is a double bond; G is O; X is a spacer moiety selected from a covalent bond, C(O), NHC(O), NH, CH.sub.2CHOHCH.sub.2NH, and O; POLY is a poly(alkylene oxide) oligomer; or pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein R.sup.5 is hydrogen.

3. The compound of claim 1, wherein R.sup.2 is alkyl or cyclopropylmethyl.

4. The compound of claim 1, wherein R.sup.1 is hydrogen.

5. The compound of claim 1, wherein the compound of Formula I is selected from the formulae: ##STR00129## and wherein n is an integer from 1 to 30.

6. The compound of claim 5, wherein n is an integer from 1 to 10.

7. The compound of claim 1, wherein R.sup.3 and R.sup.5 are taken together with their intervening atoms to form the substituted thiazole.

8. A compound, selected from (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one; and (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5,4:3,4]benzo[1,2-d]azocin-6(7H)-one; or pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.

10. A composition of matter comprising the compound of claim 1, wherein the compound is present in a dosage form.

11. The compound of claim 1, wherein the poly(alkylene oxide) oligomer is a poly(alkylene glycol) oligomer.

Description

EXAMPLES

(1) All chemical reagents referred to in the appended examples are commercially available unless otherwise indicated. The preparation of PEG-mers is described in, for example, U.S. Patent Application Publication No. 2005/0136031.

Example 1

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (1)

(2) ##STR00029##

(3) (2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (1) was prepared according to the following steps.

Step 1: Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yl trifluoromethanesulfonate

(4) ##STR00030##

(5) Ketazocine (0.50 g, 1.75 mmol) was dissolved in anhydrous dichloromethane (40 mL) and triethylamine (1.24 mL, 8.76 mmol). The light-yellow solution was cooled to 0 C. and added N-phenyl-bis(trifluoromethanesulfonimide) (0.94 g, 2.63 mmol). The yellow reaction mixture was allowed to equilibrate to room temperature. After approximately 17 hours the reaction mixture was diluted with dichloromethane (50 mL). The mixture was transferred to a separatory funnel and washed with water (40 mL), 1N sodium hydroxide (40 mL) and saturated sodium chloride (40 mL). The organic portion was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on a column of silica gel using dichloromethane/methanol (9:1) as eluent to give (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yl trifluoromethanesulfonate (0.64 g, 88%) as a yellow oil. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.09 (m, 1H), 7.22 (m, 2H), 3.32 (m, 1H), 2.93 (m, 1H), 2.67 (m, 1H), 2.23 (m, 1H), 2.09 (m, 1H), 2.01 (m, 2H), 1.95 (m, 1H), 1.53 (m, 1H), 1.50 (s, 3H), 0.87 (m, 2H), 0.50 (m, 2H), 0.07 (m, 1H), 0.05 (m, 1H); MS (EI) for C.sub.19H.sub.22F.sub.3NO.sub.4S: 418 (MH.sup.+).

Step 2: Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (1)

(6) (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yl trifluoromethanesulfonate (33 mg, 0.079 mmol) from step 1, 2-[2-(2-methoxyethoxy)ethoxy]ethanamine (40 mg, 0.24 mmol) and 1-methyl-2-pyrrolidinone (3 mL) were added to a 2-5 mL microwave vial, and then heated under microwave irradiation for 2 hours at 200 C. The reaction mixture was cooled to room temperature, poured into 12 mL water and extracted with methyl tert-butyl ether (35 mL). The combined organic portions were washed with water (20 mL) and saturated sodium chloride (20 mL) and then dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography using methanol/dichloromethane (1:9) as eluent to give 0.012 g (35%) of (2S,6R,11R)-3-(cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (1) as a yellow oil. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.85 (s, 1H), 6.50 (m, 1H), 6.39 (s, 1H), 4.84 (m, 1H), 3.74 (m, 2H), 3.72 (m, 6H), 3.66 (m, 2H), 3.37 (m, 5H), 2.91 (m, 1H), 2.76 (m, 1H), 2.12 (m, 2H), 2.01 (m, 3H), 1.52 (m, 1H), 1.31 (m, 3H), 0.89 (m, 4H), 0.47 (m, 2H), 0.25 (m, 1H), 0.05 (m, 1H); MS (EI) for C.sub.25H.sub.38N.sub.2O.sub.4: 431 (MH.sup.+).

Example 2

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (2)

(7) ##STR00031##

(8) (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yl trifluoromethanesulfonate (0.10 g, 0.24 mmol) (from Example 1, step 1), 2,5,8,11,14-pentaoxahexadecan-16-amine (0.18 g, 0.73 mmol) and 1-methyl-2-pyrrolidinone (3 mL) were added to a 2-5 mL microwave vial, and then heated under microwave irradiation for 2 hours at 200 C. The reaction mixture was cooled to room temperature, poured into 12 mL water and extracted with methyl tert-butyl ether (35 mL). The combined organic portions were washed with water (20 mL) and saturated sodium chloride (20 mL) and then dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography using methanol/dichloromethane (1:9) as eluent to give 0.012 g (35%) of (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one as a yellow oil. .sup.1H NMR (500 MHz, CDCl3): 7.85 (m, 1H), 6.48 (m, 1H), 6.39 (m, 1H), 4.92 (m, 1H), 3.72 (m, 2H), 3.63 (m, 15H), 3.55 (m, 2H), 3.37 (m, 5H), 2.90 (m, 1H), 2.74 (m, 1H), 2.12-1.95 (m, 4H), 1.51 (m, 1H), 1.38 (s, 3H), 0.89 (m, 4H), 0.47 (m, 2H), 0.25 (m, 1H), 0.05 (m, 1H); MS (EI) for C.sub.29H.sub.46N.sub.2O.sub.6: 519 (MH.sup.+).

Example 3

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (3)

(9) ##STR00032##

(10) (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-yl trifluoromethanesulfonate (0.10 g, 0.24 mmol) (from Example 1, step 1), 2,5,8,11,14,17,20-heptaoxadocosan-22-amine (0.18 g, 0.73 mmol) and 1-methyl-2-pyrrolidinone (3 mL) were added to a 2-5 mL microwave vial, and then heated under microwave irradiation for 2 hours at 200 C. The reaction mixture was cooled to room temperature, poured into 12 mL water and extracted with methyl tert-butyl ether (35 mL). The combined organic portions were washed with water (20 mL) and saturated sodium chloride (20 mL) and then dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography using methanol/dichloromethane (1:9) as eluent to give 0.08 g (55%) of (2S,6R,11R)-3-(cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one as a yellow oil. .sup.1H NMR (500 MHz, CDCl3): 7.85 (m, 1H), 6.49 (m, 1H), 6.38 (m, 1H), 3.73 (m, 2H), 3.72 (m, 24H), 3.71 (m, 2H), 3.54 (m, 5H), 2.97 (m, 1H), 2.75 (m, 1H), 2.15 (m, 1H), 2.01 (m, 3H), 1.49 (m, 1H), 1.38 (s, 3H), 0.89 (m, 3H), 0.48 (m, 2H), 0.46 (m, 2H), 0.25 (m, 1H); MS (EI) for C.sub.33H.sub.54N.sub.2O.sub.8: 607 (MH.sup.+).

Example 4

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (4)

(11) ##STR00033##

(12) Into a three-necked flask was placed ketazocine (0.47 g, 1.66 mmol), potassium carbonate (0.57 g, 4.16 mmol), 2-[2-(2-methoxyethoxy)ethoxy]ethyl methanesulfonate (0.44 g, 1.83 mmol) in acetone (35 mL). The yellow reaction mixture was heated to reflux and stirred under nitrogen. After approximately 17 hours reflux the yellow mixture was cooled to room temperature. The solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane (25 mL each). The aqueous layer was extracted with dichloromethane (312 mL). The combined organic portions were washed with water and saturated sodium chloride (225 mL each). The organic portion was filtered and concentrated and the residue was purified on a column of silica gel using dichloromethane/methanol (9:1) as eluent to give (2S,6R,11R)-3-(cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (64 mg, 37% yield), as a light-yellow oil. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.80 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), 4.19 (m, 2H), 3.75 (m, 2H), 3.75 (m, 2H), 3.58-3.42 (m, 8H), 3.33 (s, 3H), 3.13 (m, 1H), 2.77 (m, 1H), 2.47 (m, 2H), 2.05-1.85 (m, 4H), 1.45 (m, 1H), 1.38 (s, 3H), 0.85 (m, 1H0, 0.77 (m, 3H), 0.42 (m, 2H), 0.19 (m, 1H); MS (EI) for C.sub.25H.sub.37NO.sub.5: 432 (MH.sup.+).

(13) The compound was converted into the hydrochloride salt by dissolving the oil in acetonitrile and adding 1N hydrochloric acid. The solution was lyopholized to give the hydrochloride salt as a white powder.

Example 5

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (5)

(14) ##STR00034##

(15) Into a three-necked flask was placed ketazocine (0.10 g, 0.35 mmol), potassium carbonate (0.12 g, 0.87 mmol), 2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate (0.12 g, 0.38 mmol) in acetone (12 mL). The yellow reaction mixture was heated to reflux and stirred under nitrogen. After approximately 17 hours reflux the yellow mixture was cooled to room temperature. The solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane (10 mL each). The aqueous layer was extracted with dichloromethane (38 mL). The combined organic portions were washed with water and saturated sodium chloride (215 mL each). The organic portion was filtered and concentrated and the residue was purified on a column of silica gel using dichloromethane/methanol (9:1) as eluent to give (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (0.11 g, 63% yield), as a light-yellow oil. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.95 (m, 1H), 6.82 (m, 2H), 4.19 (m, 2H), 3.81 (m, 2H), 3.75-3.56 (m, 16H), 3.34 (s, 3H), 3.25 (m, 1H), 2.92 (m, 1H), 2.71 (m, 1H), 2.18 (m, 1H), 1.94 (m, 3H), 1.50 (m, 1H), 1.40 (s, 3H), 0.88 (m, 4H), 0.49 (m, 2H), 0.30 (m, 1H), 0.10 (m, 1H); MS (EI) for C.sub.29H.sub.45NO.sub.7: 520 (MH.sup.+).

Example 6

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (6)

(16) ##STR00035##

(17) Into a three-necked flask was placed ketazocine (0.10 g, 0.35 mmol), potassium carbonate (0.12 g, 0.87 mmol), 2,5,8,11,14,17,20-heptaoxadocosan-22-yl methanesulfonate (0.15 g, 0.36 mmol) in acetone (10 mL). The yellow reaction mixture was heated to reflux and stirred under nitrogen. After approximately 17 hours reflux the yellow mixture was cooled to room temperature. The solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane (10 mL each). The aqueous layer was extracted with dichloromethane (38 mL). The combined organic portions were washed with water and saturated sodium chloride (215 mL each). The organic portion was filtered and concentrated and the residue was purified on a column of silica gel using dichloromethane/methanol (9:1) as eluent to give (2S,6R,11R)-3-(cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one (0.12 g, 57% yield), as a light-yellow oil. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.95 (m, 1H), 6.84-6.81 (m, 2H), 4.18 (m, 2H), 3.87 (m, 2H), 3.73-3.52 (m, 24H), 3.38 (s, 3H), 3.24 (m, 1H), 2.92 (m, 1H), 2.71 (m, 1H), 2.15 (m, 1H), 1.98 (m, 3H), 1.52 (m, 1H), 1.41 (s, 3H), 0.86 (m, 4H), 0.47 (m, 2H), 0.26 (m, 1H), 0.06 (m, 1H); MS (EI) for C.sub.33H.sub.53NO.sub.9: 608 (MH.sup.+).

Example 7

Preparation of (2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (7)

(18) ##STR00036##

(19) (2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (7) was prepared according to the following steps.

Step 1: Preparation of tert-butyl (2-hydroxyphenyl)carbamate

(20) ##STR00037##

(21) 2-Amino phenol (6 g, 55 mmol) was dissolved in 60 mL of THF. (Boc).sub.2O (12 g, 55 mmol) was added to the above mixture and stirred for 16 h. The mixture was concentrated under vacuum to get a gummy mass. Gummy mass was precipitated using 20% MTBE/Hexane. Precipitated solid was filtered and washed with hexane to afford tert-butyl (2-hydroxyphenyl)carbamate (11.2 g, 97% yield)

Step 2: Preparation of tert-butyl (2-(2,5,8,11,14-pentaoxahexadecan-yloxy)phenyl)carbamate

(22) ##STR00038##

(23) tert-Butyl (2-hydroxyphenyl)carbamate (3 g, 14.34 mmol), mPEG.sub.5-OMs (5.21 g, 15.77 mmol) and K.sub.2CO.sub.3 (5.94 g. 43.0 mmol) were dissolved in 20 mL of DMF. The mixture was heated to 80 C. and stirred at that temperature for 18 h. Reaction was cooled to 25 C. and concentrated under vacuum to get a gummy mass. The gummy residue was dissolved in 30 mL of water (10 vol) and compound was extracted in EtOAc. Organic layer was washed with 1M aq NaOH and brine sequentially, then dried over anhydrous sodium sulfate & concentrated under vacuum to afford tert-butyl (2-(2,5,8,11,14-pentaoxahexadecan-yloxy)phenyl)carbamate (22) (4 g, 63% yield) as a viscous liquid.

Step 3: Preparation of 2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline

(24) ##STR00039##

(25) tert-Butyl (2-(2,5,8,11,14-pentaoxahexadecan-yloxy)phenyl)carbamate (3.2 g, 7.21 mmol) was dissolved in 25 mL of 4M HCl in IPA. The mixture was stirred for 1 h and concentrated under vacuum. The residue was dissolved in 50 mL of water and pH of the aqueous solution was adjusted to 9.0 (using 1M aq. NaOH). Compound was extracted into ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum to obtain (2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline as pale yellow gum (2 g, 86% yield).

Step 4: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

(26) ##STR00040##

(27) (2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (500 mg, 1.75 mmol) and triethyl amine (1.23 mL, 8.76 mmol) were dissolved in 10 mL of dichloromethane. PhNTf.sub.2 (925 mg, 18.75 mmol) was added to the above mixture and the reaction, stirred for 16 h. upon completion the reaction was concentrated, Crude thus obtained, was purified (by column chromatography) to get (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (709 mg, 97% yield).

Step 5: Preparation of (2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (7)

(28) ##STR00041##

(29) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (200 mg, 0.48 mmol) and (2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline (197 mg, 0.575 mmol) were dissolved in toluene. BINAP (89 mg, 0.144 mmol), Pd.sub.2(dba).sub.3 (88 mg, 0.096 mmol) & Cs.sub.2CO.sub.3 (219 mg, 0.671 mmol) were added to the above mixture and stirred under heating at 110 C. for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by column chromatography to get (2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (7) (163 mg, 56% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.9 (d, 1H), 7.4-7.42 (m, 1H), 6.90-7.0 (m, 5H), 6.75 (m, 1H), 4.19 (t, 2H), 3.86 (t, 2H), 3.67-3.71 (m, 2H), 3.60-3.65 (m, 12H), 3.51-3.53 (m, 2H), 3.36 (s, 3H), 3.23 (m, 1H), 2.91-2.94 (m, 1H), 2.72-2.76 (m, 1H), 2.12-2.14 (m, 1H), 1.97-2.08 (m, 3H), 1.39 (s, 3H), 1.25 (m, 1H), 0.88-0.91 (m, 4H), 0.46-0.48 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.08 (m, 1H); MS (ESI) for C.sub.35H.sub.50N.sub.2O.sub.7: 611.3289 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 8

Preparation of (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (8)

(30) ##STR00042##

(31) (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (24) was prepared according to the following steps.

Step 1: Preparation of 3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline

(32) ##STR00043##
was prepared using procedures similar to Example 7, steps 1-3, wherein 3-amino phenol was used in place of 2-amino phenol in step 1. The product, 3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline was prepared as a yellow gum (2.5 g, 90% yield)

Step 2: Preparation of (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (8)

(33) ##STR00044##

(34) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (prepared in a manner similar to Example 7, step 4) (200 mg, 0.48 mmol) and 3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline) (197 mg, 0.575 mmol) were dissolved in toluene. BINAP (89 mg, 0.144 mmol), Pd.sub.2(dba).sub.3 (88 mg, 0.096 mmol) & Cs.sub.2CO.sub.3 (219 mg, 0.671 mmol) were added to the above mixture. The reaction mixture was heated to 110 C. & stirred for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by column chromatography to yield (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (8) (200 mg, 68.3% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.88 (d, 1H), 7.2-7.24 (m, 1H), 6.92-6.94 (m, 1H), 6.83 (d, 1H), 6.74-6.78 (m, 2H), 6.62-6.64 (m, 1H), 6.19 (s, 1H), 4.12 (t, 2H), 3.85 (t, 2H), 3.63-3.73 (m, 14H), 3.53-3.55 (m, 2H), 3.36 (s, 3H), 3.23 (m, 1H), 2.91-2.94 (m, 1H), 2.72-2.76 (m, 1H), 2.11-2.13 (m, 1H), 1.97-2.08 (m, 3H), 1.38 (s, 3H), 1.25 (m, 1H), 0.89-0.91 (m, 4H), 0.46-0.49 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.08 (m, 1H); MS (ESI) for C.sub.35H.sub.50N.sub.2O.sub.7: 611.3289 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 9

Preparation of (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (9)

(35) ##STR00045##

(36) (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one hydrochloride (28) was prepared according to the following steps.

Step 1: 4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline

(37) ##STR00046##
was prepared using procedures similar to Example 7, steps 1-3, wherein 4-amino phenol was used in place of 2-amino phenol in step 1. The product, 4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline was isolated as a yellow gum (2.35 g, 96% yield)

Step 2: Preparation of (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (9)

(38) ##STR00047##

(39) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (prepared in a manner similar to Example 7, step 4) (150 mg, 0.36 mmol) and 4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)aniline (148 mg, 0.431 mmol) were dissolved in toluene. BINAP (67 mg, 0.108 mmol), Pd.sub.2(dba).sub.3 (66 mg, 0.072 mmol) & Cs.sub.2CO.sub.3 (328 mg, 1.00 mmol) were added to the above mixture and heated (110 C.) for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by column chromatography to afford (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (9) (180 mg, 61.5% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.85 (d, 1H), 7.11-7.13 (m, 2H), 6.91-6.93 (m, 2H), 6.71-6.73 (m, 1H), 6.65 (m, 1H), 5.94 (bs, 1H), 4.14 (t, 2H), 3.87 (t, 2H), 3.63-3.75 (m, 14H), 3.53-3.55 (m, 2H), 3.37 (s, 3H), 3.22 (m, 1H), 2.91-2.94 (m, 1H), 2.72-2.76 (m, 1H), 1.97-2.13 (m, 4H), 1.34 (s, 3H), 1.25 (m, 1H), 0.88-0.90 (m, 4H), 0.46-0.48 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H); MS (ESI) for C.sub.35H.sub.50N.sub.2O.sub.7: 611.3289 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 10

Preparation of (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3 (cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (10)

(40) ##STR00048##

(41) (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3 (cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (10) was prepared according to the following steps.

Step 1: Preparation of tert-butyl (2-aminophenyl)carbamate

(42) ##STR00049##

(43) Benzene-1,2-diamine (10 g. 92.47 mmol) was dissolved in 200 mL of dioxane/water (2:1 ratio) and stirred for 10 min. Boc anhydride (21.2 mL, 92.47 mmol) was added to the above mixture and stirred for 5 h. Dioxane was distilled off and mixture was cooled to room temperature. Compound was extracted into MTBE, dried over anhydrous sodium sulfate, and conc. under vacuum to get tert-butyl (2-aminophenyl)carbamate (7) (12.1 g, 63% yield)

Step 2: Preparation of tert-butyl (2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)carbamate

(44) ##STR00050##

(45) tert-Butyl (2-aminophenyl)carbamate (3 g, 14.41 mmol), sodium bicarbonate (1.45 g, 17.296 mmol) and sodium lauryl sulfate (70 mg, 0.245 mmol) were mixed in 70 mL of water. The mixture was heated to 80 C. and to it was charged mPEG.sub.5-OMs (5.71 g, 17.296 mmol). The mixture was stirred under heating for 16 h and then cooled to room temperature. The cooled reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate & conc. under vacuum. Crude was purified by column chromatography to yield tert-butyl (2-(2,5,8,11,14-pentaoxahexadecan-16 ylamino)phenyl) carbamate (2 g, 31% yield).

Step 3: Preparation of N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,2-diamine

(46) ##STR00051##

(47) tert-Butyl (2-(2,5,8,11,14-pentaoxahexadecan-16 ylamino)phenyl) carbamate (2 g, 4.52 mmol) was dissolved in 25 mL of 4M HCl in IPA. The mixture was stirred for 1 h and concentrated under vacuum. The residue was dissolved in 50 mL of water and pH was adjusted to 9.0 using 1M aq. NaOH. The Compound was extracted into ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to get N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,2-diamine as dark brown gum (1.22 g, 79% yield).

Step 4: (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

(48) ##STR00052##
was prepared in a manner similar to Example 7, step 4.

Step 5: Preparation of (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6 methanobenzo[d]azocin-1(2H)-one (10)

(49) ##STR00053##

(50) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (100 mg, 0.24 mmol) and N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,2-diamine were dissolved in toluene. BINAP (44.7 mg, 0.0718 mmol), Pd.sub.2dba.sub.3 (43.86 mg, 0.0479 mmol) & Cs.sub.2CO.sub.3 (109.25 mg, 0.3353 mmol) were added to the above mixture and heated to 110 C. for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by flash chromatography to yield (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6 methanobenzo[d]azocin-1(2H)-one (10) (93 mg, 63% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.83 (d, 1H), 7.12-7.18 (m, 2H), 6.70-6.75 (m, 2H), 6.58-6.61 (m, 2H), 5.95 (s, 1H), 4.45 (bs, 1H), 3.63-3.68 (m, 2H), 3.55-3.62 (m, 14H), 3.49-3.54 (m, 2H), 3.33 (m, 5H), 3.21 (m, 1H), 2.9-2.94 (m, 1H), 2.72-2.76 (m, 1H), 1.96-2.15 (m, 3H), 1.41-1.44 (m, 1H), 1.37 (s, 3H), 1.25 (m, 1H), 0.88-0.90 (m, 3H), 0.46-0.48 (m, 2H), 0.25-0.27 (m, 1H), 0.07 (m, 2H); MS (ESI) for C.sub.35H.sub.51N.sub.3O.sub.6: 610.3262 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 11

Preparation of (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (11)

(51) ##STR00054##

(52) (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (8) was prepared according to the following steps.

Step 1: Preparation of N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine

(53) ##STR00055##

(54) N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine was prepared in a manner similar to steps 1-3 of example 7, with the exception that Benzene-1,3-diamine was used as the starting material in step 1 in order to arrive at the present orientation on the phenyl ring to yield N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine, as a dark brown gum (1.8 g, 94% yield)

Step 2: Preparation of (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (11)

(55) ##STR00056##

(56) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (prepared in a manner similar to Example 7, Step 4) (200 mg, 0.479 mmol) and N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,3-diamine (147.66 mg, 0.431 mmol) were dissolved in toluene. DPPF (53.11 mg, 0.0958 mmol), Pd.sub.2dba.sub.3 (29.83 mg, 0.0325 mmol) & sodium tert-butoxide (55.24 mg, 0.575 mmol) were added to the above mixture. The reaction mix was heated to 110 C. and stirred at that temperature for 3 h. Thereafter the mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by preparative HPLC; giving (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (11) (95 mg, 32% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.87 (d, 1H), 7.12 (t, 1H), 6.90-6.92 (m, 1H), 6.82 (d, 1H), 6.53-6.55 (m, 1H), 6.44-6.45 (m, 1H), 6.35-6.37 (m, 1H), 6.19 (s, 1H), 4.3 (bs, 1H), 3.69-3.71 (t, 2H), 3.62-3.65 (m, 14H), 3.53-3.55 (m, 2H), 3.36 (s, 3H), 3.28 (t, 2H), 3.23 (m, 1H), 2.92-2.94 (m, 1H), 2.72-2.76 (m, 1H), 2.14-2.06 (m, 1H), 1.93-2.10 (m, 3H), 1.49-1.51 (m, 1H), 1.37 (s, 3H), 1.25-1.29 (m, 1H), 0.89-0.91 (m, 3H), 0.44-0.50 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.07 (m, 1H); MS (ESI) for C.sub.35H.sub.51N.sub.3O.sub.6: 610.3419 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 12

Preparation of (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (12)

(57) ##STR00057##

(58) (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (12) was prepared according to the following steps.

Step 1: N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine

(59) ##STR00058##
was prepared in a manner similar to steps 1-3 of Example 8, with the exception that benzene-1,4-diamine was used as the starting material in step 1 in order to arrive at the present orientation on the phenyl ring to arrive at N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine as dark brown gum (3.1 g, 98% yield)

Step 2: Preparation of (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino) phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (12)

(60) ##STR00059##

(61) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (prepared in a manner similar to Example 7, Step 4) (3.6 g, 8.62 mmol) and N1-(2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine (2.95 g, 8.62 mmol) were dissolved in toluene. BINAP (1.61 g, 2.58 mmol), Pd.sub.2dba.sub.3 (1.58 g, 1.72 mmol) & Cs.sub.2CO.sub.3 (3.93 g, 8.62 mmol) were added to the above mixture. The reaction mixture was heated to 110 C. and was stirred for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by flash chromatography to yield (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino) phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (12) (1.7 g, 33.7% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.83 (d, 1H), 7.03 (d, 2H), 6.64-6.66 (m, 3H), 6.82 (d, 1H), 5.87 (s, 1H), 4.18 (bs, 1H), 3.72-3.74 (t, 2H), 3.63-3.67 (m, 14H), 3.53-3.55 (m, 2H), 3.37 (s, 3H), 3.30 (t, 2H), 3.21 (m, 1H), 2.88-2.96 (m, 1H), 2.72-2.76 (m, 1H), 1.93-2.10 (m, 4H), 1.48-1.50 (m, 1H), 1.37 (s, 3H), 1.25 (m, 1H), 0.88-0.90 (m, 3H), 0.44-0.50 (m, 2H), 0.25-0.27 (m, 1H), 0.05-0.07 (m, 1H); MS (ESI) for C.sub.35H.sub.51N.sub.3O.sub.6: 610.3393 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 13

Preparation of (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one, hydrochloride salt (13)

(62) ##STR00060##

(63) (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one, hydrochloride salt (13) was prepared according to the following steps.

Step 1: Preparation of (6S,10R,12R)-2-amino-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one

(64) ##STR00061##

(65) (2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (synthesized as per Example 15, Step 3) (160 mg, 0.56 mmol) and potassium thiocyanate (280 mg, 2.88 mmol) were sonicated in 5 mL of acetic acid for 2 minutes. 8.9M Bromine in acetic acid (0.07 mL, 0.62 mmol) was then added into the solution. The mixture was stirred for 3 hours at 60 C. and then was concentrated. The residue was dissolved in dichloromethane (10 mL) and filtered, washed with 5N aqueous sodium hydroxide (230 mL), water (30 mL) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by recrystallization in dichloromethane yielded (6S,10R,12R)-2-amino-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one (180 mg, 94% yield).

Step 2: Preparation of tert-butyl ((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-2-yl)carbamate

(66) ##STR00062##

(67) (6S,10R,12R)-2-amino-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one (180 mg, 0.15 mmol), triethyl amine (0.184 mL, 1.318 mmol) and dimethylamino pyridine (12 mg, 0.1 mmol) were dissolved in 2 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 10 min and then to it was added di-tert-butyl dicarbonate (150 mg, 0.68 mmol). The mixture was stirred for 4 hours at 60 C. and concentrated. The residue was purified by flash chromatography to yield tert-butyl ((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-2-yl)carbamate (80 mg, 34% yield).

Step 3: Preparation of tert-butyl ((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-2-yl)(2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate

(68) ##STR00063##

(69) tert-butyl ((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-2-yl)carbamate (80 mg, 0.18 mmol), triphenyl phosphine (57 mg, 0.21 mmol), and mPEG.sub.5-OH (45 mg, 0.18 mmol) were dissolved in 2 mL of dichloromethane. The mixture was stirred for 5 minutes at room temperature and then cooled to 0 C. Diisopropyl azodicarboxylate (DIAD) (0.46 mL, 0.23 mmol) was added into the solution. The reaction mixture was stirred for 18 hours and then was concentrated. The residue was purified by flash chromatography to yield tert-butyl ((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-2-yl)(2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate (70 mg, 57% yield).

Step 4: Preparation of (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one, hydrochloride salt (13)

(70) ##STR00064##

(71) tert-butyl ((6S,10R,12R)-7-(cyclopropylmethyl)-10,12-dimethyl-5-oxo-5,6,7,8,9,10-hexahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-2-yl)(2,5,8,11,14-pentaoxahexadecan-16-yl)carbamate (110 mg, 0.16 mmol) was dissolved in 1 mL of 4N hydrochloride in 2-propanol and stirred at room temperature for 1 hour, and concentrated. The residue partitioned between saturated sodium bicarbonate and dichloromethane, and the organic layer dried on sodium sulfate. Evaporation of solvent yielded (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4,5:4,5]benzo[1,2-d]azocin-5(6H)-one (13) (80 mg, 85% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 8.21 (s, 1H), 7.42 (s, 1H), 6.71 (bs, 1H), 3.75-3.62 (m, 19H), 3.56-3.54 (m, 2H), 3.36 (s, 3H), 3.27 (d, 1H), 2.92-2.89 (m, 1H), 2.73 (dd, 1H), 2.17-2.14 (m, 1H), 2.03-1.96 (m, 2H), 1.51-1.53 (m, 1H), 1.47 (s, 3H), 0.88 (d, 3H), 0.89-0.86 (m, 2H), 0.49-0.46 (m, 2H), 0.26-0.24 (m, 1H), 0.06-0.04 (m, 1H). MS (ESI) for C.sub.30H.sub.45N.sub.3O.sub.6S: 576 (MH.sup.+). The free base was dissolved in 1 mL of 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 14

Preparation of (2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (14)

(72) ##STR00065##

(73) (2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (14) was prepared according to the following steps.

Step 1: (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

(74) ##STR00066##
was prepared in a manner similar to Example 7, Step 4.

Step 2: Preparation of (2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (14)

(75) ##STR00067##

(76) (2S,6R,11R)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl trifluoromethanesulfonate hydrochloride (120 mg, 0.33 mmol), Cs.sub.2CO.sub.3 (214.9 mg, 0.6494 mmol) and mPEG.sub.2-Br (78.45 mg, 0.4286 mmol) were dissolved in acetonitrile. The mixture was heated to 75 C. for 16 h and cooled to room temperature. The mixture was concentrated under vacuum and purified by flash chromatography to yield (2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy) ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (14) (51.5 mg, 47% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 8.02 (d, 1H), 6.85 (m, 2H), 4.21-4.23 (m, 2H), 3.89 (t, 2H), 3.57-3.59 (m, 2H), 3.39 (s, 3H), 3.27 (d, 1H), 2.72-2.75 (m, 1H), 2.55-2.61 (m, 1H), 2.08-2.13 (m, 1H), 1.87-1.94 (m, 1H), 1.45-1.48 (m, 1H), 1.41 (s, 3H), 0.85 (d, 3H); MS (ESI) for C.sub.19H.sub.27NO.sub.4: 334.1965 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 15

Preparation of N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide (15)

(77) ##STR00068##

(78) N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide (15) was prepared according to the following steps.

Step 1: (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

(79) ##STR00069##
was prepared in a manner similar to Example 7, step 4.

Step 2: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((diphenylmethylene) amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(80) ##STR00070##

(81) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (450 mg, 1.08 mmol) and benzophenone imine (292.7 mg, 1.61 mmol) were dissolved in 2 mL of toluene. BINAP (134.25 mg, 0.21 mmol), Pd.sub.2dba.sub.3 (177.7 mg, 0.19 mmol) & Cs.sub.2CO.sub.3 (1053.7 mg, 3.23 mmol) were added to the above reaction mixture and heated to 110 C. for 8-10 h. Reaction mixture was concentrated, the crude thus obtained was purified by column chromatography; yielding (2S,6R,11R)-3-(cyclopropylmethyl)-8-((diphenylmethylene)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (400 mg, 83% yield).

Step 3: Preparation of (2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(82) ##STR00071##

(83) (2S,6R,11R)-3-(cyclopropylmethyl)-8-((diphenylmethylene)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (400 mg, 0.89 mmol), hydroxylamine hydrochloride (124 mg, 1.78 mmol) and sodium ethoxide (220 mg, 2.67 mmol) were dissolved in 10 mL of MeOH. The reaction mixture was stirred for 20 h and concentrated. The residue was partitioned between 5 M HCl (10 mL) & ethyl acetate (10 mL). The Aq. layer was washed with MTBE and retained. The pH of aqueous layer was adjusted to 11 and the product was extracted into dichloromethane. DCM layer was dried over anhydrous Sodium sulfate. and concentrated under vacuum to get (2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, as a light yellow syrup (221 mg, 87% yield).

Step 4: Preparation of 2-(2-methoxyethoxy)acetic Acid

(84) ##STR00072##

(85) 2-Methoxyethanol (10 g, 131.4 mmol) and potassium tert-butoxide (17.67 g, 157.68 mmol) were dissolved in 100 mL of THF. The mixture was heated to 45 C. for 1 h and cooled to room temperature. tert-Butylbromo acetate (25.63 g, 131.41 mmol) was added to the above mixture and stirred for 16 h at room temperature. Reaction mixture was concentrated, the residue dissolved in water. pH of the aq. layer was adjusted to 12-12.5 (using 1M aq. NaOH) and stirred for 12-14 h at room temperature. Thereafter, pH of the aq. layer was adjusted to 2 using 10% aq. phosphoric acid. Product was extracted into DCM. Recovery of DCM on a rotovap yielded 2-(2-methoxyethoxy)acetic acid, as an oily mass (4.1 g, 23% yield).

Step 5: Preparation of N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide (15)

(86) ##STR00073##

(87) (2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (150 mg, 0.527 mmol), 2-(2-methoxyethoxy)acetic acid (5) (106 mg, 0.79 mmol) and HOBT (93 mg, 0.68 mmol) were dissolved in 8 mL of dichloromethane. DCC (131 mg, 0.633 mmol) was added and the mixture was stirred for 70 h. RM was filtered through Celite and the bed, washed with DCM. The filtrate was concentrated and purified using preparative HPLC to get N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide (15) as a yellow gum (84 mg, 40% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 9.957 (s, 1H), 7.8 (d, 1H), 7.68-7.70 (m, 2H), 4.1 (s, 2H), 3.66-3.68 (m, 2H), 3.52-3.54 (m, 2H), 3.3 (s, 3H), 3.15 (d, 1H), 2.78-2.81 (m, 1H), 2.45-2.48 (m, 1H), 2.05-2.06 (m, 1H), 1.82-1.96 (m, 2H), 1.41-1.44 (m, 1H), 1.37 (s, 3H), 0.9 (m, 1H), 0.77-0.83 (m, 3H), 0.39-0.46 (m, 2H), 0.18-0.21 (m, 1H), 0.01-0.02 (m, 2H); MS (ESI) for C.sub.23H.sub.32N.sub.2O.sub.4: 400.2005 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 16

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (16)

(88) ##STR00074##

(89) (2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (16) was prepared according to the following steps.

Step 1: (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate

(90) ##STR00075##
was prepared in a manner similar to Example 7, step 4.

Step 2: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carbonitrile

(91) ##STR00076##

(92) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (800 mg, 1.92 mmol), Zn(CN).sub.2 (1351 mg, 5.75 mmol) and Pd(PPh.sub.3).sub.4 (886 mg, 0.77 mmol) were dissolved in 10 mL of DMF in sealed tube. The mixture was heated to 130 C. for 5 h and cooled to room temperature. DMF was concentrated under vacuum and residue was dissolved in water. Aq. layer was extracted with EtOAc, The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography; to afford (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carbonitrile (520 mg, 92% yield).

Step 3: (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxylic Acid

(93) ##STR00077##

(94) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano benzo[d]azocine-8-carbonitrile (120 mg, 0.410 mmol) was dissolved in MeOH. 25% aq. KOH (5 mL) and 30% H.sub.2O.sub.2 (1 mL) were added to it. Reaction mix was stir heated at 85 C. for 15 h. Reaction mixture was cooled to room temperature and diluted with water (5 mL). pH of the above mixture was adjusted to 2-3 using 1 M aq. HCl. Compound was extracted into EtOAc, dried over anhydrous sodium sulfate and the ethyl acetate layer was concentrated under vacuum to afford (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxylic acid (120 mg, 94% yield)

Step 4: (2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide

(95) ##STR00078##

(96) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxylic acid (120 g, 0.383 mmol), mPEG.sub.1-NH.sub.2 (31.6 mg, 0.421 mmol) and TEA (0.067 mL, 0.479 mmol) was dissolved in 1.2 mL of DCM. HOBt (62 mg, 0.46 mmol) and DCC (79 mg, 0.383 mmol) were added to the above mixture and stirred for 4 h at room temperature. Reaction mixture was filtered through celite and concentrated under vacuum to a residue. Residue was purified by column chromatography to yield (2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide (16) (130 mg, 92% yield). .sup.1H NMR (500 MHz, DMSO-D6): 8.72 (t, 1H), 7.85-7.90 (m, 2H), 7.79-7.81 (m, 1H), 3.42-3.48 (m, 4H), 3.27 (s, 3H), 3.23 (m, 1H), 2.80-2.83 (m, 1H), 2.10-2.12 (m, 1H), 1.94-1.98 (m, 2H), 1.60-1.78 (m, 3H), 1.24 (s, 3H), 0.84-0.88 (m, 1H), 0.77 (d, 3H), 0.40-0.47 (m, 2H), 0.19-0.21 (m, 1H), 0.01-0.03 (m, 1H); MS (ESI) for C.sub.22H.sub.30N.sub.2O.sub.3: 371.1961 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 17

Preparation of N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide (17)

(97) ##STR00079##

(98) N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide (17) was prepared according to the following steps.

Step 1: Preparation of (2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(99) ##STR00080##

(100) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methano benzo[d]azocine-8-carbonitrile (320 mg, 1.09 mmol), prepared in a manner similar to Example 16, step 2, was dissolved in methanol. 10% Pd/C (50% wet) (50 mg) was added to the above mixture and reaction was under hydrogen balloon pressure for 4 h. Reaction mixture was filter through celite bed, the bed washed with methanol. Organic layer was concentrated under vacuum to yield (2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (320 mg, 99% yield).

Step 2: Preparation of N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy) acetamide

(101) ##STR00081##

(102) (2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (110 mg, 0.37 mmol), 2-(2-methoxyethoxy)acetic acid (64.3 mg, 0.48 mmol) and TEA (0.8 mL, 0.461 mmol) were dissolved in 1 mL of DCM. The mixture was stirred for 10 min. Following which, HOBT (59.7 mg, 0.442 mmol) and DCC (114 mg, 0.553 mmol) were added and stirring was continued for another 2 h. Reaction mixture was filtered and concentrated under vacuum to get a residue. The residue was purified by column chromatography to afford N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide (17) (62 mg, 41% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 8.1 (m, 1H), 7.5 (m, 1H), 7.21-7.23 (m, 2H), 3.88 (s, 2H), 3.6-3.7 (m, 4H), 3.55 (s, 2H), 3.37 (s, 3H), 2.85 (m, 1H), 2.92-2.95 (m, 1H), 2.63-2.67 (m, 1H), 1.93-2.22 (m, 4H), 1.45 (s, 3H), 1.25 (m, 1H), 0.87-0.88 (m, 4H), 0.46-0.53 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H); MS (ESI) for C.sub.24H.sub.34N.sub.2O.sub.4: 415.2243 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 18

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy) ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(103) ##STR00082##

(104) (2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy)ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (18) was prepared according to the following steps.

Step 1: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy) ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (18)

(105) ##STR00083##

(106) (2S,6R,11R)-8-(aminomethyl)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (160 mg, 0.54 mmol) prepared in a manner similar to Example 17, step 1, and mPEG.sub.1-Br (981 mg, 5.4 mmol) was dissolved in 1.6 mL of DMF. NaOH (214 mg, 5.4 mmol) was added to the above mixture and reaction was stirred for 20 h at room temperature. Reaction mixture was filtered and concentrated under vacuum to get a residue. Residue was purified by column chromatography to yield (2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy) ethyl)amino)methyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (18) as gummy oil (110 mg, 51% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.95 (d, 1H), 7.3 (m, 2H), 3.88 (s, 2H), 3.6-3.7 (m, 4H), 3.52-3.55 (m, 2H), 3.37 (s, 3H), 3.3 (m, 1H), 2.92 (m, 1H), 2.85 (m, 1H), 2.91-2.94 (m, 1H), 2.72-2.76 (m, 1H), 1.97-2.13 (m, 4H), 1.34 (s, 3H), 1.25 (m, 1H), 0.88-0.90 (m, 4H), 0.46-0.48 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H), MS (ESI) for C.sub.24H.sub.36N.sub.2O.sub.3: 401.2616 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 19

Preparation of (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, hydrochloride salt (19)

(107) ##STR00084##

(108) (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, hydrochloride salt (19) was prepared according to the following steps.

Step 1: Preparation of (2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(109) ##STR00085##

(110) (2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimeth yl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (ketazocine) (400 mg, 1.4 mmol) and 8.9M bromine in acetic acid (0.34 mL, 3.0 mmol) were dissolved in 4 mL of acetic acid. The mixture was stirred for 18 hours at 80 C. and then was concentrated. The residue was dissolved in methanol (10 mL) and charged with 10% palladium-carbon (10% w/w). The mixture was stirred under hydrogen atmosphere for 30 minutes at room temperature. The reaction mixture filtered, evaporation of the solvent and purification of the residue by flash chromatography yielded (2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (220 mg, 43% yield).

Step 2: Preparation of (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, hydrochloride salt (19)

(111) ##STR00086##

(112) mPEG.sub.5-OH (770 mg, 3.0 mmol) was dissolved in 2 mL of toluene:N,N-dimethylformamide (9:1), and sodium hydride (138 mg of 60% in mineral oil, 3.4 mmol) was added into the solution. (2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (140 mg, 0.38 mmol) and cuprous iodide (50 mg, 0.26 mmol) were then added under stirring. The reaction mixture was stirred at 120 C. for 3 hours. 15 mL of dichloromethane was added into the reaction mixture. The solution was washed with water (10 mL3) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (19) (90 mg, 43% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 8.8 (bs, 1H), 7.81 (d, 1H), 6.88 (d, 1H), 4.10-4.07 (m, 1H), 3.95-3.82 (m, 5H), 3.76-3.74 (m, 2H), 3.68-3.62 (m, 10H), 3.54-3.52 (m, 2H), 3.37 (s, 3H), 3.24 (bs, 1H), 2.97-2.96 (m, 1H), 2.72 (dd, 1H), 2.05-1.98 (m, 1H), 1.82-1.73 (m, 2H), 1.63 (s, 3H), 0.91 (d, 3H), 0.89-0.86 (m, 2H), 0.49-0.45 (m, 2H), 0.25-0.24 (m, 1H), 0.07-0.04 (m, 1H). MS (ESI) for C.sub.29H.sub.45NO.sub.3: 536 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. Evaporation of volatiles afforded product as hydrochloride salt.

Example 20

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (20)

(113) ##STR00087##

(114) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (20) was prepared according to the following steps.

Step 1: Preparation of S-methyl O-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) carbonodithioate

(115) ##STR00088##

(116) 1-Phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (T. Shiyama et al., Bioorg. Med. Chem. (2004), #12, 2831) (13.0 g, 39.6 mmol) was dissolved in 250 mL of tetrahydrofuran and sodium hydride (1.9 g of 60% in mineral oil, 47.5 mmol) was added into the solution. The mixture was stirred for 10 minutes at room temperature and then cooled to 0 C. Carbon disulfide (3.1 mL, 51.5 mmol) was then added under stirring. The reaction mixture stirred for 1 hour and then methyl iodide (3.2 mL, 51.5 mmol) was added drop wise at 0 C., stirred for 18 h at room temperature, and concentrated. The residue was dissolved in ethyl acetate (200 mL) and was washed with water (2300 mL), brine (300 mL) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded S-methyl O-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) carbonodithioate (150 g, 91% yield).

Step 2: Preparation of 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ol

(117) ##STR00089##

(118) To the suspension of 1,3-dibromo-5,5-dimethylhydantoin (34.0 g, 120.0 mmol) in dichloromethane (300 mL) was added HF-pyridine (40.0 mL, 1600 mmol) at 78 C., and then S-methyl O-(1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl) carbonodithioate (15.0 g, 40.0 mmol) added at same temperature. The reaction mixture was stirred at 78 C. further for 1 hour and subsequently warmed to 0 C. and stirred at the same temperature for 2 hours. 150 mL of dichloromethane was added into the reaction mixture. The solution was washed with water (100 mL3), saturated sodium bisulfite and dried over sodium sulfate. Then the crude was dissolved in MeOH and hydrogenated at room temperature with addition of PdC (10%) (1.5 g) under hydrogen atmosphere. The reaction mixture was filtered and evaporated, giving the 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ol (10.0 g, 86% yield).

Step 3: Preparation of 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate

(119) ##STR00090##

(120) To the mixture of 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-ol (8.0 g, 26.1 mmol), and TEA (4.7 mL, 34.0 mmol) in dichloromethane (150 mL) was added methane sulfonyl chloride (2.2 mL g, 28.7 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 hour. 150 mL of dichloromethane was added into the reaction mixture. The solution was washed with water (200 mL3) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate (9.0 g, 90% yield).

Step 4: Preparation of N1-(1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine

(121) ##STR00091##

(122) tert-butyl (4-aminophenyl)carbamate (Karra et. al., Bioorganic & Medicinal Chemistry Letters (2013), #23, 3081) (0.9 g, 2.3 mmol) was dissolved in 3 mL of N,N-dimethylformamide and sodium hydride (0.112 g of 60% in mineral oil, 2.81 mmol) was added into the solution. The mixture was stirred for 10 minutes at room temperature and then cooled to 0 C. 1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl methanesulfonate (0.6 g, 2.6 mmol) was then added under stirring. The reaction mixture was stirred for 18 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate (20 mL) and was washed with water (230 mL), brine (30 mL) and was dried over sodium sulfate. Residue obtained after evaporation was dissolved in 3 mL of 4N hydrochloride in 2-propanol. Evaporation of volatiles afforded product as hydrochloride salt The residue partitioned between saturated sodium bicarbonate and dichloromethane, and the organic layer dried on sodium sulfate. Evaporation of solvent and purification of residue by flash chromatography yielded N1-(1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine (0.4 g, 51% yield).

Step 5: (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (20)

(123) ##STR00092##

(124) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl trifluoromethanesulfonate (prepared in a manner similar to Example 7, Step 4) (170 mg, 0.4 mmol), Pd.sub.2dba.sub.3 (88 mg, 0.09 mmol), BINAP (88 mg, 0.13 mmol), N1-(1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)benzene-1,4-diamine (160 mg, 0.44 mmol) and Cs.sub.2CO.sub.3 (470 mg, 1.22 mmol) were suspended in 5 mL of toluene. The mixture was stirred at 110 C. for 1 hour. 20 mL of dichloromethane was added into the reaction mixture. The solution was washed with water (10 mL3) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2,5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (20) (110 mg, 40% yield). 7.83 (d, 1H), 7.04-7.02 (m, 2H), 6.66-6.59 (m, 3H), 6.59 (d, 1H), 5.85 (bs, 1H), 4.20 (bs, 1H), 4.09 (m, 2H), 3.73-3.71 (m, 4H), 3.68-3.67 (m, 12H), 3.30 (t, 2H), 3.21-3.20 (m, 1H), 2.92-2.90 (m, 1H), 2.74 (dd, 1H), 2.12-1.93 (m, 3H), 1.50-1.48 (m, 1H), 1.33 (s, 3H), 0.91 (d, 3H), 0.89-0.86 (m, 2H), 0.47-0.43 (m, 2H), 0.26-0.24 (m, 1H), 0.07-0.04 (m, 1H). MS (ESI) for C.sub.35H.sub.48F.sub.3N.sub.3O.sub.6: 664 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 21

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (21)

(125) ##STR00093##

(126) (2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (21) was prepared according to the following steps.

Step 1: Preparation of 16-(benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-amine

(127) ##STR00094##

(128) 16-(Benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-yl methanesulfonate (500 mg, 0.11 mmol) was dissolved in 5 mL of acetonitrile in a sealed tube. 25% aq. ammonia (5 mL) was added and reaction mixture was heated at 80 C for 16 h. Reaction mixture was cooled to room temperature and compound was extracted into EtOAc, dried over anhydrous sodium sulfate, conc. under vacuum to get crude compound. Crude was purified by column chromatography, to afford 16-(benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-amine (300 mg, 72.8% yield) as a thick yellow colored liquid.

Step 2: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((16-(phenoxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(129) ##STR00095##

(130) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yltrifluoromethanesulfonate (300 mg, 0.719 mmol) prepared in a manner similar to Example 7, step 4 and 16-(benzyloxy)-2,5,8,11,14-pentaoxaheptadecan-17-amine (293 mg, 0.719 mmol) were dissolved in toluene. BINAP (89.6 mg, 0.144 mmol), Pd.sub.2(dba).sub.3 (118 mg, 0.0129 mmol) & Cs.sub.2CO.sub.3 (705 mg, 0.215 mmol) were added to the above mixture and heated to 110 C. for 2 h. The mixture was cooled to room temperature and conc. under vacuum. Crude was purified by column chromatography to yield (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((16-(phenoxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (200 mg, 43.6% yield).

Step 3: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(131) ##STR00096##

(132) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((16-(phenoxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (200 mg). 10% Pd/C (50% wet) (40 mg) was added to the above mixture and reaction was stirred under hydrogen gas (balloon pressure) for 4 h. Reaction mixture was filtered through celite bed and the bed was washed with methanol. Organic layer was conc. under vacuum to yield (2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (21) (125 mg, 81.7% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.9 (m, 1H), 7.6 (m, 1H), 7.4 (s, 1H), 4.05 (m, 1H), 3.9 (m, 2H), 3.6-3.7 (m, 16H), 3.55 (s, 2H), 3.37 (s, 3H), 2.85 (m, 1H), 2.92-2.95 (m, 1H), 2.63-2.67 (m, 1H), 1.93-2.22 (m, 4H), 1.45 (s, 3H), 1.25 (m, 1H), 0.87-0.88 (m, 4H), 0.46-0.53 (m, 2H), 0.26 (m, 1H), 0.04-0.07 (m, 1H); MS (ESI) for C.sub.30H.sub.46N.sub.2O.sub.7: 549.3317 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 22

Preparation of (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5,4:3,4]benzo[1,2-d]azocin-6(7H)-one (22)

(133) ##STR00097##

(134) (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5,4:3,4]benzo[1,2-d]azocin-6(7H)-one (22) was prepared according to the following steps.

Step 1: Preparation of 1-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-3-(2,5,8,11,14-pentaoxahexadecan-16-yl)thiourea

(135) ##STR00098##

(136) (2S,6R,11R)-8-amino-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (prepared in a manner similar to Example 15, Step 3) (60 mg, 0.21 mmol), and O,O-di(pyridin-2-yl) carbonothioate (49 mg, 0.22 mmol) were dissolved in 2 mL of tetrahydrofuran. The mixture was stirred for 2 hours at 65 C. and then cooled to room temperature. mPEG.sub.5-NH.sub.2 (53 g, 0.22 mmol) was added into the solution. The reaction mixture was stirred for 1 hour and then was concentrated. Residue was purified by flash chromatography to yield 1-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-3-(2,5,8,11,14-pentaoxahexadecan-16-yl)thiourea (70 mg, 57% yield)

Step 2: Preparation of (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5,4:3,4]benzo[1,2-d]azocin-6(7H)-one (22)

(137) ##STR00099##

(138) 1-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-3-(2,5,8,11,14-pentaoxahexadecan-16-yl)thiourea (120 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane and benzyltrimethyl ammonium tribromide (80 mg, 0.2 mmol) was added into the solution. The reaction mixture was stirred at room temperature for 18 hours. 20 mL of dichloromethane was added into the reaction mixture. The solution was washed with 5% aqueous NaHCO.sub.3 (30 mL), water (10 mL3) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5,4:3,4]benzo[1,2-d]azocin-6(7H)-one (22) (55 mg, 46% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 8.02 (d, 1H), 7.43 (d, 1H), 6.43 (bs, 1H), 3.75-3.63 (m, 19H), 3.55-3.53 (m, 2H), 3.36 (s, 3H), 3.27 (d, 1H), 2.92-2.89 (m, 1H), 2.71 (dd, 1H), 2.16-2.13 (m, 1H), 2.01-1.82 (m, 2H), 1.63 (s, 3H), 0.96 (d, 3H), 0.89-0.86 (m, 2H), 0.48-0.45 (m, 2H), 0.26-0.23 (m, 1H), 0.06-0.02 (m, 1H). MS (ESI) for C.sub.30H.sub.45N.sub.3O.sub.6S: 576 (MH.sup.+). The free base was dissolved in 1 mL of 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 23

Preparation of (2S,6R,11R)-3-(Cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (23)

(139) ##STR00100##

(140) (2S,6R,11R)-3-(Cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (23) was prepared according to the following steps

Step 1: Preparation of tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate

(141) ##STR00101##

(142) 2-Amino-2-methyl-1-propanol (5 g, 56.1 mmol), (Boc).sub.2O (13.46 g, 61.7 mmol) and triethyl amine (6.24 g, 61.7 mmol) were dissolved in 50 mL of dichloromethane. The reaction mixture was stirred for 4 h at 22 to 25 C. Above mixture was washed with water (25 mL2), dried over anhydrous sodium sulfate and concentrated under vacuum to get tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (10.3 g, 97% yield).

Step 2: Preparation of tert-butyl (1-(benzyloxy)-2-methylpropan-2-yl)carbamate

(143) ##STR00102##

(144) tert-Butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (2) (2 g, 10.57 mmol), potassium hydroxide (1.10 g, 19.55 mmol), and benzyl bromide (3.34 g, 19.55 mmol) were dissolved in 20 mL of DMF. The mixture was stirred for 2 h and concentrated under vacuum. Crude was purified by column chromatography yielded tert-butyl (1-(benzyloxy)-2-methylpropan-2-yl)carbamate (2.65 g, 90% yield).

Step 3: Preparation of 1-(benzyloxy)-2-methylpropan-2-amine

(145) ##STR00103##

(146) tert-Butyl (1-(benzyloxy)-2-methylpropan-2-yl)carbamate (2 g, 7.16 mmol) was dissolved in 25 mL of 4M HCl in IPA. The mixture was stirred for 1 h and concentrated under vacuum. The residue was dissolved in 50 mL of water and pH was adjusted to 9.0 using 1M aq. NaOH. The compound was extracted into ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum to yield 1-(benzyloxy)-2-methylpropan-2-amine as brown gum (0.90 g, 70% yield).

Step 4: Preparation of (2S,6R,11R)-8-((1-(benzyloxy)-2-methylpropan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(147) ##STR00104##

(148) (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl trifluoromethanesulfonate (0.450 mg, 1.078 mmol) and 1-(benzyloxy)-2-methylpropan-2-amine (0.193 g, 1.078 mmol) were dissolved in toluene. BINAP (0.199 g, 0.32 mmol), Pd.sub.2dba.sub.3 (0.198 g, 0.216 mmol) and Cs.sub.2CO.sub.3 (0.490 g, 1.51 mmol) were added to the above mixture and heated to 110 C. for 3 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by flash chromatography to yield (2S,6R,11R)-8-((1-(benzyloxy)-2-methylpropan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (200 mg, 42% yield).

Step 5: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (23)

(149) ##STR00105##

(150) (2S,6R,11R)-8-((1-(benzyloxy)-2-methylpropan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (190 mg, 0.425 mmol) was dissolved in 10 mL of methanol. 10% Pd/C (50% wet) (20 mg) was added to the above mixture and the reaction was performed under hydrogen balloon pressure for 4 h. Reaction mixture was filtered through a celite bed and washed with methanol. Evaporation of solvent under vacuum yielded (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (160 mg, 99% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6): 11.36 (bs, 1H), 7.71 (d, 1H), 6.69-6.73 (m, 3H), 3.86 (bs, 1H), 3.4-3.43 (m, 2H), 3.17 (s, 1H), 3.06-3.16 (m, 1H), 2.6-2.67 (m, 3H), 2.24-2.31 (m, 1H), 1.63-1.66 (m, 1H), 1.37 (m, 3H), 1.23-1.29 (m, 10H), 0.81-0.87 (m, 3H), 0.6-0.63 (m, 2H), 0.47-0.49 (m, 2H); MS (ESI) for C.sub.22H.sub.32N.sub.2O.sub.2: 357.2401 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 24

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (24)

(151) ##STR00106##

(152) (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (24) was prepared according to the following steps.

Step 1: Preparation of tert-butyl (1,3-dihydroxypropan-2-yl)carbamate

(153) ##STR00107##

(154) Serinol (2.00 g, 21.96 mmol) and (Boc).sub.2O (4.80 g, 21.96 mmol) was dissolved in 20 mL of dichloromethane. The reaction mixture was stirred for 4 h at 22 to 25 C. The above mixture was washed with water (25 mL2), dried over anhydrous sodium sulfate and concentrated under vacuum to yield tert-butyl (1,3-dihydroxypropan-2-yl)carbamate (4.1 g, 97% yield).

Step 2: Preparation of tert-butyl (1,3-bis(benzyloxy)propan-2-yl)carbamate

(155) ##STR00108##

(156) tert-Butyl (1,3-dihydroxypropan-2-yl)carbamate (3.7 g, 19.35 mmol), potassium hydroxide (4.0 g, 71.59 mmol), and benzyl bromide (12.24 g, 71.59 mmol) were dissolved in 50 mL of DMF. The mixture was stirred for 2 h and concentrated under vacuum. The crude product was purified using column chromatography to yield tert-butyl (1,3-bis(benzyloxy)propan-2-yl)carbamate (3.25 g, 45% yield).

Step 3: Preparation of 1,3-bis(benzyloxy)propan-2-amine

(157) ##STR00109##

(158) tert-butyl (1,3-bis(benzyloxy)propan-2-yl)carbamate (3.00 g, 8.076 mmol) was dissolved in 25 mL of 4M HCl in IPA. The mixture was stirred for 1 hour and concentrated under vacuum. The residue was dissolved in 50 mL of water and pH was adjusted to 9.0 using 1M aq. NaOH. The compound was extracted into ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum to yield 1,3-bis(benzyloxy)propan-2-amine as a brown gum (2.00 g, 91% yield).

Step 4: Preparation of (2S,6R,11R)-8-((1,3-bis(benzyloxy)propan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(159) ##STR00110##

(160) (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl trifluoromethanesulfonate (0.450 mg, 1.078 mmol) and 1,3-bis(benzyloxy)propan-2-amine (0.351 g, 1.29 mmol) were dissolved in toluene. BINAP (0.199 g, 0.32 mmol), Pd.sub.2dba.sub.3 (0.198 g, 0.216 mmol) and Cs.sub.2CO.sub.3 (0.490 g, 1.51 mmol) were added to the above mixture and heated to 110 C. for 3 hours. The mixture was cooled to room temperature and concentrated under vacuum. Crude on purification using flash chromatography yielded (2S,6R,11R)-8-((1,3-bis(benzyloxy)propan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.545 g, 94% yield).

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (24)

(161) ##STR00111##

(162) (2 S,6R,11R)-8-((1,3-bis(benzyloxy)propan-2-yl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.545 g, 1.01 mmol) was dissolved in 10 mL of methanol. 10% Pd/C (50% wet) (50 mg) was added to the above mixture and reaction was performed under hydrogen balloon pressure for 4 hours. The reaction mixture was filter through a celite bed and washed with methanol. Concentration of the organic layer under vacuum yielded (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.350 g, 97% yield). .sup.1H NMR (500 MHz, DMSO-d.sub.6): 10.99 (bs, 1H), 7.72 (d, 1H), 6.9-6.96 (m, 1H), 6.59-6.67 (m, 2H), 3.87 (bs, 1H), 3.41-3.52 (m, 10H), 3.17 (s, 1H), 3.08-3.12 (m, 1H), 2.57-2.68 (m, 3H), 2.19-2.25 (m, 1H), 1.65-1.67 (m, 1H), 1.38 (m, 3H), 1.22-1.29 (m, 3H), 0.81-0.86 (m, 3H), 0.6-0.62 (m, 2H), 0.47-0.48 (m, 2H); MS (ESI) for C.sub.22H.sub.32N.sub.2O.sub.2: 359.2196 (MH.sup.+). The free base was dissolved in 4M hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 25

Preparation of (1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol (25)

(163) ##STR00112##

(164) (1R,2S,6R,11R)-1-(2,5,8,11,14-Pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol (25) was prepared according to the following steps.

Step 1: Preparation of (2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(165) ##STR00113##

(166) (2S,6R,11R)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (1.0 g, 3.5 mmol) was dissolved in 20 mL of acetonitrile and cesium carbonate (4.5 g, 14.0 mmol) was added into the solution. The mixture was stirred for 10 minutes at 60 C. Benzyl bromide (0.4 mL, 3.5 mmol) was then added under stirring. The reaction mixture stirred for 1 hour at 60 C., filtered and concentrated. The residue was dissolved in ethyl acetate (60 mL) and was washed with water (250 mL), dried over anhydrous sodium sulfate. Evaporation of the solvent and purification of residue by flash chromatography yielded (2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (1.2 g, 91% yield).

Step 2: Preparation of (1R,2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-1-ol

(167) ##STR00114##

(168) To the solution of (2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (1.0 g, 2.6 mmol) in tetrahydrofuran (30 mL) was added 1M lithium aluminium hydride solution in THF (2.6 mL, 2.6 mmol) at 0 C. The reaction mixture was stirred at room temperature for 18 hours. 10 mL of ethyl acetate was added into the reaction mixture. The suspension was passed through plug of celite. Evaporation of the solvent and purification of the residue by flash chromatography yielded (1R,2S,6R,11R)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-1-ol (0.7 g, 69% yield).

Step 3: Preparation of (1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine

(169) ##STR00115##

(170) (1R,2S,6R,11R)-8-(Benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-1-ol (0.7 g, 1.8 mmol) was dissolved in 3 mL of N,N-dimethylformamide and sodium hydride (0.148 g of 60% in mineral oil, 3.7 mmol) was added into the solution. The mixture was stirred for 10 minutes at room temperature and then heated to 70 C. mPEG.sub.5-OMs (0.86 g, 2.6 mmol) was then added under stirring. The reaction mixture was stirred 70 C. for 18 h. Reaction mixture was dissolved in ethyl acetate (20 mL) and was washed with water (250 mL), brine (30 mL) and was dried over any sodium sulfate. Evaporation of solvent and purification of residue by flash chromatography yielded of (1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine (0.4 g, 35% yield).

Step 4: Preparation of (1R,2S,6R,11R)-1-(2,5,8,11,14-Pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol (25)

(171) ##STR00116##

(172) (1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine (0.400 g, 0.4 mmol) was dissolved in MeOH and hydrogenated at room temperature with addition of PdC (10%) (0.100 g) under hydrogen atmosphere. The reaction mixture filtered and evaporated and the purification of residue by flash chromatography yielded (1R,2S,6R,11R)-1-(2,5,8,11,14-Pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol (0.170 g, 49% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.47 (d, 1H), 6.74 (dd, 1H), 6.64 (d, 1H), 5.85 (bs, 1H), 4.54 (d, 1H), 3.94-3.95 (m, 1H), 3.57-3.74 (m, 19H), 3.39 (s, 3H), 3.17 (t, 1H), 2.96 (dd, 1H), 2.81 (dd, 1H), 2.63 (dd, 1H), 2.48 (dt, 1H), 2.04-2.10 (m, 1H), 1.78 (dt, 1H), 1.30 (s, 3H), 1.13-1.15 (m, 1H), 0.87 (d, 3H), 0.79-0.81 (m, 1H), 0.47-0.52 (m, 1H), 0.36-0.42 (m, 1H), 0.06-0.12 (m, 2H). MS (ESI) for C.sub.29H.sub.47NO.sub.7: 522 (MH.sup.+). The free base (170 mg) was dissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 26

Preparation of (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, hydrochloride Salt (26)

(173) ##STR00117##

(174) (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, hydrochloride salt (26) was prepared according to the following steps.

Step 1: Preparation of (2S,6R,11R)-8-(benzyloxy)-7-bromo-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(175) ##STR00118##

(176) (2S,6R,11R)-7-bromo-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.450 g, 1.2 mmol) was dissolved in 10 mL of acetonitrile and cesium carbonate (0.80 g, 2.4 mmol) was added into the solution. The mixture was stirred for 10 minutes at 60 C. Benzyl bromide (0.15 mL, 1.2 mmol) was then added under stirring. The reaction mixture stirred for 1 hour at 60 C., filtered and concentrated. The residue was dissolved in ethyl acetate (20 mL) and was washed with water (220 mL), dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded (2S,6R,11R)-8-(benzyloxy)-7-bromo-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.450 g, 80% yield).

Step 2: Preparation of (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one

(177) ##STR00119##

(178) (2S,6R,11R)-8-(benzyloxy)-7-bromo-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.370 g, 0.8 mmol), BrettPHOS palladacycle (0.065 g, 0.08 mmol), BrettPHOS (0.044 g, 0.08 mmol), 2,5,8,11,14-pentaoxahexadecan-16-amine (0.37 g, 1.4 mmol) and 2M Sodium ter-butoxide solution in THF (1.2 mL, 2.4 mmol) were suspended in 3 mL of toluene. The mixture was stirred at 90 C. for 4 hours. 20 mL of ethyl acetate was added into the reaction mixture. The solution was washed with water (210 mL) and was dried over sodium sulfate. Evaporation of the solvent and purification of the residue by flash chromatography yielded (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.200 g, 40% yield).

Step 3: Preparation of (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, hydrochloride salt (26)

(179) ##STR00120##

(180) (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(benzyloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.220 g, 0.35 mmol) was dissolved in MeOH and hydrogenated at room temperature with addition of PdC (10%) (50% wet) (0.050 g) under hydrogen atmosphere. The reaction mixture filtered and evaporated, and the purification of residue by flash chromatography yielded (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.105 g, 55% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 8.3-8.7 (bs, 1H), 7.87 (d, 1H), 6.89 (d, 1H), 3.72-3.78 (m, 4H), 3.62-3.69 (m, 14H), 3.53-3.57 (m, 2H), 3.37 (s, 3H), 3.21 (d, 1H), 3.08-3.12 (m, 2H), 2.97-2.98 (m, 1H), 2.91-2.94 (m, 1H), 2.71 (dd, 1H), 1.92-2.03 (m, 2H), 1.73-1.75 (m, 1H), 1.65 (s, 3H), 0.93 (d, 3H), 0.83-0.90 (m, 1H), 0.43-0.49 (m, 2H), 0.22-0.24 (m, 1H), 0.03-0.06 (m, 1H). MS (ESI) for C.sub.29H.sub.46N.sub.2O.sub.7: 535 (MH.sup.+). The free base (100 mg) was dissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 27

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (27)

(181) ##STR00121##

(182) (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (27) was prepared according to the following steps.

Step 1: Preparation of 1-(2-methoxyethyl)piperidin-4-amine

(183) ##STR00122##

(184) 4-amino piperidine (2 g. 19.96 mmol) and anhydrous sodium carbonate (5.29 g, 49.9 mmol) was dissolved in 25 mL of methyl isobutyl ketone. The heterogeneous reaction mass was heated to reflux, and maintained for 4 h. 2-Methoxyethyl methanesulfonate (2.77 g, 17.96 mmol) was added to the above mixture and stirred for 16 h at 22 to 25 C. The reaction mass was filtered and 25 mL of 1N aq.HCl was added and stirred for another 1 h. The aqueous phase was separated, and pH was adjusted to 11.0 using 1N aq. NaOH. Compound was extracted into DCM, dried over anhydrous sodium sulfate and conc under vacuum to get 1-(2-methoxyethyl)piperidin-4-amine ((300 mg, 9.5% yield)

Step 2: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (27)

(185) ##STR00123##

(186) (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl trifluoromethanesulfonate (0.350 g, 0.8384 mmol) and 1-(2-methoxyethyl)piperidin-4-amine (0.159 g, 1.006 mmol) were dissolved in toluene. BINAP (0.156 g, 0.2515 mmol), Pd.sub.2dba.sub.3 (0.153 g, 0.1676 mmol) & Cs.sub.2CO.sub.3 (0.39 g, 1.1737 mmol) were added to the above mixture and heated to 110 C. for 2 h. The mixture was cooled to room temperature and concentrated under vacuum. Crude was purified by silica gel column chromatography to get pure (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (0.170 g, 48% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.8 (d, 1H), 7.68-7.70 (m, 2H), 3.5 (t, 2H), 3.35 (s, 3H), 3.15 (d, 1H), 2.9 (m, 2H), 2.78-2.81 (m, 1H), 2.65 (m, 2H), 2.55 (t, 2H), 2.45-2.48 (m, 1H), 2.05-2.06 (m, 2H), 1.82-1.96 (m, 3H), 1.41-1.44 (m, 3H), 1.37 (s, 3H), 1.1-1.3 (m, 2H), 0.9 (m, 1H), 0.77-0.83 (m, 3H), 0.39-0.46 (m, 2H), 0.18-0.21 (m, 1H), 0.01-0.02 (m, 2H); MS (ESI) for C.sub.26H.sub.39N.sub.3O.sub.2: 426.3116 (MH.sup.+). The free base was dissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

Example 28

Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (1)

(187) ##STR00124##

(188) (2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (28) was prepared according to the following steps

Step 1: Preparation of tert-butyl 4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate

(189) ##STR00125##

(190) To a mixture of tert-butyl piperazine-1-carboxylate (2 g, 10.74 mmol), K.sub.2CO.sub.3 (4.45 g, 32.22 mmol) in acetone (20 mL) was charged 2-(2-(2-methoxyethoxy)ethoxy)ethyl methanesulfonate (2.86 g, 11.81 mmol). The mixture was stirred for four hours at 50 C. The reaction mass was concentrated under vacuum. The obtained crude was dissolved in EtOAc (20 mL) and washed with water (10 mL2) and brine (10 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give tert-butyl 4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate (2.49 g, 70% yield) as a brown color gum.

Step 2: Preparation of 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine

(191) ##STR00126##

(192) To a mixture of tert-butyl 4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine-1-carboxylate (1.0 g, 3.00 mmol) in DCM (10 mL), was added 4.0 M HCl in IPA (1 mL) at ambient temperature. The mixture was stirred for two hours, and washed with saturated NaHCO.sub.3 (15 mL2), water (10 mL1) and brine (10 mL1). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, and concentrated under vacuum to give 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine (0.63 g, 90% yield) as a brown gum.

Step 3: Preparation of (2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (28)

(193) ##STR00127##

(194) (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl trifluoromethanesulfonate (200 mg, 0.479 mmol) and 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazine (122 mg, 0.527 mmol) were dissolved in toluene. BINAP (98 mg, 0.144 mmol), Pd.sub.2dba.sub.3 (88 mg, 0.096 mmol) and Cs.sub.2CO.sub.3 (219 mg, 0.671 mmol) were added to the above mixture and heated to 110 C. for two hours. The mixture was cooled to room temperature and concentrated under vacuum. A crude product was purified by column chromatography to obtain a pure (2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one (28) (124 mg, 55% yield). .sup.1H NMR (500 MHz, CDCl.sub.3): 7.8 (d, 1H), 7.70-7.65 (m, 2H), 4.05 (br, s, 1H), 3.7-3.54 (m, 10H), 3.45 (s, 3H), 3.40-3.25 (m, 8H), 2.57-2.51 (m, 4H), 2.35-2.28 (m, 4H), 2.20 (t, 2H), 1.41-1.44 (m, 3H), 1.37 (s, 3H), 0.46-0.39 (m, 2H), 0.21-0.18 (m, 1H), 0.20-0.10 (m, 2H); MS (ESI) for C.sub.29H.sub.45N.sub.3O.sub.4: 500.39 (MH.sup.+). The free base was dissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture was concentrated to afford product as hydrochloride salt.

(195) It is understood that each of Examples 1-28 described above may be modified to introduce oligomers of various lengths for each compound, as disclosed herein.

Example 29

Radioligand Competition Binding Assay

(196) The binding affinities of certain compounds of the present invention were evaluated using radioligand binding assays in membranes prepared from CHO-K1 cells expressing recombinant human kappa (KOR) or mu (MOR) opioid receptors.

(197) Competition binding experiments were conducted by incubating membrane protein to equilibrium in triplicate in the presence of a fixed concentration of radioligand and increasing concentrations of test compound for evaluation of binding to KOR or single concentration (10 M) of test compound for evaluation of binding to MOR in 101 L final volume. The radioligands used were specific for each receptor type, and the assay conditions are described in Table 1. Following incubations, the membranes were rapidly filtered through GF/B filter plate (presoaked with 0.5% polyethyleneimine), washed five times with cold 50 mM Tris-HCl, pH 7.5, and the bound radioactivity was then measured by liquid scintillation counting. Non-specific binding was measured in the presence of excess ligand; this value was subtracted from the total binding to yield the specific binding at each test concentration. Assay conditions are reported in Table 1 below.

(198) TABLE-US-00001 TABLE 1 Non- Receptor Membrane specific Receptor Source Protein Radioligand K.sub.d binding Methods Kappa Human 2.5 [.sup.3H] 0.3 U-50488 Reaction in 50 mM Tris-HCl Opioid recombinant g/well Diprenorphine nM (10 M) (pH 7.5), 5 mM MgCl.sub.2, 0.05% in CHO-K1 (1 nM) BSA at room temperature for 1 h cells with shaking Mu Opioid Human 5 g/well [.sup.3H] Naloxone Naloxone Reaction in 50 mM Tris-HCl recombinant (4 nM) (10 M) (pH 7.5), 5 mM MgCl.sub.2 at room in CHO-K1 temperature for 1 h with shaking cells

(199) For KOR binding, IC.sub.50 (concentration of test compound required to inhibit 50% of specific binding) values were obtained from non-linear regression analysis of dose-response curves, using GraphPad's Prism 5.01 software, and were calculated for those compounds that showed >50% inhibition of specific binding at the highest concentration tested. K.sub.i (affinity of test compound) was obtained using the Cheng Prusoff correction using experimental K.sub.d (affinity of radioligand) values that were previously determined under these assay conditions. For MOR binding, compounds were tested at one concentration, 10 M, to evaluate its ability to inhibit specific radioligand binding. The values are expressed as percent inhibition of specific binding and greater than 50% inhibition of binding was considered to be significant.

(200) With respect to determining MOR binding, an approach similar to one used for KOR binding was used.

(201) Data are expressed as means of one experiment in triplicate determination and reported in Table 2.

(202) TABLE-US-00002 TABLE 2 Binding Activities of Selected Compounds Kappa Mu receptor receptor binding % inhibition Compound at single No. concentration Mu receptor (Example IC50 % inhib binding No.) (nM) Ki (nM) @ 10 uM IC50 (nM) Ki (nM) 1 2682 618.9 81.9 2 2380 549.2 85.5 3 3333 769.2 80.6 4 879 202.9 89.2 5 12820 2959 51.2 6 6079 1403 48.6 12 5.004 58.48 20 2.861 44.3 23 1055 7957 24 493.9 1807 25 955.2 3918 Ketazocine 5.6 1.3 99.2 8.4

(203) Ketazocine was assayed as a known kappa and mu opioid agonist. The notation -- indicates that the assay was not performed for the referenced compounds.

Example 30

cAMP Accumulation Assay

(204) Inhibition of cAMP accumulation by select compounds was measured in forskolin-stimulated CHO-K1 cells stably expressing KOR. CHO-K1 cells stably expressing KOR were harvested using Invitrogen Cell Dissociation Buffer, and then centrifuged at 1200 rpm for five minutes. The supernatant was aspirated and cells were resuspended in assay buffer to a density of 410.sup.5 cells/mL. 25 L of cells were added into a white half-area 96 well plate. Fourteen point serial dilutions of test compounds were carried out in assay buffer (PBS with 0.5 mM IBMX). Ketazocine was used as a positive control for each assay. 12.5 L of compound was added to the cells in duplicate for each test concentration. The cells were then stimulated with 12.5 L forskolin at a final concentration 20 M. Cells were incubated for 45 minutes in a 37 C., 5% CO.sub.2 water jacketed incubator. CisBio HTRF cAMP assay reagent was used for cAMP quantitation. Two hours after substrate addition, signal at 665/615 nm was measured using the Perkin Elmer Victor X4 HTRF reader. Data analysis was done using GraphPad Prism, sigmoidal dose-response (variable slope) curve fitting.

(205) Using a similar approach, inhibition of cAMP accumulation by select compounds was also determined in forskolin-simulated CHO-K1 cells stably expressing MOR (wherein for this assay a density of 8105 cells/mL was used and the positive control was DAMGO). Certain compounds of the present invention were tested as described above. Data is reported in Table 3 below.

(206) TABLE-US-00003 TABLE 3 EC50 cAMP EC50 cAMP Compound (nM) - KOR (nM) - MOR 1 153 2 139 3 122 4 9.35 5 350 6 357 12 7 189.1 20 6.1 127.9 23 395.2 3288 24 106.8 597.8 25 195 1209 Ketazocine 0.55

(207) The data in Table 3 indicates that the tested compounds were effective in reducing cAMP in cells following KOR and MOR binding, indicating that the compounds function as agonists at the kappa and mu opioid receptors.

Example 31

In Situ Rat Brain Perfusion

(208) The in situ perfusion experiment measures the relative permeability of compounds across a model of the blood-brain barrier. In situ perfusion of opioids into rat brain is performed as described in Summerfield et al., J Pharmacol Exp Ther 322: 205-213 (2007).

(209) Adult male Sprague Dawley rats are used for the study. Rats are anaesthetized and the left common carotid artery is surgically cannulated for perfusion. Test compounds are perfused at concentrations of 5-50 M in a Krebs Ringer perfusion buffer (pH 7.4). Atenolol and antipyrine are included as low and moderate permeability markers, respectively. At the end of a 30 second perfusion, the brains are removed, the left brain hemisphere is excised and homogenized. Test compounds are extracted and analyzed using LC-MS/MS. The brain permeability of the test compounds is calculated as follows:
P=Kin/S,
where P is the permeability in cm/s, Kin is the unidirectional transfer constant (ml/min/gram), and S is the luminal area of the brain vascular space.

(210) The relative permeability as determined in the in situ brain perfusion experiment provides information regarding the rates at which compounds enter the central nervous system from the periphery. It is used to characterize and compare the degree to which compounds of the present invention penetrate the BBB as compared to known compounds or analogs of the tested compounds.

Example 32

Acetic Acid Writhing

(211) An analgesic assay was used to determine whether a given compound can reduce and/or prevent visceral pain in mice. The assay utilizes Swiss Albino or CD-1 male mice (5-10 mice per group), each mouse being approximately 0.015-0.030 kg on the study day. Mice were treated according to standard protocols.

(212) Mice were given a single pretreatment dose of a compound of the present invention, a known compound, such as diclofenac (which is a known analgesic which has been shown to reduce writhing behavior in this model), or control solution at fifteen minutes (for subcutaneous route) or thirty minutes (for orally route) prior to the administration of the acetic acid solution. The animal was given an intraperitoneal (IP) injection of an irritant (acetic acid) that induces writhing which may include: contractions of the abdomen, twisting and turning of the trunk, arching of the back and the extension of the hindlimbs. Mice are given a single IP injection (0.1 mL/10 g bodyweight) of a 0.5% acetic acid solution. After the injection the animals were returned to their observation enclosure and their behavior was observed. Contractions were counted between 0 and 20 minutes after the injection. The animals were used once. In certain instances, the test articles were administered at multiple doses to determine a dose response curve.

(213) Table 4 provides the results for certain compounds of the present invention that were administered subcutaneously. Table 5 provides the results for certain compounds of the present invention that were administered orally.

(214) TABLE-US-00004 TABLE 4 AAW Efficacy Following Subcutaneous Administration Example No. Dose (mg/kg) % Efficacy ketazocine 0.01 10.57 0.1 50.03 1 100.00 4 3 0.0 10 39.7 30 100.0 7 3 38.8 30 84.8 8 3 38.0 30 100.0 9 0.3 13.3 3 67.8 3 61.4 10 95.4 30 99.2 10 3 34.0 30 100.0 11 0.3 21.1 3 62.2 3 64.3 10 99.1 30 100.0 12 3 68.6 30 100.0 15 10 100.0 16 10 26.4 13 10 40.2 Step 1 of 13 10 100 17 10 23.3 14 10 13.2 18 10 31.9 19 10 31.6 20 10 88.1

(215) TABLE-US-00005 TABLE 5 AAW Efficacy following Oral Administration Example No. Dose (mg/kg) % Efficacy ketazocine 0.1 12.8 1 34.5 10 58.9 100 100.0 4 200 3.8 9 10 38.5 11 10 31.2 12 0.1 22.5 1 56.9 10 97.2 10 90.2 20 0.3 39.1 3 79.5 30 100.0

(216) In some instances, the percent efficacy following subcutaneous administration reported in Table 4 was derived with outlier data. If the outlier data is removed, the following percent efficacy values are obtained: Compound 7 (3 mg/kg)31.95; Compound 8 (3 mg/kg)31.07; Compound 9 (0.3 mg/kg)13.18, (3 mg/kg)64.20, (3 mg/kg)57.09 and (10 mg/kg)94.93; Compound 10 (3 mg/kg)26.63; Compound 11 (0.3 mg/kg)12.30, (3 mg/kg)56.21, (3 mg/kg)60.30 and (10 mg/kg)99.00; and Compound 12 (3 mg/kg)65.09.

Example 33

Locomotor Activity

(217) Male Swiss Albino mice were treated orally with vehicle (0.5% HPMC+0.1% Tween80), ketazocine, Compound 12 (0.3, 3 and 30 mg/kg) or Compound 20 (0.3, 3 and 30 mg/kg) thirty minutes prior to placement in the locomotor activity chamber. Total distance traveled was measured over the twenty minute observation time following placement in the locomotor activity chamber. Data are normalized relative to percent distance traveled in the vehicle group. The efficacy of Compound 12 (reported as percent distance traveled in comparison to vehicle) was 88.85%, 83.74% and 0.08% at 0.3, 3 and 30 mg/kg dosages, respectively, while the locomotor activity of Compound 20 (reported as percent distance traveled in comparison to vehicle) was 100%, 88% and 0.03% at 0.3, 3 and 30 mg/kg dosages, respectively.