PT97438A - PREPARATION PROCESS OF PHARMACEUTICAL COMPOSITIONS BASED ON RENIN INHIBITORS - Google Patents

Description

72500 4805.ΡΘ.01 '"2"

MEMORY ..... DESCRIPTIVE

This is a continuation in part of U.S. Application Serial No. 678,111, filed April 4, 1991, which is a continuation in part of U.S. Patent Application Serial No. 513,367 filed April 23, 1990 The present invention relates to the use of renin inhibitors and renin inhibitory compositions for the treatment of psoriasis.

Ar. Psoriasis is a chronic skin disease that is difficult to treat. Psoriasis is characterized by discrete, confluent, reddish maculopapulae with silver scales. This psoriatic injury often occurs frequently in the elbows, knees, trunk and scalp. Current treatments for psoriasis include the use of agents such as anthralin (dihydroxy anthrax), azarabine, colchicine, fluorouracil, methotrexate, methoxysalen (8-methoxypsoralen), resorcinol, petinoids (e.g., retinoic acid), corticosteroids (e.g., colbetasol, pro-pionate, triamcinolone acetonide and the like), ciloesporine, iodocloxyhydroxy, salicylic acid, vitamin 0, dapsone, somatostatin, sulfur, tars and zinc oxide. Treatment with ultraviolet light alone or in combination with other agents such as psoralen (i.e. PIJVA treatment) is also used to treat psoriasis.

There are reports that the activity of the renin-angiotensin-aldosterone system is increased in patients with psoriasis (Ena et al., Cardiovascular Act XL 199 (1985); Ryder et al., Clin. Chem., 153, 143 (1985) )). However, there is no established cause-and-effect relationship between the renin-angiotensin-aldosterone system and psoriasis. Renin is a proteolytic enzyme synthesized and stored primarily in the specific part of the kidney called the juxtaglomerular apparatus. Renin inhibitors have been disclosed as agents for the treatment of hypertension, congestive heart failure and glaucoma.

Sescrigão ..... do ..... inyen.to

It has now been found that the renin inhibitors are useful for the treatment of psoriasis'

Examples of renin inhibitors and processes for the preparation of renin inhibitors include, but are not limited to, those described in the following references which are incorporated herein by incorporated herein by reference. Luly, et al., U.S. Pat. No. 652,551 issued March 24, 1987, 2, Luly, et al., U.S. Patent No. 4,645,759, issued Feb. 24, 1987, Luly, et al. U.S. Pat. No. 4,680,284, issued July 14, 1987, 4, Luly, et al., U.S. Patent 4,725,583, issued February 16, 1988, 5, Luly, et al., U.S. Pat. And U.S. Patent 4,725,584, issued February 16, 1988, 6, Riniker, et al., U.S. Patent 4,595,567 issued June 17, 1986, Fuhrer et al. , U.S. Patent No. 4,613,676, issued September 23, 1986, 8, Buhlmayer, et al., U.S. Patent No. 4,727,060, issued February 23, 1988, Buhlmayer, et al., U.S. Patent No. 4,758,584, issued July 19, 1988, 10, lizuka, et al., U.S. Patent No. 4,665,269, issued to 7 April 1987, 11, 11, lizuka, et al., U.S. Patent No. 4,711,958, issued December 8, 1987, 12, Veber, et al., U.S. Patent No. 4 384 994, issued May 24, 1983, ????????????????????????????????????????????????????????????????????????? 22. 23. 24-25 25. 27-28. 29. 30. 31. ΐ ..... .....ϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋϋ granted the granted the granted the granted the granted one to the granted to NQ 4 665 055, granted to NQ 4 668 770, granted to

Boger, et al., U.S. Patent No. 4,470,971, September 11, 1984.

Boger, et al., U.S. Patent No. 4,477,440, October 16, 1984.

Boger, et al., U.S. Patent No. 4,477,441, October 16, 1984.

Veber, et al., U.S. Patent No. 4,479,941, October 30, 1984.

Boger, et al., U.S. Patent No. 4,485,099, 27 Novem- ber, 1984.

Boger, et al., U.S. Patent No. 4,668,663, May 26, 1987.

Boger, et al., U.S. Patent No. 4,665,052, May 12, 1987.

Bock, et al., U.S. Patent No. 4,636,491, issued November 3, 1987.

Boger, et al., U.S. Patent No. 4,661,473, issued April 28, 1987.

Bock, et al., U.S. Patent No. 4,663,310, issued May 5, 1987.

Evans, et al., U.S. Patent No. 4,609,641, issued September 2, 1986.

Evans, et al., U.S. Patent 12 May 1987.

Boger, et al., U.S. Patent 26 May 1987.

Boger, U.S. Patent No. 4,743,584, issued May 10, 1988.

Raddatz, et al., U.S. Patent No. 4,666,888, issued May 19, 1987.

Holzemann, et al., U.S. Patent No. 4,709,010, issued November 24, 1987.

Raddatz, et al., U.S. Patent No. 4,721,766, issued January 26, 1988.

Raddatz, et al., U.S. Patent No. 4,755,592, issued July 5, 1988.

Hoover, U.S. Patent No. 4,599,198, issued July 8, 1986. 72500 4805 PO-0132, Bindra, et al., U.S. Patent 4,479,985, issued March 8, 1988 33, Hoover, U.S. Patent No. 4,468,769, issued May 26, 1987, 34, Bindra, et al., U.S. Patent 4,449,687, issued June 7, , 1988, 35, Matsueda, et al., U.S. Patent 4,448,926, issued October 22, 1985, Matsueda, et al., U.S. Patent 4,488,846, 329, issued October 6, 1987).

37, Cazaubon, et al., U.S. Pat. NS 4, 481,192, issued November 6, 1984, 38, Wagnon, et al. U.S. Patent 4,725,580, issued February 16, 1988, 39, Hansen, et al., U.S. Patent 4,510,085, issued April 9, 1985, Hansen, et al., U.S. Patent No. 4,514,332, issued April 30, 1985, 41, Barari, et al. U.S. Patent 4,657,931, issued April 14, 1987, 42, Hansen, et al., U.S. Patent 4,722,922, issued February 2, 1988, 43 Ryono, et al., U.S. Patent No. 4,686,088, issued Oct. 7, 1986.

I

44, Ryono, et al., U.S. Patent No. 4,665,193, issued May 12, 1987, 45, Ryono et al., U.S. Patent 4,469,724, issued to 16 December, 1986, 46, Natarajan, et al., U.S. Patent 4,757,888, issued July 12, 1988, 47, Fordord, U.S. Patent No. 4,449,781, issued to June 7, 1988, 48, Szelke, et al., U.S. Patent 4,609,643, issued September 2, 1986, 49, Szelke, et al., U.S. Pat. NS 4 650 661, issued March 17, 1987, 50, Szelke, et al., U.S. Patent 4,713,445, issued December 15, 1987, 72500, 4805-PG.01

51. 52. granted to 10 30. 54, 55-56-57. 58-59. 60, 61 62-63 64-65-66-67-68-6, Thaisrivongs, U.S. Patent No. 4,705,846, November, 1987. Hudspeth, et al., U.S. Patent No. 4,735 to 5 April, 1988, Hudspeth, et al., U.S. Pat. 4 743 to 10 May, 1988-Sham, U.S. Patent No. 4,826,958, issued May 2, 1989-Rosenberg, et al., U.S. Patent No. 4,857,507, issued August 13, 1989. Luly, et al. U.S. Patent 4,826,815 issued May 2, 1989 Rosenberg, et al., U.S. Patent No. 4,837,204, issued June 6, 1989. Luly, et al., U.S. Patent No. 4 No. 845,079, issued July 4, 1989- Bender, et al., U.S. Patent No. 4,818,748, issued April 4, 1989-Kleinman, et al., U.S. Patent No. 4,729,995, issued March 8, 1988, Hoover, et al., U.S. Patent No. 4,814,342, issued March 21, 1989-Wagnon, et al., U.S. Patent No. 4,746,648, issued May 24, 1988 Natarajan, et al. U.S. Patent No. 4,757,050, issued July 12, 1988 Patel, U.S. Patent No. 4,820,691, issued April 11, 1989 Kaltenbronn, et al., U.S. Patent No. 4,804,743 , issued Feb. 14, 1989. Pinori, et al., U.S. Patent No. 4,560,505, issued December 24, 1985 Yamato, et al., U.S. Patent No. 4,683,220, issued July 28, 1987- Boger, et al., U.S. Patent No. 4,812,442, issued March 14, 1989 Patche tt, et al. U.S. Patent 4,839,357, issued June 13, 1989, 933, granted " 85, issued 07 72500 4805 'Pfâ' 01

"7, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86.

Boger et al., U.S. Patent No. 4,812,442, issued March 14, 1989.

Veber et al., U.S. Patent 4,478,826, issued October 23, 1984.

Raddatz * et al., U.S. Patent 4,812,555 * issued March 14, 1989

Wagnon, et al., U.S. Patent 4,840,935 issued June 20, 1989, Lizuka et al. U.S. Patent 4,441,067 issued June 20, 1989.

Raddatz et al., U.S. Patent 4,828,053, issued May 9, 1989.

Huanci et al. U.S. Patent 4,874,745, issued October 17, 1989

Wagner, et al. U.S. Patent 4,855,286 * issued August 8, 1989

Hoover et al., U.S. Patent 4,855,303, issued August 8, 1989, Lizuka et al., U.S. Patent 4,853,463, issued August 1, 1989

Hoover et al., U.S. Patent 4,859,654, issued Aug. 22, 1989.

Fuhrer et al., U.S. Patent 4,863,903, issued September 5, 1989, Lizuka et al., U.S. Patent 4,863,904, issued September 5, 1989

Hudspeth * et al., U.S. Patent 4,883,905, issued September 5, 1989

Thaisrivongs, et al., U.S. Patent 4,864,017, issued September 5, 1989.

Hudspeth * et al., U.S. Patent 4,895,834, issued January 23, 1990

Hester et al. U.S. Patent 4,880,781, issued Nov. 14, 1989.

Preferred renin inhibitors and processes for their preparation include those described in; U.S. Patent 4,826,815 * issued May 2, 1989; U.S. Patent No. 72500 4805.Ρθ.01

8,877,507 issued August 15, 1989; U.S. Patent No. 4,266,958, issued May 2, 1989; U.S. Patent No. 4,837,204, issued June 6, 1989; U.S. Patent No. 4,845,079, issued July 4, 1989, which are hereby incorporated by reference. Preferred renin inhibitors and processes for their preparation also include those described in; U.S. Patent Applications U.S. Pat. No. 403,906, filed September 1, 1989; USSN 231 869, filed August 16, 1988 (EP 0 307 377, published March 22, 1989); USSN 132,356, filed December 18, 1987 (W088 / 05050, issued July 14, 1988); PCT / USB9 / 04385, filed October 3, 1989 (W090 / 03971, published April 19, 1990); PCT / US89 / 04649, filed October 18, 1989 (WQ90 / 04917, published May 17, 1990); and USSN 564 925, filed August 9, 1990 which are incorporated by reference.

The preferred renin-inhibiting compounds in this invention are selected from the group consisting of compounds of the formula;

in which A is hydrogen, lower alkyl, arylalkyl, -OR2 wherein it is hydrogen, or lower alkyl, wherein R21 and R22 are independently selected from hydrogen and lower alkyl . or A is

in which B is NH, O, CH 2 or NHCH 2; and arylalkoxyalkyl-R 23 is lower alkyl, alkoxy, arylalkoxy,

Amino, alkylamino, dialkylamino, carboxyalkyl, alkoxycarbonylalkyl, (dihydroxyalkyl) (alkyl) amirio, amino-alkyl, amino-protected N-alkyl, (heterocyclo) alkyl, or a substituted or unsubstituted heterocycle ? W is C = O, CH 2 or CHOH; U is CH 2 or NR 2 wherein R 2 is hydrogen or lower alkyl, provided that when W is CHOH, then U is CH? R2 is lower alkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl) methyl, (2a naphthyl) methyl, (4-imidazolyl) methyl, (alpha, alpha) -dimethylbenzyl benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino group; provided that when it is phenoxy, thiophenoxy or anilino, then B is CH 2 or A is hydrogen? R 3 is lower alkyl, (thioaleoxy) alkyl, benzyl or methyl substituted with a heterocyclic ring -

Rk is hydrogen or lower alkyl; R6 is lower alkyl, cycloalkylmethyl, or benzyl;

Ry, Rg. and R9 are hydrogen or lower alkyl and may be the same or different? V is NH, Q, Q,, SO2 or CH2 - R 10 is lower alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, arylalkyl or a protecting group of N, or V and R 1 taken together are N 3 ' with the proviso that it may be an N-protecting group only when V is NH? f? 3b *? 5b

(2). 72500 4805-ΡΘ.01

-10

in which Ab is hydrogen, lower alkyl, arylalkyl, OR2bb or SR2ot) is hydrogen, lower alkyl or aminoalkyl, NR21b R22b in which P21b and R22b are independently selected from hydrogen, lower alkyl , aminoalkyl, cyanoalkyl and hydroxyalkyl; or Ab is R 23b%

0 or

in which Bb is NH, alkylamino, S, O, GH2 or CHOH; and R 23b is lower alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, arnyl, alkylamino, dialkylamino, (hydroxy-alkyl) (alkyl) amino, (dihydroxyalkyl) alkyl) amino, aminoalkyl, amino (with protected N) alkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (alkyl) amino (with proprotected N) alkyl, dialkylaminoalkyl, (heterocyclic) alkyl, or a substituted or unsubstituted heterocycle;

Wb is C = O or CHOH;

Ub is CH2 or NR2b wherein R2b is hydrogen or lower alkyl, provided that when Wb is CHOH, then Ub is CH2;

R1 is lower alkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxycarbonyloxy, halobarizyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (4-imidazolyl) methyl, (alpha, dimethylbenzyl, 1-benzyloxyethyl, ferethyl, ferioxy, thiophenoxy or anilino; provided that when R4b is phenoxy, thiophenoxy or anilino, then Bb is CH2 or CHOH or Ab is hydrogen; R 3b is lower alkyl, lower alkenyl, benzyl or methyl substituted with a heterocyclic ring; hydrogen or lower alkyl; R6b is lower alkyl, cycloalkylmethyl, or benzyl; R10b is lower alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, arylalkyl or a N-protecting group, or Lb and Rbb,

72500 and 480 taken together may be Mg, with the proviso that when Lj- is NH, then a N-protecting group; R13b is CHOH or co > R14b is oh2 > CF 2 or CF 3 with the proviso that R 13b is CO, then R 1 L 4, p is CF 2; R 15b is CH 2, CHR 25b in R 25b lower alkenyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or R 5b, R 5b,

F H with the proviso that when R 2 is CF 2 then R 2 is CH 2; is 0, S, SQ, SO2, RR26b in that R26b is hydrogen or lower alkyl, or NR2 and R3) wherein R27t> is hydrogen or lower alkyl;

in which Bc is NH, or CH2; and R 23c is lower alkyl, alkoxy, or a substituted or unsubstituted heterocycle;

Wc is C? O;

R 2c is hydrogen or lower alkyl;

Cyclopropylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl) methyl, (2 "'- naphthyl) Imidazolyl) methyl, (alpha * alpha) -dimethylbenzyl, 1-benzyloxyethyl, or phenethyl; Lower alkyl, benzyl or methyl substituted with a heterocyclic ring; R5 is hydrogen or lower alkyl; R6c is lower alkyl, cycloalkylmethyl, benzyl, or CH2 R24C wherein < 24c is selected from 1,3-dioxan-2-yl; 1,3-dioxolan-2-yl, 1,3-dithiolan-2-yl or 1,3-dithian-2-yl; CH 2, CF 2 or CHR 63c wherein R 63c is lower alkyl, hydroxy, hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl; R17c is hydrogen or lower alkyl; lower alkyl or a lipophilic or aromatic amino acid side chain;

D c is hydrogen, lower alkyl, or " Chlorophenyl < RTI ID = 0.0 > R11c < / RTI > hydrogen, lower alkyl or arylalkyl;

in which R20 is hydrogen, lower alkyl, arylalkyl, -OR20d or -R20d in R20d is hydrogen, lower alkyl or amino alkyl, wherein R21d and R22d are independently selected from hydrogen, lower alkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or is

in which is NH, alkylamino, 3.0, CH 2 or NHCH 2, R 23d is lower alkyl, cycloalkyl, aryl, arylalkyl, alkoxy,

(Hydroxyalkyl) amino, (dialkylamino) alkyl) (alkyl) amino, (di-hydroxyalkyl) alkylamino, dialkylamino, alkylamino, dialkylamino, dialkylamino, hydroxy (alkyl) (amino) aminoaminoalkyl, amino (with protected N) alkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (alkyl) amino (protected N-alkyl), dialkylaminoalkyl, (heterocyclo) alkyl, or a substituted or unsubstituted heterocycle Wd is C0-C or CHDHs

Ud is CHj > or NR2d wherein it is hydrogen or lower alkyl,

provided that when Wd is CHOH, then Ud is CHâ,ƒS is CHRâ,24d wherein R24q is lower alkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (4-imidazoyl) methyl, (alpha, alpha) -dimethylbenzyl, 1-benzyloxyethyl, or phenethyl, or R d1 is C = CHR25d wherein R5 sd

Rsd is lower alkyl, alkenyl, benzyl or methyl substituted with a heterocyclic ring

R 1a is hydrogen or lower alkyl; R6d is lower alkyl, cycloalkylmethyl, or benzyl;

R1 is hydrogen or hydroxy; n is 0 or 1; when n is 0 then Td is alkylidene or alkylidene oxide; and when n is 1 then Zd is hydrogen or hydroxy and Td is lower alkyl, hydroxyalkyl, aminoalkyl, haloalkyl or azidoalkyl; R12d is hydrogen, lower alkyl, cycloalkylalkyl, arylalkyl, aminoalkyl, or dialkylaminoalkyl;

in which A 1 is hydrogen, lower alkyl, arylalkyl, -OR 2 and or wherein R 20 is hydrogen, lower alkyl or aminoalkyl, -NR 21 and R 22 and R 22 are selected, 72500 4805

Independently of one another, from hydrogen, lower alkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or A ^ is

or 0

in which Be is NH, alkylamino, S, O, CH 2 or CHOH; alkoxy, alkyloxy, hydroxy-alkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxy-alkyl) (alkyl) amino, (dihydroxyalkyl) amino), aminoalkyl, amino (with protected N) alkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, (alkyl) amino (with protected N) alkyl, dialkylaminoalkyl, (heterocyclic) alkyl, or a substituted or unsubstituted heterocycle; is C = O;

Ue is NR 2 e where R 2 e is hydrogen or lower alkyl;

R 1 is lower alkyl, cycloalkylalkyl, benzyl, 4-methoxycarbonyl, 4-hydroxybenzyl, halobenzyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (4-imidazolyl) methyl, (alpha, alpha) dimethyl benzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino, provided that when R 1 is phenoxy, thiophenoxy or anilino, then B 2 is CH 2 or CHOH, or A 1 is hydrogen; R 3e is lower alkyl, benzyl or methyl substituted with a heterocyclic ring; RSe is hydrogen or lower alkyl; R1 is lower alkyl, cycloalkylmethyl, or benzyl; M-j is 0, NH or S; R10e is hydrogen, lower alkyl, cycloalkyl, (cycloalkyl) -alkyl, aryl, arylalkyl or a N-protecting group;

0

H I N

(6) -15- Λ. 72500 4805 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein A5 is hydrogen, lower alkyl, arylalkyl, -OR10, or -SR10, wherein R10 is hydrogen, lower alkyl or aminoalkyl; alkylamino, carboxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, (amino) carboxyalkyl, (amino (with protected N)) carboxyalkyl, (alkylamino) carboxyalkyl, carboxyalkyl) (dialkylamino) carboxyalkyl, (amino) alkoxycarbonylalkyl, (amino (with protected N)) alkoxycarbonylalkyl, (alkylamino) alkoxycarbonylalkyl, (alkylamino (with protected N)) alkoxycarbonylalkyl and (dialkylamino) alkoxycarbonylalkyl; or Af is

OR

R " " ' Fig.

in which Bf is NH, alkylamino, S, O, CH 2 or CHOH and R 23 is lower alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, hydroxyalkyl) (alkyl) amino, dihydroxyalkyl (alkyl) amino, aminoalkyl, amino (with protected N) alkyl, alkylaminoalkyl, (alkyl) amino (with protected N) alkyl, dialkylaminoalkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, (amino) carboxyalkylamino, (amino-protected), carboxyalkyl, (amino (with protected N)) carboxyalkylamino, (alkylamino) carboxyalkylamino, carboxyalkylamino, (dialkylamino) carboxyalkyl, (dialkylamino) carboxyalkylamino, (amino) alkoxycarbonylalkyl, (aminoalkyl) carboxyalkylamino, (alkylamino) carboxyalkylamino, (alkylamino) carboxyalkylamino, ) alkoxycarbonylalkylamine alkoxycarbonylalkyl, (amino (with protected N)) alkoxycarbonylalkylamino, (alkylamino) alkoxycarbonylalkyl, (alkylamino) alkoxycarbonylalkylamino, (alkylamino (with N

(Dialkylamino) alkoxycarbonylalkyl, (dialkylamino) alkoxycarbonylalkylamino, aminocycloalkyl, aminoalkylamino, dialkylaralkenyl (alkyl) amiriol), alkoxycarbonylalkyl (alkoxycarbonylalkyl), alkoxycarbonylalkylamino, arylalkylamino, arylalkyl (alkyl) amino, alkoxyalkyl, (alkyl) amino! (polyalkyloxy) alkyl (alkyl) amino, di (alkoxyalkyl) amino, di (hydroxy) alkylamino, di - (polyalkoxy) alkylamino, polyalkoxy, (polyalcoxy) alkyl, (heterocyclo) or a substituted or unsubstituted heterocycle in which the saturated heterocycles may be unsubstituted, monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or lower alkyl; the unsaturated heterocycles may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or lower alkyl;

Wf is C = Q or OHOH

Uf is CH2 or NR2f provided that when Wf is CHGH, then it is CH2; (1-naphthyl) methyl, (2-naphthyl) methyl, (4-imidazolyl) methyl, (alpha, alpha) -dimethylbenzyl, 1-benzyloxyethyl phenethyl, phenoxy, thiophenoxy or anilino; provided that when R 1 L 2 is phenoxy, thiophenoxy or anilino, then B 2 is CH 2 or CHOH or A 2 is hydrogen; F 2 is hydrogen or lower alkyl; is lower alkyl, lower alkenyl, ((alkoxy) alkoxy) lower alkyl, (thioalkoxy) alkyl, benzyl or methyl substituted with a heterocyclic ring; R? is lower alkyl, cycloalkylmethyl or benzyl;

Raf is vinyl, formyl, hydroxymethyl or hydrogen; R 2 is hydrogen or lower alkyl; R 1 and R 2 are independently selected from OH and H 2; and

R f is hydrogen, lower alkyl, vinyl or arylalkyl;

(7)

(Alkyl) aminoalkyl, dialkylaminoalkyl, (alkoxy) aminoalkyl, (alkoxy) (alkyl) aminoalkyl, phenylalkyl, (substituted phenyl) -alkyl wherein the phenyl ring is substituted with one, two or three substituents independently selected from lower alkoxy, lower alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamido , naphthylalkyl, (naphthyl substituted) alkyl wherein the naphthyl ring is substituted with one, two or three substituents independently selected from lower alkoxy, lower alkyl, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide, substituted or unsubstituted heterocycle, wherein the saturated heterocyclic can be unsubstituted, non-substituted substituted or unsubstituted or substituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, lower alkyl, haloalkyl or polxhaloalkyl; the unsaturated heterocyclic groups may be unsubstituted or monosubstituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, lower alkyl, haloalkyl or polyhaloalkyl, or Ag is (unsubstituted heterocycle) alkyl or (substituted heterocycle) alkyl wherein the unsubstituted or substituted heterocycle is defined as above, or Ag is -OR7g or -SRyg wherein Ryg is hydrogen, lower alkyl, aminoalkyl, (alkyl) aminoalkyl, dialkylaminoalkyl, (alkoxy) aminoalkyl, (alkoxy) (alkyl) aminoalkyl, (substituted phenyl) alkyl wherein the substituted phenyl is defined as above, naphthylalkyl, (substituted naphthyl) alkyl wherein the substituted naphthyl is as defined above, substituted or unsubstituted heterocycle as defined above, (unsubstituted heterocycle) alkyl or substituted (heterocyclic) alkyl wherein the substituted or unsubstituted heterocycle is defined as above, (unsubstituted heterocycle) C (O) -or (substituted heterocycle) C (O) wherein the unsubstituted or substituted heterocycle is defined above as:

wherein R8, 8 and R9g are independently selected, 72500 4805-PS-01

Between each other, hydrogen, hydroxy, alkoxy, lower alkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or Ag is

R B.

or δ

in which Bg is HH, alkylamino, S, O, CH2, NHCH2 or GH1 R2 R3), which is hydrogen, lower alkyl or lower alkylC1-6 alkyl, and R1 is hydrogen, lower alkyl, cycloalkyl, substituted naphthyl, substituted naphthyl, naphthyl substituted as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, phenylallyloxy, (phenyl substituted) alkoxy wherein the substituted phenyl is defined as above, naphthylalkoxy, (substituted naphthyl) alkoxy wherein the substituted naphthyl is defined as above, phenylalkoxyalkyl, (substituted phenyl) alkoxyalkyl wherein the substituted phenyl is defined as above, naphthylalkoxyalkyl, (naphthyl substituted) alkoxyalkyl wherein the substituted naphthyl is as defined above, thioalkoxyalkyl , (lower alkyl) sulfonylalkyl, (lower alkyl) sulfonylalkyl, phenylthioalkyl, (substituted phenyl) thioalkyl wherein the substituted phenyl is defined as above (substituted naphthyl) thioalkyl wherein the substituted naphthyl is defined as above, phenylsulfonylalkyl, (substituted phenyl) sulphonylalkyl wherein the substituted phenyl is defined as above, naphthylsulfonylalkyl, (naphthyl substituted) sulfonylalkyl wherein the naphthyl aminoalkyl, alkylamino, dialkylamino, (hydroxyalkyl) (Alkylamino) (dihydroxyalkyl) (alkyl) amino, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, amino (with protected N) alkyl, alkylaminoalkyl, (alkyl) amino, (dialkylaminoalkyl) (alkyl) amino, phenylalkylamino, (substituted phenyl) alkylamino wherein R 1, R 2, R 3, R 4, the substituted phenyl is defined as above, naphthylalkylamino, (substituted naphthyl) alkylamino wherein the

Substituted naphthyl is defined as above, (phenylalkyl) (alkyl) amino, ((substituted phenyl) alkyl) (alkyl) -amino wherein the substituted phenyl is defined as above, (naphthylalkyl) (alkyl) amino, di (alkoxyalkyl) amino, (C 1 -C 4) alkylamino (C 1 -C 4) alkylamino, (heterocyclic) alkyl, amino (alkyl) amino, (alkyl-aminoalkyl) amino, (heterocyclo) alkylamino, di (polyalkoxy) alkylamino, alkyl) amino, (dialkylaminoalkyl) (alkyl) amino, (alkoxy) (alkyl) aminoalkyl) (alkyl) amino ((alkoxy) aminoalkyl) (alkyl) amino, polyalkoxy or (polyalkoxy) alkyl; or A g is R 41g CH (OH) CH 2 - or R 41g CH (OH) CH (OH) - wherein R 41g is lower alkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above, ) alkyl wherein the substituted phenyl is defined as above, naphthylalkyl, (substituted naphthyl) alkyl wherein the substituted naphthyl is as defined above, phenylalkoxyalkyl, (substituted phenyl) alkoxyalkyl wherein the substituted phenyl is defined as above, naphthylalkoxyalkyl, (substituted naphthyl) alkoxyalkyl wherein the substituted naphthyl is defined as above, thioalkoxyalkyl, (lower alkyl) sulfinylalkyl, (lower alkyl) sulfonylalkyl, phenylthioalkyl, (substituted phenyl) thioalkyl wherein the substituted phenyl is defined as , naphthylthioalkyl, (substituted naphthyl) thioalkyl wherein the substituted naphthyl is as defined above, phenylsulfonylalkyl, (phenyl sub substituted naphthylsulfonylalkyl, wherein the substituted naphthyl is defined as above, aminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, amino (protected N-alkyl), alkylaminoalkyl, (alkyl) ) amino (with protected N) alkyl, dialkylaminoalkyl, (heterocyclo) alkyl, a substituted or unsubstituted heterocycle defined above as, aminocycloalkyl or (polyalkoxy) alkyl;

Wg is C = O, CHOH or NR2g wherein R2g is hydrogen or lower alkyl; (

72500 4805.ΡΘ.01 -20

Ug is C = O, CH2 or NR2g wherein R2g is lower hydrogen, with the proviso that when Wg is CHOH then Ug is CH2 and with the proviso that Ug is C = O or CH2 when Wg is NR2g;

Vg is CH, C (OH) or C (halogen) with the proviso that Vg is CH when

Ug is NR2g?

R 2 is lower alkyl, cycloalkylalkyl, benzyl, (alpha, alpha) -dimethylbenzyl, 4-methoxybenzyl, halobenzyl, 4-hydroxybenzyl, (1-naphthyl) methyl, (2-naphthyl) methyl, (unsubstituted heterocycle) (substituted heterocycle) methyl wherein the unsubstituted or substituted heterocycle is defined as above, phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, provided that Bg is CH 2 or CHOH or Ag is hydrogen when R 2g is phenoxy, thiophenoxy or anilino;

R 1 is lower alkyl, lower alkenyl, (alkoxy) alkoxy) alkyl, carboxyalkyl, (thioalkoxy) alkyl, azidoalkyl, aminoalkyl, (alkyl) aminoalkyl, dialkylaminoalkyl, (alkoxy) (alkyl) aminoalkyl, (alkoxy) aminoalkyl, benzyl or methyl substituted with a heterocyclic ring; R1 is lower alkyl, cycloalkylmethyl or benzyl; R 5g is OH or NH 2; and

OH or ^ 49g

C, S, S, 8 (O), S (O) - or CH

Tq is C ~ Q, 2! in which Mg is O, S or NH.

Wherein R6 is hydrogen, lower alkyl, hydroxyalkyl, hydroxy, alkoxy, amyl, or alkylamino, or Eg is CR6 and R42, wherein R6g is as previously defined and R42g is hydrogen or lower alkyl, or Eg is C  € ƒâ € ƒâ € ƒwherein R43g and R44g are independently selected from hydrogen and lower alkyl, wherein n is absent, is CH2 or NR11g wherein Ρ1ΐ9 is hydrogen or lower alkyl, with the proviso that when NR11 is then R 6g is lower alkyl or hydroxyalkyl, R 4g CR 45g R 4, and R 45g R 46g are each independently selected from hydrogen and alkyl wherein R 47g R 48g is lower or Q g is C = CR 47g R 4gg

Selected from each other independently of one another being hydrogen and lower alkyl, and -CH2 OH, carboxy, alkoxycarbonyl or -CONR50 R5 R5, wherein R4 is hydrogen or lower alkyl and R1 is hydrogen, lower alkyl, amino , alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl;

in which Aâ € ² is hydrogen, lower alkyl, arylalkyl, â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒO2 or -SR2OH is hydrogen, lower alkyl or aminoalkyl, among hydrogen, lower alkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; or is R 23h

0

in which Bh is NH, alkylamino, S, O, CH2 NHCH2 or CHOH; and R 23 (-) is lower alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) amino, (dialkylamino) (alkyl) amino, (di) hydroxyalkyl (alkyl) amino, aminoalkyl, amino (with protected N) alkyl, alkylaminoalkyl, (alkyl) amino (with protected N-alkyl), dialkylaminoalkyl, ) alkyl, or a substituted or unsubstituted heterocycle;

Wh is C-Q or CHOH;

Uh is CH2 or NR2h wherein R2p, is hydrogen or lower alkyl, provided that when it is CHOH then it is CH2; (1-naphthyl) methyl, (2-naphthyl) methyl, (4-imidazolyl) methyl, (alpha, alpha) -dimethylbenzyl, (4-methoxybenzyl), 4-hydroxybenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or 72500 4805.PQH 01

Anilino, provided that when R 1 is phenoxy, thiophenoxy or anilino then it is CH 2 or CHOH or Aj-, is hydrogen; F '3h is lower alkyl, lower alkenyl, ((alkoxy) alkoxy) -alkyl, carboxyalkyl, (thioalkoxy) alkyl, benzyl or methyl substituted with a heterocyclic ring; R5h is hydrogen or lower alkyl; is lower alkyl, cycloalkylmethyl or benzyl;

O

in which A 1 is W and Q is 4 and i) hydroxy ii) alkoxy iii) thioalkoxy, iv) amino or v) substituted amino; (II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl; (III) aryl, arylalkyl, heterocycle or (heterocyclic) alkyl; or (IV) R90 or R90 (NHCON); in which Râ,, is a straight or branched C ^ to C carbon carbon chain substituted by a substituent selected from 1) carboxy, 2) alkoxycarbonyl, 3) alkylsulfonyl, 4) aryl, 5) arylsulfonyl, 6) heterocycle or 7- ) (heterocyclo) sulfonyl) -23- 72500 4805.ΡΘ.01

(III) lower alkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) aryloxyalkyl, (VII) thioaryloxyalkyl, (IV) arylalkoxyalkyl, (IX) arylthioalkoxyalkyl or (X) a straight or branched C12 to C12 carbocyclic substituted with a substituent selected from 1) alkoxy, 2) thioalkoxy, 3) aryl and 4) heterocycle; (VI), (VII) S (Q), (VIII) is 2, (IX) N (O) ) (I) lower alkyl, (II) haloalkyl, (III) lower alkenyl, (IV) cycloalkylalkyl, (V) cycloalkenylalkyl, (VI) alkoxyalkyl, (VII) thioalkoxyalkyl (IX) (XI) (XI) (XII) â € ¢ (alkoxyalkoxy) alkyl · hydroxyalkyl â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (CH2) eeNHRi2i wherein 1 and e is 1 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR121 is I) hydrogen; ii) lower alkyl or (i) an N-protecting group; arylalkyl or (heterocyclic) alkyl; and

D. wherein (D (II) (III) (IV)) is lower alkyl, cycloalkylalkyl, cycloalkenylalkyl or arylalkyl;

(II) wherein R1 is lower alkyl;

(I) (ii) (ii) (i) (i) (ii) (i) (ii)

(iv) wherein: R1 is lower alkyl, C1 -C4 alkyl or NR18 i wherein R18i is a) hydrogen, b) lower alkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and is absent, is CH 2 or is NR 2 -j which is hydrogen or lower alkyl, with the proviso that when G 2 is NR 19, then R 15 is lower alkyl or hydroxyalkyl; in which 1) 2) Λ "λ * (CH2) v - -C (O) -N R21, / / v" is 0 or 1 and R 2 is (i) NH, i) 0, i i) or iv) or (IV) a substituted methylene group; and

~ 26

(10) wherein X 1 is (I) N, (II) O or (III) CH 2

(I) is absent, (II) is hydrogen, (III) is a protecting group of N, (IV) aryl, (V) heterocycle, or (VI) wherein R 1 is R 1 is lower alkyl, amino), (vii) aryl, (viii) arylalkyl, (ix) aminoalkyl, (x) amino (with the proviso that: N (protected) alkyl) xi) alkoxy, xii) substituted lower alkyl wherein the substituent is selected from alkoxy, thioalkoxy, halogen, alkylamino, (alkyl) amino (protected H), and dialkylamino,

Wherein R 1 is hydrogen, hydroxy, alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, amino (protected N), alkylamino, (alkyl) amino (C 1 -C 5) protected N) or dialkylamino; or

xiv) in which Rjj is 0, S, 80., O = C or RjNN wherein R j is hydrogen, lower alkyl or a N-protecting group; and â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (2) â € ƒâ € ƒâ € ƒâ € ƒâ € ƒis i) Câ, â, (VII) in which R 1> 4 is 1) amino. 2) alkylamino, 3) dlalkylamino, 4) lower alkyl, 5) haloalkyl, 6) aryl, 7) p-biphenyl, 8) heterocycle or VIII) (Rgg 1) alkoxy, 2) alkylamino or 3) dialkylamino ; and L.j are independently selected from (I) absent, (II) OG, (III) SO2 and (IV) CH2; (I) or (II): wherein R1 is selected from the group consisting of:

r25 is

(III) (IV) hydrogen * lower alkyl * cycloalkylalkyl * - (CH 2) n - (CH 2) q " 5 is 0 * 1 or 2 * 2) R10j is absent or R4a is NH2 when q < 5 is 1 or 2 * and 3) R113 is i) aryl or ii) heterocycle; (I) (II) is hydrogen or -R283C (O) R293 -R28jS (O) 2R29a or C (S) wherein R283 is i) NH2; R 20 is lower or benzyl or

2) (ii) CH 2 and R 293 is i) alkoxy; ii) benzyloxy; III) alkylamino; iv) dialkylamino; v) aryl or vi) heterocycle; (VI) (VI) hydrogen * lower alkyl * lower alkenyl * cycloalkylalkyl * cycloalkenylalkyl * alkyloxyalkyl *

(VIII) (alkoxyalkoxy) alkyl (IX) (polyalkoxy) alkyl, (X) arylalkyl or (XI) (heterocyclic) alkyls is 0 or 1; and

wherein R1 is (I) (II) (III) lower alkyl cycloalkylalkyl or arylalkyl; and

R (73)

Wherein R1 is lower alkyl, (II) M: ΎQ. in which 1) 2) m 5 is i) 0): (iii) NH 4 is D). ii) S9 3) 72500

4805 «PO» 01

W

(a) hydrogen, (b) lower alkyl, (c) hydroxyalkyl, (d) hydroxy, (e) alkoxy, (f) ) amino or g) alkylamino; and

i) is absent, ii) is CH2 or iii) is NR19j wherein R1 < 1 > is hydrogen or lower alkyl, with the proviso that when G3 is NR1 R2 then R3 is lower alkyl or hydroxyalkyl; (III) in which (l) v 'is 0 or 1 and

i) NH, ii) 0, iii) or iv) SO2 'or (IV) a substituted methylene group; or a pharmaceutically acceptable salt, ester or prodrug thereof. D " lower alkyl " used in the present invention refers to straight or branched chain alkyl radicals containing from 1 to 7 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, N-pentyl, 2-methylbutyl, tilprapyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,2-dimethylbutyl, 2,2-dimethylbutyl, 2-methylhexyl and the like - the term " lower alkenyl " used in the present invention refers to a straight or branched chain lower alkyl radical containing at least one carbon-carbon double bond. The term " cycloalkyl " used in the present invention relates to an aliphatic ring having 3 to 7 carbon atoms. The term " cycloalkylalkyl " used in the present invention relates to a cycloalkyl residue attached to a lower alkyl radical and includes, but is not limited to, cyclohexylmethyl and cyclopentylmethyl. The term " cycloalkenyl " used in the present invention relates to an aliphatic ring having 3-7 carbon atoms and also having at least one carbon-carbon double bond including, but not limited to, cyclohexenyl and the like, the term " cycloalkenylalkyl " used in the present invention relates to a cycloalkenyl group attached to a lower alkyl radical including, but not limited to, cyclohexenylmethyl, cyclopentenylethyl and the like. The term " arylalkyl " used in the present invention refers to an aryl group, defined as in the present invention, attached to a lower alkyl radical including but not limited to benzyl, 1- and 2-naphthylmethyl, halobenzyl, and alkoxybenzyl. The term " phenylalkyl "; used in the present invention refers to a phenyl group attached to a lower alkyl radical including, but not limited to, benzyl, ferethyl, and the like. The term " (substituted phenyl) alkyl " present invention relates to a substituted phenyl group attached to a lower alkyl radical in which the phenyl ring is substituted with one, two or three substituents selected from the group consisting of lower alkoxy, lower alkyl, amino, lower alkylamino, hydroxy , halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including but not limited to halobenzyl, alkoxy benzyl and the like. The term " naphthylalkyl " used in the present invention relates to a naphthyl group attached to a lower alkyl radical, including, but not limited to, N-naphthylmethyl, 2-naphthylmethyl and the like " (substituted naphthyl) alkyl " used in the present invention refers to a substituted naphthyl group bonded to a lower alkyl radical wherein the naphthyl ring is substituted with one, two or three substituents selected from the group consisting of lower alkoxy, lower alkyl, amino, lower alkylamino alkyl, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy and carboxamide, including, but not limited to, halonaphthylmethyl, alkoxynaphthylmethyl and the like " (heterocyclic) alkyl " used in the present invention relates to a substituted or unsubstituted heterocyclic ring, defined as below, attached to a lower alkyl radical, including, but not limited to, imidazolyl " methyl, thiazolylmethyl, and the like " hydroxyalkyl " used in the present invention refers to -OH attached to a lower alkyl radical, the term " alkoxyalkyl " used in the present invention relates to an alkoxy group attached to a lower alkyl radical, the term " arylalkoxyalkyl " used in the present invention relates to an arylalkoxy attached to a lower alkyl-

The term " phenylalkoxyalkyl " used in the present invention relates to a phenylalkoxy group attached to a lower alkyl radical, including, but not limited to, phenylmethoxy-methyl and the like. The term " phenyl substituted with alkoxyalkyl " used in the present invention relates to a substituted (substituted phenyl) alkoxy group attached to a lower alkyl radical, including but not limited to 4-chlorophenylmethoxymethyl, the term " naphthylalkoxyalkyl " used in the present invention refers to a naphthylalkoxy group attached to a lower alkyl radical , including, but not limited to, 1-naphthylmethoxymethyl and the like. The term " (substituted naphthyl) alkoxyalkyl " used in the present invention refers to a (substituted naphthyl) alkoxy group attached to a lower alkyl radical, including , but not limited to, halonaphthylmethoxymethyl and the like. The term " thioalkoxyalkyl " used in the present invention refers to a thioalkoxy group attached to a lower alkyl radical, the term " ((alkoxy) alkoxy) alkyl " used in the present invention relates to an alkoxy group attached to an alkoxy group which is attached to a lower alkyl radical, including but not limited to methoxymethoxymethyl and the like. The term " polyalkoxyalkyl " refers to a polyalkoxy residue attached to a lower alkyl radical, including, but not limited to, methoxyethoxy methoxymethyl and the like, the term " aminoalkyl " used in the present invention refers to -N1-alkyl linked to a lower alkyl radical, the term " alkylaminoalkyl " used in the present invention 72500 4805.PQ M 01

refers to -NHRyQ linked to a lower alkyl radical, wherein Ryo is a lower alkyl radical. The term " dialkylaminoalkyl " used in the present invention refers to a dialkylamino linked to a lower alkyl radical. The term " amiocycloalkyl " "Used in the present invention refers to a β2 linked to a cycloalkyl radical. The term " amino (with protected N) alkyl " used in the present invention refers to -MHRyj, attached to a lower alkyl group, wherein is a N-protecting group. " (alkyl) amino (with protected N) alkyl " used in the present invention relates to which is attached to a lower alkyl radical, wherein R77 is as defined above and R72 is a lower alkyl group. The term " alkoxycarbonylalkyl " used in the present invention relates to wherein R73 is an alkoxy group and R74 is a lower alkyl radical. The term " carboxyalkyl " used in the present invention relates to a carboxylic acid group (-C H H) attached to a lower alkyl radical. The term " cyanoalkyl " used in the present invention refers to -CN bonded to a lower alkyl radical. The term " azidoalkyl " used in the present invention refers to -N3 linked to a lower alkyl radical. The term " (alkoxy) aminoalkyl " used in the present invention relates to an alkoxy group attached to an amino group which in turn is attached to a lower alkyl radical. The term " (alkoxy) (alkyl) aminoalkyl " used herein 72500 4805 ηPG.01 -35

invention relates to a group -NR7SR76 bonded to a lower alkyl radical wherein R78 is an alkoxy group and R7 is a lower alkyl group. The term " (lower alkyl) sulfinylalkyl " used in the present invention relates to a group R 77 S (q) - attached to a lower alkyl radical wherein R 77 is a lower alkyl group. The term " lower alkylsulfonylalkyl " used in the present invention relates to a compound of the formula: linked to a lower alkyl radical wherein R 78 is a lower alkyl group; The term " phenylthioalkyl " used in the present invention relates to a Rye> S group attached to a lower alkyl radical in which it is a phenyl group. The term " (substituted phenyl) thioalkyl " used in the present invention relates to a RggS- group attached to a lower alkyl radical in which Rg0 is a substituted phenyl group. The term " naphthylthioalkyl " used in the present invention refers to a R8 '' group attached to a lower alkyl radical in which R8 'is a naphthyl group. The term " (substituted naphthyl) thioalkyl " used in the present invention refers to a group Rq28 linked to a lower alkyl radical in which R82 is a substituted naphthyl group. The term " phenylsulfonylalkyl " Accordingly, the present invention relates to a group 338 (O) 2 " linked to a lower alkyl radical in which Rgg is a phenyl group- " (substituted phenyl) sulfonylalkyl " used in the present invention refers to a R84S (O) 2-group attached to a lower alkyl radical wherein R84 is a substituted phenyl group. The term " naphthylsulfonylalkyl " used herein 72500 4805.Ρθ.01

invention relates to a R85S (O) 2-group attached to a lower alkyl group wherein R8S is a naphthyl group. The term " (substituted naphthyl) sulfonylalkyl " used in the present invention refers to a group R6 = SCO2 - attached to a lower alkyl group wherein R86 is a substituted naphthyl group. The term " carboxyalkoxyalkyl " used in the present invention relates to a carboxylic acid group (-C H H) attached to an alkoxy group which is attached to a lower alkyl radical, the term " alkoxycarbonylalkoxyalkyl " used in the present invention relates to an alkoxycarbonyl group (RgyCO- wherein Rg is an alkoxy group) attached to an alkoxy group which is attached to a lower alkyl radical - the term " (amino) carboxyalkyl " used in the present invention refers to a lower alkyl radical to which is attached a carboxylic acid group (-CONH) and a C1- NH2 amino group). The term " (protected amino-N-protected) carboxyalkyl " used in the present invention refers to a lower alkyl radical to which is attached a carboxylic acid (-000H) and -NHR 88 group wherein R88 is a N-protecting group (" alkylamino ") carboxyalkyl " used in the present invention refers to a lower alkyl radical to which is attached a carboxylic acid group (-C H H) and an alkylamino group, " (alkylamino (N-protected)) carboxyalkyl " used in the present invention relates to a lower alkyl radical to which is attached a carboxylic acid group (-C H H) and a " NR 39 R 90 where R 39 is as defined above and R 1 q is a lower alkyl group; dialkylamino) carboxyalkyl " used in the present invention refers to a lower alkyl radical to which

72500 4805 "PQ" Q1 is attached to a carboxylic acid (-CONH2) group and in which R1 and R2 are selected independently of one another from lower alkyl. The term " (amino) alkoxycarbonylalkyl " used in the present invention refers to a lower alkyl radical to which is attached an alkoxycarbonyl group as previously defined and an amino group (-NH2). The term " (amino (protected N) alkoxycarbonylalkyl " used in the present invention refers to a lower alkyl radical to which is attached an alkoxycarbonyl group as defined above and -NHR93 in which R93 is defined as above. The term " (alkylamino) alkoxycarbonylalkyl " used in the present invention refers to a lower alkyl radical to which is attached an alkoxycarbonyl group as defined above and an alkylamino group as defined above. The term " (alkylamino (with protected N)) alkoxycarbonylalkyl " used in the present invention refers to a lower alkyl radical to which is attached an alkoxycarbonyl group defined as above and " NR " wherein R 94 is a N-protecting group and R 9 is a lower alkyl group. The term " (dialkylamino) alkoxycarbonylalkyl " used in the present invention refers to a lower alkyl radical to which is attached an alkoxycarbonyl group as defined above and wherein R96 and R9y are independently selected from lower alkyl. The term " carboxyalkylamino " used in the present invention refers to-NHR9q wherein R9g is a carboxyalkyl group. The term " alkoxycarbonylalkylamino " used in the present invention relates to -NHR99 wherein R99 is an alkoxycarbonylalkyl group. 72500

4805-ΡΘ.01 -38 ™ The term " (amino) carboxyalkylamino " used in the present invention relates to wherein a carboxylic acid (amino (with protected N)) carboxyalkylamino " used in the present invention relates to a group (amino (with protected N) carboxyalkyl) The term " (alkylamino) carboxyalkylamino " used in the present invention refers to -NHR 2 R 2 (alkylamino) carboxyalkyl group "The term " (alkylamino (with protected N)) carboxyalkylamino " used in the present invention relates to "NHR-j" in which is a (alkylamino (with protected N)) carboxyalkyl group. The term " (dialkylamino) carboxyalkylamino " used in the present invention relates to -NHR104 wherein R4 is a (dialkylamino) carboxyalkyl group " (amino) alkoxycarbonylalkylamino " used in the present invention relates to -NHR 105 in which R 20 is an (amino) alkoxycarbonylalkylamino group (" amino (with protected N) ") alkoxycarbonylalkylamine " used in the present invention relates to wherein R1 is a (protected amino) alkoxycarbonylalkyl- " Alkylamino) alkoxycarbonylalkylamino " used in the present invention relates to -NHR 11 wherein R 10 ' is an (alkylamino) alkoxycarbonylalkyl group. " (C 1 -C 4 -alkylamino protected) alkoxycarbonylalkylamino " used in the present invention relates to -NHRâ, "wherein Râ, ‡ is a C1 -C6 alkylamino (with the protected N) alkoxycarbonylalkyl " (dialkylamino) alkoxycarbonylalkylamino " used

In the present invention refers to -NHR-y- wherein R 2 is a (dialkylamino) alkoxycarbonylalkyl- group, " alkylidene " used in the present invention refers to a straight or branched chain alkyl radical which is attached by a carbon-carbon double bond and includes, but is not limited to, methyl ethylene, 1-propylidene, 1-butylldene 2-pentylidene, 3-pentylidene * 3-hexylidene, 3-heptylidene and 4-heptylidene. The term " alkylidene oxide " used in the present invention relates to an epoxide moiety which is derived from an alkylidene group - the term " amino " used in the present invention relates to a substituent the term " alkylamino " used in the present invention relates to " dialkylamino " and " dialkylamino " used in the present invention refers to " χχχχχχ2 < 2 >, as selected from each other independently of one another. The term " arylalkylamino " used in the present invention relates to RggNNH-? Arylalkyl (alkyl) amino " and " arylalkyl " used in the present invention relates to < RTI ID = 0.0 > 114 < / RTI > in which R114 is an arylalkyl residue and Rx1 is a lower alkyl residue- " phenylalkylamino " used in the present invention relates to a phenylalkyl group bonded to an amino radical, including but not limited to benzylamino and the like used in the " substituted phenyl " alkylamino group 72500 480S.PS.01

-40 &quot; present invention relates to a (phenyl substituted) phenyl group attached to an amino radical, including but not limited to them. 4-chlorobenzylamino and the like. The term &quot; naphthylalkylamine &quot; used in the present invention relates to a naphthylalkyl group attached to an amino radical, including, but not limited to, naphthylmethylamino and the like. The term &quot; (substituted naphthyl) alkylamino &quot; used in the present invention refers to a (substituted naphthyl) alkyl group linked to an amino radical. The term &quot; (phenylalkyl) (alkyl) amino &quot; used in the present invention relates to R117 which is a phenylalkyl residue and R117 is a lower alkyl residue. The term &quot; ((substituted phenyl) alkyl) (alkyl) amino &quot; used in the present invention relates to (substituted phenyl) alkyl and R <1> <1>. is a lower alkyl group. The term &quot; (naphthylalkyl) (alkyl) amino &quot; used in the present invention relates to R 1, R 2, R 3, R 4, R 5, R 9, and R 9 is a naphthylalkyl and R 9 is a lower alkyl. The term &quot; (((substituted naphthyl) alkyl) (alkyl) amino used in the present invention refers to R 1,223,123 in a substituted naphthyl group and R123 is a lower alkyl group. 0 &quot; aminoalkylamino &quot; used in the present invention relates to R1, 24nh "where RjL24 is an aminoalkyl residue. The term &quot; dialkylamino (alkyl) amino &quot; used in the present invention relates to a dialkylamino residue attached to a lower alkyl residue and R6 is a lower alkyl residue. 72500 4805.PG.01

The term &quot; ((dialkylamino) alkyl) (alkyl) amino &quot; used in the present invention relates to NR127R128 wherein R127 is a dialkylamino residue attached to a lower alkyl residue and R128 is a lower alkyl residue. The term &quot; (hydroxyalkyl) (alkyl) amino &quot; used in the present invention refers to a hydroxyalkyl group and R 30 is a lower alkyl group. The term &quot; (dihydroxyalkyl) (alkyl) amino &quot; used in the present invention refers to a lower alkyl group which is di-substituted with -OH "radicals attached to an amino group, which amino group also has attached another lower alkyl group. The term &quot; di- (hydroxyalkyl) amino &quot; used in the present invention relates to R133 1321 in R131 and R132 are hydroxyalkyl residues. The term &quot; alkoxyalkyl (alkyl) amino &quot; used in the present invention relates to where R133 is a lower alkyl group and R134 is an alkoxyalkyl group. The term &quot; di- (alkoxyalkyl) amino &quot; used in the present invention relates to &lt; RTI ID = 0.0 &gt; 135 &lt; / RTI &gt; Which is lower alkoxy residues attached to lower alkyl residues. The term &quot; di- (polyalkoxyalkyl) amino &quot; used in the present invention relates to R137R138N- wherein R137 is as defined above. Polyalkoxy residues attached to lower alkyl residues. The term &quot; ((polyalkoxy) alkyl) (alkyl) amino &quot; used in the present invention relates to a polyalkoxy residue attached to a lower alkyl radical and R 40 is a lower alkyl residue. The term &quot; ((heterocyclo) alkyl) (alkyl) amino &quot; used in the present invention relates to 14, 14251 in a (heterocyclic) alkyl group and R242 is a lower alkyl group. 4805 -PQ- 01

The term &quot; ((heterocycloalkyl) amino &quot; used in the present invention refers to &quot; NHR1 &gt; wherein R3 is a heterocycloalkylalkyl group; &quot; Cheterocycle) (alkyl) amino &quot; used in the present invention relates to -NR144R45Rm wherein R144 is a substituted or unsubstituted heterocyclic group and R145 is a lower alkyl group, the term &quot; (alkylaminoalkyl) (alkyl) amino &quot; used in the present invention relates to -NR146R147 wherein R146 is an alkylaminoalkyl group and R14y is a lower alkyl group. The term &quot; (dialkylaminoalkyl) (alkyl) amino &quot; used in the present invention relates to -NR148R149 wherein R148 is a dialkylaminoalkyl group and R149 is a lower alkyl group. The term &quot; (alkoxy) (alkyl) aminoalkyl) (alkyl) amino, used in the present invention refers to -NRisoR151 wherein R59 is NR132, a lower alkyl radical in which R152 is an alkoxy group and R3 is a lower alkyl group and R151. is a lower alkyl group. The term &quot; ((alkoxy) aminoalkyl) (alkyl) amino &lt; / RTI &gt; is as defined above. wherein Alkoxy and R155 is a lower alkyl group. The term &quot; (alkoxyalkoxyalkyl) (Alkylamino) &quot; used in the present invention refers to &quot; NR 305R 306 wherein R 30 S is an alkoxyalkoxyalkyl group and R 306 is a lower alkyl group. The term alkylsulfonylamino used in the present invention refers to R309NH- wherein R309 is an alkylsulfonyl group. The term &quot; alkoxyalkoxyalkyl &quot; used in the present invention refers to "NR 30 and R 308 wherein R 30y and R 308 are alkoxyalkoxyalkyl groups.

72500 4805.Ρθ.01 &quot; 43- &quot; arylsulfonylamino &quot; used in the present invention refers to% χ, where% xq is an arylsulfonyl group, the term &quot; alkylaminocarbonylamino &quot; used in the present invention refers to Β 31 0 0 (0) ΝΗ- wherein R 31 is an alkylamino group, the term &quot; alkylaminocarbonyloxy &quot; used in the present invention relates to R312a (O) (O) 0.1). The term &quot; alkoxycarbonyloxy &quot; used in the present invention refers to% χ 3θ (ϋ) ΰ where it is an alkoxy group, the term &quot; lower alkylcarbonyl &quot; used in the present invention relates to R 157 C (O) "wherein Rt57 is a lower alkyl group" including but not limited to acetyl propionyl and the like

The terms &quot; alkoxy &quot; and &quot; thioalkoxy &quot; used in the present invention relate, respectively, to Râ,ƒSâ,,Oâ, "and Râ,ƒâ," Sâ,, wherein â € ƒâ € ƒâ € ƒa Sltupo lower alkyl, the term &quot; alkoxyalkoxy &quot; used in the present invention relates to an alkoxy group attached to an alkoxy radical, but not limited to, methoxymethoxy and the like, the group of the term &quot; aryloxyalkyl &quot; used herein is attached to an aryloxy group (â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (R303) - (nyl) used in the present invention is a thioaryloxy group (wherein R 304 is an aryl group) attached to a lower alkyl radical

The terms &quot; arylalkoxy &quot; and &quot; arylthioalkoxy &quot; used in the present invention refer, respectively, to an aryl group

Linked to an alkoxy radical or a thioalkoxy radical, including, but not limited to, phenoxymethyl, thiophenoxymethyl and the like.

The terms &quot; arylalkoxyalkyl &quot; and &quot; arylthioalkoxyalkyl &quot; used in the present invention each relate to an arylalkoxy group or an arylthioalkoxy group, attached to a lower alkyl radical, the term &quot; alkenyloxy &quot; used in the present invention relates to R59-8 where R159 is an alkyl group of 1 to 7 carbon atoms containing at least one carbon-carbon double bond. The term &quot; hydroxyalkoxy &quot; used in the present invention relates to -OH attached to an alkoxy radical. The term &quot; dihydroxyalkoxy &quot; used in the present invention refers to an alkoxy radical which is disubstituted with -OH radicals. The term &quot; arylalkoxy &quot; used in the present invention refers to an aryl group attached to an alkoxy radical. The term &quot; alkylaryloxy &quot; used in the present invention refers to which is an alkylaryl group. The term &quot; phenylalkoxy &quot; used in the present invention relates to a phenyl group attached to an alkoxy radical, including but not limited to benzyloxy and the like, &quot; (substituted phenyl) alkoxy &quot; used in the present invention relates to a substituted phenyl group attached to an alkoxy radical, including but not limited to 4-chloro-1-alkoxy and the like, the term &quot; naphthylalkoxy &quot; used in the present invention relates to a naphthyl group attached to an alkoxy radical. The term &quot; (substituted naphthyl) alkoxy &quot; used in the present invention refers to a substituted naphthyl group attached to an alkoxy radical. The term &quot; polyalkoxy &quot; used in the present invention relates to a linear or branched chain containing 1-5 C-O-Cm bonds, wherein m and m are independently of one another from 1 to 3.

The terms &quot; halo &quot; or &quot; halogen &quot; used in the present invention refer to substituents Cl, Br, F or I. The term &quot; haloalkyl &quot; used in the present invention refers to a lower alkyl radical in which one or more hydrogen atoms are substituted by halogen, including, but not limited to, fluoromethyl, 2-chloroethyl, trifluoromethyl, 2,2-dichloroethyl and The term &quot; polyhaloalkyl &quot; used in the present invention refers to a lower alkyl radical substituted with one or more halogens, including, but not limited to, trifluoromethyl, 2,2-dichloroethyl and the like. The term &quot; halobenzyl &quot; used in the present invention refers to a halo substituent attached to the phenyl ring of a benzyl radical. The term &quot; halophenyl &quot; used in the present invention relates to a halo substituent attached to a phenyl radical. The term &quot; alkylsulfonyl &quot; used in the present invention relates to the term &quot; (aryl) sulfonyl &quot; used in the present invention refers to a compound of the formula (I). The term &quot; (heterocyclic) sulfonyl &quot; used in the present invention relates to R3 R2, R3, R4, R4, R4,

•P

72500 4805. -6.01 heterocyclic. The term &quot; arylsulfonylalkyl &quot; The present invention relates to an arylsulfonyl group attached to a lower alkyl radical. The term &quot; aryl &quot; used in the present invention relates to a monocyclic or bicyclic carbocyclic ring system having one or more aromatic rings, including but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and the like; or &quot; aryl &quot; refers to a heterocyclic aromatic ring defined as in the present invention. The aryl groups may be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy , alkoxycarbonyl and carboxamide. The term &quot; substituted phenyl &quot; used in the present invention refers to a phenyl ring substituted with one, two or three substituents selected from the group consisting of lower alkoxy, lower alkyl, amino, lower alkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy , carboalkoxy, and carboxamide, including, but not limited to, halophenyl, lower alkylphenyl, alkoxyphenyl and the like. The term &quot; substituted naphthyl &quot; used in the present invention relates to a naphthyl ring substituted with one, two or three substituents selected from the group consisting of lower alkoxy, lower alkyl, amino, lower alkylamino, hydroxy, halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy , carboalkoxy and carboxamide, including but not limited to halonaphthyl, alkoxynaphthyl and the like. The term &quot; alkylaryl &quot; used in the present invention refers to a lower alkyl group attached to an aryl radical. The term &quot; heterocyclic group &quot; or &quot; heterocycle &quot; used in the

The present invention relates to any 3- or 4-membered ring containing one heteroatom selected from oxygen, sulfur and nitrogen, or a 5- or 6-membered ring containing from one to three nitrogen atoms; or a nitrogen atom and an oxygen atom; or a nitrogen atom and a sulfur atom; wherein the 5-membered ring has 0 to 2 double bonds and the 6-membered ring has 0 to 3 double bonds; wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, wherein the nitrogen heteroatom may be optionally quaternized, and including any bicyclic group in which any of the foregoing heterocyclic rings is fused to a benzene ring. that the heteroatom is nitrogen. Completely saturated heterocycles are also preferred. Preferred heterocycles are; pyridyl, pyrrolinyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.

The heterocycles may be unsubstituted or monosubstituted or substituted with substituents independently selected from hydroxy, halo, oxo (O), alkylimino (wherein R 'is a lower alkyl group), amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, polyalkoxy, lower alkyl, haloalkyl, or cycloalkyl.

More preferred heterocycles include imidazolyl, pyridyl, piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, thiazolyl, 2-aminothiazolyl, thienyl, triazolyl and the following; 72500 4805 "PO" 01-48 "

in which k is 1 or 2 and X is N, NH, O or S, provided that X is the bonding point only when X is N, t ~ Γ &quot; γ wherein Y is NH, N-lower alkyl, O, S, or 8G2, or

in which (i), (ii) and (iii) represent 5-membered heterocycles containing one or more heteroatoms and containing 2 double bonds; wherein Z 1 is N, O or S and is not the point of attachment and Z 2 is N when it is the attachment point and NH, O or 8 when it is not the attachment point; with the proviso that when Z 2 is the point of attachment, then N 2 is the &quot; N-protecting group &quot; or &quot; with N protected &quot; used in the present invention refers to the groups with which it is intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the compounds commonly used N protecting groups are described (Sreene, &quot; Protective Oroups in Grganic

72500 4805.Ρθ.01 • 49 "

Synthesis, &quot; (John Wiley & Sons, New York, 1981)), which is incorporated herein by reference. N-protecting groups comprise carbamates, amides, N-alkyl derivatives, aminoacetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives and N-heteroatom derivatives. In particular, N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), carbonylbenzyloxycarbonyl (Cbz). The protecting groups also include an L- or D-aminoacyl residue, which may itself have the N protected similarly. The term &quot; protecting group &quot; used in the present invention relates to a substituent which protects the hydroxyl groups against undesirable reactions during synthetic procedures such as the protecting groups disclosed in Qreene, &quot; Protective Qroups in Organic Synthesis &quot; (John Wiley & Sons, New York (1981)), and comprises substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzylic and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example trimethylsilyl ether, t-butyldimethylsilyl and t-butyldiphenylsilyl ether; ketals and cyclic acetals, for example, methyleneacetal, acetonidoacetal and benzylideneacetal; cyclic ortho esters, for example methoxymethylene; cyclic carbonates; cyclic boronates and the like, the term &quot; substituted amino &quot; used in the present invention refers to: I) alkylamino, II) dialkylamino, III) (hydroxyalkyl) (alkyl) amino, IV) (dihydroxyalkyl) (alkyl) amino, V) alkoxycarbonylalkylamino, VI) carboxyalkylamino, VII) amino) carboxyalkylamino, VIII) ((amino) (with protected N)) carboxyalkylamino, IX) (alkylamino) carboxyalkylamino,

4805.Ρθ.01 "50"

X) (dialkylamino) carboxyalkylamino, XII) (amino) alkoxycarbonylalkylamino, XIII) ((amino) (with protected N)) alkoxycarbonylalkylamino, XIV) (alkylamino) alkoxycarbonylalkylamino (C1 -C4) alkoxycarbonylalkylamino, XVI) (dialkylamino) alkoxycarbonylalkylamino, XVII) (alkoxyalkyl) (alkyl) amino, XVIII) (alkoxyalkoxyalkyl) (alkyl) amino, XIX) di (alkoxyalkyl) amino, XX) di (alkoxyalkoxyalkyl) amino, XXI) di (hydroxyalkyl) amino, XXII) ((unsubstituted heterocycle) alkyl) XXIV)

independently of one another, from 1) hydrogen, 2) hydroxy, 3) alkoxy, 4) thioalkoxy, 5) alkoxyalkoxy, 6) carboxy, 7) alkoxycarbonyl, 8) halogen, 9) amino, 10) alkylamino, 11) dialkylamino, 12) alkylsulfonylamino, 13) arylsulforylamino, 14) alkylaminocarbonylamino, 72500

15) alkylaminocarbonyloxy, 16) alkoxycarbonyloxy, 17) (CH 2) dd -N- wherein dd "is 1 to 5, and 18) wherein is 0, 8 or NH and Rg q is a C ^- linear or branched C6 alkyl substituted with a substituent selected from hydroxy, alkoxy, thioalkoxy, alkoxyalkoxyaminoalkylamino, dialkylamino, carboxy, alkoxycarbonyl, aryl and heterocycle, XXV)

wherein Rc 1 is 1) 0S 2) 8, 3) SO 2 or 4) C 10; or XXVI)

wherein R 10q is 1) hydrogen, 2) lower alkyl, 3) a protecting group of N or 4) wherein R 1a is aminoalkyl, amino (with protected N) amino-2-phenylethyl or 1-amino (with protected N) -2-phenylethyl. 72500 4805 ηPQ »01 &quot; used in

The term &quot; substituted methylene group &quot; invention relates to: (1) â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ â € ‡ alkoxy, (vi) alkoxy, vi) alkoxyalkyl, vii) azido, viii) azidoalkyl, ix) amino, x) amino (with protected N), xi) (x) alkylalkyl, (x) alkylalkyl, (x) alkylalkyl, (x) alkylalkyl, (x) alkylalkyl, (x) (xxiv) thioaryloxyalkyl, xxvi) arylsulfonyl, xxvii) arylsulfonylalkyl, xxviii) (unsubstituted heterocycle) alkyl or xxvix) (substituted heterocycle) alkyl such that when R3a is hydroxy then R14q is not hydroxy, alkoxy, azido, amino, alkylamino, dialkylamino, amino (with protected N), (alk (N-protected) amino, thioalkoxy, alkylsulfonyl, or arylsulfonyl, and such that when it is hydrogen then R14 is hydrogen or lower alkyl;

(II) -C (= CH 2) C (O) NHR 15qS (III) -C (OH) (R 16q) C (O) NHR 15q or 72500 4805-PQ.01

(Iii) alkoxyalkyl, (iv) aminoalkyl, (v) alkylaminoalkyl, (vi) dialkylaminoalkyl, (vii) aryl, (viii) heterocyclic or (ix) (heterocyclo) alkyl and i) hydrogen, ii) lower alkyl, iv) haloalkyl or v) azidoalkyl iii) hydroxyalkyl, R21q (V) -CH2C (Q) NH - (CH3) ff

Wherein: 1) t 'is 0 to 3, 2) R20q is i) CH2 or ii) N and R21q is i) NH, ii) 0,

iii) S and iv) amp Q2, such that when t 'is 0 then R2oq ® CH2 and double ts is 1 to 3 then R3> (CH2) (i) lower alkyl, or (ii) cycloalkylalkyl, and (2) R 23 q i) lower alkyl, ii) hydroxyalkyl, iii) alkoxyalkyl, iv) aminoalkyl, (VI) arylalkyl (ix) heteroaryl, (x) (heteroaryl) alkyl or xi) wherein: a) u is 0 R24q is NH, O-, or SO2: &quot; mR24q

Wherein when R3 is 0 then R24q is CH? and when u3 is 1 to 3 then R24q is N; (VII) /?

-CH 2 CH (R 22q) c (O) --- R 1 wherein R 22q is as defined above &amp; 2) R74q is i) hydrogen; ii) lower alkyl; iii) an N-protecting group; or iv) wherein R4a is aminoalkyl or protected amino-N-alkyl) alkyl; (VIII) â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (VIII) â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒwherein R26q is i) lower alkyl or ii) »01 ti

-55 U *

ϋ) cycloalkylalkyl; (IX) -CH2CH (R8lq) NHC (O) R82q or -CH2eH (R81q) NHS (O) 2R82q wherein R81q is i) lower alkyl or ii) cycloalkyl and 2) R82q is (i) lower alkyl, (ii) alkoxy, (iii) alkylamino, iv) dialkylamino, v) -QR * wherein R * is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or (heterocyclo) alkyl or vi)

R 21q N * wherein R2iq is as defined above; (X) -QH2NHC (Q) R82q or &quot;CH2NHS2O2R82qquot; R82q is as defined above; or (XI) -CF2 CH (OH) Rg3q wherein R83q is lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylenylalkyl, aryl, arylalkyl, heterocycle or (heterocyclic) alkyl group.

The terms &quot; lipophilic or aromatic amino acid side chains &quot; used in the present invention refer to side chains of amino acids selected from the group isobutyl, isopropyl, sec-butyl, benzyl, p-methoxybenzyl, imidazol-4-yl-methyl, p-hydroxybenzyl, 1- and 2 (thiazolyl) methyl, cyclohexylmethyl, (3-indolyl) methyl, CH 2 SCH 2 - and the like. General references to amino acid side chains in both the description and the claims of the present invention are to be taken as references thereto, whether naturally occurring in proteins or not, and to both D- and L- forms.

The terms &quot; Wing &quot;, &quot; His &quot;

Leu '&quot; Phe &quot;, &quot; Tyr &quot;

Cys &quot; fâly &quot; '56 '72500 4805.ΡΘ.01 1 Ly! 'Sar &quot;, &quot; Pro &quot;, &quot; &quot; HomoPhe &quot; and &quot; norLeu &quot; used in the present invention are, respectively, alanine, histidine, leucine, phenyland, tyrosine, cysteine, gliein, lysine, sarcosine, proline, homophenylalanine and norleucine. In general, amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem., 1984, 158, 9-31).

Inhibitors of renin having an asymmetric carbon atom may exist as a racemic mixture or as pure enantiomers. Renin inhibitors having two or more asymmetric carbon atoms may exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of racemic, The present invention includes in its scope all isomeric forms. The terms &quot; configuration &quot; and &quot; R &quot; are those defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30,

Renin inhibitors having the general structure shown in the group (9) can be prepared as described in Furig, et al., PCO patent application WO90 / 03971 (PCT / US89 / 04385), published April 19, 1990 , which is incorporated by reference herein. Syntheses of segments containing D substituents are described in the Examples or have been previously described (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly et al. J. Med. Chem., 1987, 30, 1960. Buhlmayer, et al., U.S. Patent No. 4,727,060, Morisawa, et al., European Patent Application No. 0228192; of PCT No. WO87 / 02986)

Renin inhibitors having the general structure shown in the group (10) can be prepared as described in De, et al., PCT patent application NS WQ90 / 04917 (PCT / US89 / 04649), published May 1.7 1990, which is incorporated by reference herein. Syntheses of segments containing R1 substituents are described in the Examples or have been described above (Kempf et al., J. Med. Chem., 1978, 30, 1978; Luly et al., Med. Chem. 1987, 30 , 1609, Buhlrnayer, et al., U.S. Patent No. 4,727,060, Morisawa, et al.

72500 4805.PG.01 • "57-

European Patent 0228192; Ten Brink, PCT Patent Application No. W087 / 02986) "

A useful intermediate in the preparation of some renin inhibitors is compound 8. (Scheme I). Scheme I outlines a process for the preparation of isosorphic acid D (X) can be converted into the known lactone 3 (J. Am. Chem. Soc. the alcohol 4. Oxidation to aldehyde 5., followed sequentially by reaction with benzylamine and cyclohexylmagnesium bromide / CeCl2 affords the amine 7. Deprotection of the amino group, reduction of the olefin and removal of the acetonide protecting group provides 8. An alternative preparation of the reduced form of compounds 5 (ic 1.3) is shown in Scheme 11. The epoxyalcohol 10 J. Am. Chem. Soc. 109, 1525 (1987)), can be protected and then reacted with isopropyl The reaction with camphorsulfonic acid (CSA), followed by ozonolysis, gives the aldehyde 13.

SCHEME I 1. HjOj

Bn · benzyl) 7 3 72500 4805-Ρθ-01 '-58

SCHEME.II &amp;

Another intermediate useful in the preparation of some of the renin is compound 21 (Scheme III). Reaction of n-butylmagnesium bromide * followed by resolution affords 15 as a single enantiomer. The reaction of the oxidative aldehyde 14, The reaction with bromoacetic acid, optionally followed by esterification gives 1.6 or 1.7. Alternatively, the reaction with t-butyl bromoacetate gives 1.8. Alkylation with benzyl bromide affords a mixture of 1.9 and 7.5. The hydrogenolysis or ester hydrolysis, coupling with 4-methoxymethoxypiperidine and oxidation provides the desired carboxylic acid 2.1.

SCHEME. III

16 R-H 17 R = CH (Ph) 2 R * t -butyl

1 9 »20 1: 2 0

co2h

D) CH 2 N 2 or C (Ph) 2 N 2, e) KN (TMS) 2 BrCH 2 CO 2 (a) n-BuMgBr, b) (-) DIPT t-BuOOH Ti (OCH -Bu, f) NaN (TMS) 2BnBr, g) when R = CH (Ph) 2 H 2 Pd / C when R = t-Bu HCl methanol, h) EDC 4-methoxymethoxypiperidine, i) O 3 or Nalo

72500 4805, PQ-01

The following examples will further illustrate the preparation of the novel compounds of the invention.

Example 1

2 (S) - (1 (S) - (4- (methoxy) methoxy) piperidin-1-yl) carbonyl-2-phenylethylhexanoic acid of 3- (4-morpholinyl) propyl- S (S) -amino-Î ± -cyclohexyl-4 (S) -hydroxy-2 (S) -isopropyl-hexanamide

Example 4A: 4 (S) -t-butyloxycarbonylamino-5-cyclohexyl-5 (R, S) -h, ir. ,

Diisobutylaluminum hydride (34 ml of a 1.5 M solution in toluene) was added to a stirred solution of Boe-cyclohexylalanine methyl ester (10.2 g, 35.8 g) mmol) in dry toluene (60 ml). After 30 minutes, vinylmagnesium bromide (108 ml of a 1M solution in tetrahydrofuran (THF)) was added. After stirring for 15 h at 0Â ° C, the mixture was quenched with methanol, treated with Rochelle salts (22 ml of saturated aqueous solution in 140 ml of H2 O) and filtered. After extraction of the solids 5 times with acetate The extracts and the filtrate were combined and the organic phase was washed with brine, dried, filtered and evaporated to an oil (10.2 g). Chromatography on silica gel eluting with hexane / ethyl acetate mixtures gave 6.1 g of the desired product. Anal. Calc'd for 1/4 Η 20: C, 66.8; H, 10.3; N, 4.9. Found: C, 66.9; H, 10.2; N, 4.7

Example ..... JLB »3- (t-butyloxycarbonyl) -4- (cyclohexylmethyl) -2,2-dimethyl-5-vinyloxagol idina.

The procedure of Thaisrivong (J. Med. Chem. 1987, 30, 976) was used. A solution of 40 g of the resultant compound of Example 1A and 102 g of 2-methoxy- propene in 250 ml of dichloromethane. Solid pyridine p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After the addition was complete, the reaction mixture was stirred for neutralization by addition of solid sodium bicarbonate. The solids were filtered and the filtrate was concentrated. Flash chromatography on silica gel gave 57 g of the desired product.  € ƒâ € ƒâ € ƒIR (CDClâ,ƒ) 1690 (C carbCama): ¹H NMR (CDClâ,ƒ) 5.95 (m, 1H), 5.32 (m, 1H), 5.20 (dt, 1H), 4.27 dd, 1H), 1.47 (s, 9H).

Anal. for C 19 H 9 NO 3: C, 70.55; H, 10.28; N, 4.33. Found: C, 70.47; H, 10.27; N, 4.09.

Example ...... 10 3- (t-butyloxycarbonyl) -4- (cyclohexylmethyl) -2,2-dimethyloxazolidine-5 carboxaldehyde.

A solution of 10 g of the compound resulting from Example 1B in 150 ml of dichloromethane: methanol 2: 1 was cooled in an ice-cold acetone bath. Ozone was bubbled through the solution until a blue color (1 h) persisted. Dry nitrogen was then bubbled through the reaction mixture to remove excess dissolved ozone. The reaction mixture was led to a suspension of 8 g of zinc powder, 8 ml of glacial acetic acid, 200 ml of water, and 200 ml of methanol cooled to -45 ° C. After 5 minutes the bath was removed and the mixture was allowed to warm to room temperature overnight. 100 ml of saturated sodium chloride were added and the entire reaction mixture was extracted with two 300 ml portions of dichloromethane. The combined dichloromethane extracts were decanted, dried (MgSO4), filtered, and evaporated. The crude aldehyde was purified by flash chromatography, ethyl acetate: hexane (1: 4), to give 9.7 g of the desired compound as a mixture of diastereomers (trans: cis, 3: 1) as judged by resonances of the two aldehyde protons.  € ƒâ € ƒâ € ƒIR (CDClâ,ƒ) 1735 (C Q alde aldealkoxy), 1690 (C = Q carbamate) cm ~¹; 1 H-NMR (CDCl 3): 9.83 (s, 1H, CHO), 9.73 (d, 1H, CHO cis diastereomer), 4.14 (m, 1H), 1.46 (s, 9H).

Anal. Calc. Calc'd for C 21 H 28 N 4 O 4: C, 66.43; H, 9.60; N, 4.30. Found: C, 65.27; H, 9.79; N, 4.20. 0 • &quot; 62 72500 4805 «ΡΘ.01 €.

Equilibrium of the isomers ..... aldehyde

A suspension of 25 g of the above aldehyde in 300 ml of methanol and powdered potassium carbonate (10.7 g) was stirred at room temperature for 6 h. The reaction mixture was cooled in an ice-water bath and treated with 9.3 g of glacial acetic acid for 5 min. A 0.5 M solution of sodium dihydrogenphosphate (300 ml) was added to the mixture. After 30 min, the solution was concentrated to half its volume under reduced pressure and extracted with ether (600 ml). The combined ether extracts were dried (MgSO4), filtered, and concentrated. The aldehyde was purified by flash chromatography using ethyl hexyl acetate (1: 4) to give 19.5 g of the desired compound as an 8: 1 mixture of the transspecific diastereomers.

Example 1D: 5-f (R) -3-tert-butoxycarbonyl) -2-2- (methyl) -1,4- 3-hydroxy-2 (R), 4-isoxazol-3-yl] -amide. (R) -methyl-5 (S) -phenyl-2-oxazolidinone

The title compound was prepared in analogy to the procedure of 8 Thaisrivongs, D.T.Pais, L.T.Kroll, 8-R-Turner and F-S-Hari, J-Med-Chem. 1987, 30, 976-82, from the compound resulting from Example 1C in 63% yield, mp 97-8 HR HNMR (COCl 3) 0.91 (d, 3H), 1.06 (d, 3H) (Bm, 12 H total), 2.12 (bd, 1H), 2.3 (m, 1 H) 1H), 3.81 (dd, 1H), 3.84 (d, 1H), 4.04 (bm, 1H), 4.22 (dd, 1H) 61 (d, 1H), 7.31-7.45 (m, 4H). High resolution mass spectrum. Calc. for (M + H) + 587.3698-

Calc'd for C 33 H 50 N 7 O: C, 67.55; H, 8.59; N, 4.77 Found; C, 67.41; H, 8.61; N, 4.77.

Example 3 3- (3 (R) - (3- (tert-butylcarbonyl) -1,2-di-methoxy- (S) -cyclohexylmethyl-5 (R) -oxazolidin-11-yl) -3 - ((1-imidazolyl) methylthio) (1-oxo-4-oxo) -1,2-oxazolidinone

The compound resulting from Example 1D 72500 4805 was refluxed.

(1.128 g, 6.330 mmol) was dissolved in 8 ml of 1,2-dichloroethane under nitrogen under a nitrogen atmosphere for 24 h. The residue was purified by flash chromatography (25% HCl-CH2 Cl2) to give 1.896 g (87%) of the title compound.1 H NMR (CDCl3): 0.93 (d, 3H), 1.04 (d, 3H , 1.08 (d, 3H), 1.5 (bs, 9H), 0.9-1.9 (several bm, 13H total), 2.05 (m, 1H), 4.13 (bm, 1H), 4.23 (dd, 1H), 4.81 (dd, 1H), 4.94 (dq, 1H), 5.70 (d, 1H) 06 (bs, 1H), 7.3-7.5 (m, 5H), 7.61 (bs, 1H), 8.40 (bs, 1H) - High resolution mass spectrum -Cal- + H) + for O 37 H 53 N 4 G 7 S: 697.3635.

Found: 697.3629- Calc'd for C37 H52 N4 O7 S: C, 63.77; H, 7.52; N, 8.04 Found: C, 63.58; H, 7.44; N, 7.94.

Example ..... IFJ ...... 3- (3- (3- (tert-butoxycarbonyl) -2,2-dimethyl-4 (5) -cyclohexylmethyl -5 (8) -pazazolidinyl) -2 (R) -isopropyl-1-oxopropyl) -4 (R) -methyl- (8) -phenyl-2-oxazolylidene-

A solution of the product of Example 1E (6.50 g, 9.33 mmol) in a dry toluene (275 mL) was degassed with argon for 30 min, then heated to reflux (under argon) A solution of tri-n-butyltin hydride (5.43 g, 18.6 mmol) in 75 mL of degassed toluene was added dropwise over 15 min. After an additional 2 h of reflux, The reaction was concentrated, and purified by flash chromatography (5% EtOAc-hexanes) to give 4.82 g (90%) of the title compound as a white foam.1 H NMR (CC%)) 0.90 (d, 3H), 0.92 (d, 3H), 0.9-1.1 (bm, 3H), 1.06 (d, 3H), 1.15-1.35 (br, 3H), 1.51 (s, 9H), 1.57-2.14 (multiple bm, 16H total), 3.84 (m, 1H), 3.97 (m, 1H), 4.85 1H), 5.68 (d, 1H), 7.3-7.46 (m, 5H) Mass spectrum: (M + H) + = 571 Calc'd for C 69.44; H, 8.83; N, 4.91 Found: C, 69.31; H, 8.82; N, 4.89.

72500 4805.PG.01 ~ 64 ~

Example ..... 1G: ...... Acid ..... 2 (3) - ((3- (tert-Butyloxycarbonyl-2, 2-dimethyl-4 (S) -cyclohexylmethyl 5 (S) -oxazolidinyl) methyl) -3-methylbutanoic acid.

Using the procedure of D.A.Evans, T.C.Britton and J.A.Ellman, Tetrahedron Lett. 1987, 28 (49), 6141-44, the product resulting from Example 1F (6.10 g, 10.7 mmol) was hydrolyzed with aq. and hydrogen peroxide in THF. The crude material was purified by flash chromatography (15% EtOAc-0.5% HOAc-hexanes) to afford 3.53 g (90%) of the title compound as a colorless oil (dm, 3H), 1.00 (d, 3H), 1.1-1.3 (bm, 5H), 1.48 (s, 9H), 1.5-1 (Bm, 1H), 3.90 (m, 1H). Mass spectrum: (M + H) + = 412. Calc'd. Calc'd for C 23 H 41 N 5 O • 0.25 h 2 O: c &gt;06,39; H, 10.05; N, 3.37: Found: C, 66.46; H, 9.84; N, 3.36.

Example ..... 1H: ...... 3- (4-morpholinyl) propyl ..... 2 (8) - ((3- tert -butyloxycarbonyl) -2,2-dimethyl-4- S) -cyclohexylmethyl-5 (S) -oxazolidinyl) methyl) -3-methylbutanamide.

The procedure of P.Buhlmayer, et al., J. Med. Chem. 1988, 31 (9), 1839-46. The resulting compound of Example 1G (75 mg, 0.182 mmol), HOBT (42.0 mg, 0.274 mmol) and M-methylmorpholine (55 mg, 0.55 mmol) were dissolved in 1.0 mL of dry DMF and cooled The solution was cooled to -20 ° C (under nitrogen). EDAC (53 mg, 0.28 mmol) was added as a solid and the resulting mixture was stirred at -20 ° C for 1 h. The mixture was sealed and allowed to react at 0 ° C (in a refrigerator) for 48 h. 4- (3-Aminopropyl) morpholine (0.23 mmol) was added to the resulting solution. The resulting solution was stirred at 0 ° C for 4 h and a further 20 h, allowing to slowly warm to room temperature. The volatiles were removed by distillation under high vacuum, and the residue was partitioned between 0-20 ° C (NaHCO 3, aq. The aqueous phase was extracted with CH 2 Cl 2 and the combined organic phases were washed with brine, dried (Na 2 SO 4) and concentrated. Purification by flash chromatography (4% MeOH-CM2 Cl2) provided the desired compound / t

1 H NMR (CDCl 3) 0.92 (d 3H), 0.95 (d, 3H), 1.46 (s) and 1.48 (s, 12H total), 1.57 (bs, 3H) 8-1.8 (various biti, 18H total).

(bm, 5H), 6.80 (bt, 1H). High resolution mass spectrum Cal, for (ΜΉ-O + C 30 H 5 N 3 O 5 538.4220, Found: 538.4220)

Example II: 1 - ((S) - (4- (roethoxymethoxy) piperidine-1-ylcarbonyl) -2-phenylethanol,

A solution of 176 g (1.3 mmol) of 1-hydroxybutyrazotriazole (Aldrich), 80 g (0.48 mol) of L-3-phenyl-1- (prepared from L-phenylalanine), 76 g (0.52 mol) of 4- (methoxymethoxy) piperidine in 800 ml of DMF was added while 132 g of EDC HCl (Saber Labs) (mechanical stirring) was added. After addition, the reaction was stirred at room temperature for 24 h. The excess DMF was removed under high vacuum and the residue was dissolved in 1.5 L of ethyl acetate. The ethyl acetate solution was washed with 4 L of saturated sodium bicarbonate. The ethyl acetate layer was separated, dried (MgSO4) and evaporated to give approximately 138 g of crude amide . The product was isolated by chromatography on silica gel using ethyl acetate / hexane as eluent. Yield: 120 g (79%): 1 H NMR (CDCl3, , 3.56 (m, 2H), 3.69 (m, 2H), 3.96 (m, 1H), 4.62 (t, 1H), 4.68 (s, 2H),

Example 2: Sodium 2 (S) - (1 S) -4- (methoxymethoxy) piperidinyl-1-ylcarbonyl-2-phenylethoxy) hexane »

The resulting compound of Example II (1.45 g, 4.95 mmol) in 10 mL of THF was added dropwise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 , 11.2 mmol) in 4 mL of THF (0-5 ° C). The suspension was stirred for 20 min at 0-5 ° C and then warmed to room temperature and stirred for an additional 1 h. It was added dropwise to

A solution of D-2-bromohexanoic acid in 6 ml of THF under a N 2 atmosphere is cooled (0-5øC). It was then allowed to warm to room temperature and stirred overnight, quenched with cold H2 O and extracted with ethyl acetate to remove undesirable starting material. Acidified with 1 M sodium hydrogen sulfate and extracted with chloroform. After filtration and evaporation, the crude product was purified on silica gel, eluting with CH 2 Cl 2: CH 2 OH: AcOH (19.4: 0.3: 0.3) to obtain 0.79 g of the desired acid (yield 43%). NMR (CDClâ,ƒ): 0.88 (t, 3H), 3.35 (s, 3H), 3.98 (bt, 1H), 4.6 (m, 1H), 4.64 (s, 2H) , 7.38 (m, 5H). Mass spectrum: (M + H) + = 408.

Example 1 (S) - (1 (S) - (4- (Methoxymethoxy) piperidin-4-yl)

(4-morpholinyl) propoxy] -5 (S) -amin O-6-cyclohexyl] -4- (4-methoxy- 8) -hexahydroxy-2 (8) -isopropylhexanamide

The resulting compound of Example 1b (0.161 mmol) was deprotected by dissolving in 1.0 mL of dry CH 2 Cl 2, cooling the solution to -10 ° C (under nitrogen) and treating with 1.0 mL of trifluoroacetic acid. the resulting solution at -10 ° C for 4 h. The solvents were largely removed with a stream of nitrogen, and the residue (as a concentrated solution in trifluoroacetic acid) was dissolved in 1.0 mL of THF and 0.3 mL of H2 O at 0 ° C. The solution was allowed to warm slowly to ambient temperature for 18 h. The crude amino alcohol was isolated by basifying the reaction with an excess of aq. 1.0 M, saturation of the solution with NaCl and extraction with 5 x 10 ml of 5% EtOH-CHCl 3. The combined organic phases were washed with brine, dried (Na280), concentrated and the residue was placed under high vacuum overnight to give yellow viscous oil (66.2 mg, 100%).

Coupling was achieved by combining the resultant compound of Example 1J (72 mg, 0.177 mmol), the above aminoalcohol (0.168 mmol), HQBT (34 mg, 0.22 mmol) and N-methylmorpholine (25 mg, 0.25 Ψ 72500 4805.PG.01 67

mmol) in 1.0 mL of dry DMF. The resulting solution was cooled to &quot; 20 ° C (under argon) and EDAC (45 mg, 0.23 mmol) was added. The reaction was allowed to warm slowly to room temperature as the ice bath melted for a total of 24 h. The solvent was removed by distillation under high vacuum, and the residue was partitioned between 15 ml CH2 Cl2 (9 ml) aq. sat. and 1 ml of H2 0. The aqueous layer (3 x 10 mL CH2 Cl2) was further extracted and the combined organic phases washed with brine (10 mL), dried (Na2 SO4) and concentrated. Purification by flash chromatography afforded the title compound as a hygroscopic glassy solid, m.p. 49-51Â ° C. NMR (CDCW) 0.90 (m), 0.91 (d) and 0.92 (d, 9H total), 0.65-1.90 (various bm, about 28H total), 2.02 1H), 2.45 (bm, 6H), 2.95 (m, 1H), 3.05 (dd, 1H), 3.20 (bm, 2H), 3.36 (s, 3H). (M, 2H), 4.48 (dd, 1H), 4.68 (s, 2H), 5.36 (m, 2H) 80 (d) and 5.88 (d, total 1H), 6.87 (bt, 1H), 7.3 (bm, 5H) Mass spectrum: (M + H) + = 787.

Example ..... 2

2 (S) - (1S) -1 - ((4-Methoxyethoxy) piperidine-1-carbonyl-2-phenyl) ethoxyhexanoic acid of 3- ( 4-morpholinyl) propyl-5- (8) -amino-

-6-cyclohexyl] -3H-pyrazole-2 (S) -isopropylhexanamide (Alternative Preparation) Example 2A

Salt ..... hydrochloride of 2 (S) -cyclohexylalanine methyl ester

L-Phenylalanine (215 g, 1.3 mole) was hydrogenated over Pd / C in HOAc, filtered and concentrated. The resulting cyclohexylalanine was taken up in MeOH (1200 ml). Thionyl chloride (427 g, 3.59 mole) was slowly added to the slurry which finally became homogeneous. The reaction mixture was cooled in an ice / water bath and the addition of thionyl chloride was continued. The reaction mixture was refluxed for 2 h, cooled and concentrated to give a solid, which was taken up in ether and filtered. The white solid was washed with ether 72500 4805-θθ.01 68-

The filtrate was dried in vacuo to give 2.7.19 g of product, 94% yield in two steps.

Example 2 (3) - N - (triphenylmethyl) cyclohexylalanine

The HCl salt of cyclohexylalanine methyl ester (88 g, 398 mmol) in chloroform (400 mL) was added.

Triethylamine (84.6 g, 836 mmol) was then added in one portion to the slurry and stirred for five minutes. Triphenylmethyl chloride (111 g, 398 mmol) was then added and stirred the reaction mixture for 5 h at room temperature. The reaction mixture was washed with 1 M KHSO 4 solution (2 x 100 mL), saturated NaHCO 3 (200 mL), brine (100 mL), and brine and then dried over magnesium sulfate. The solution was then concentrated to give 200% residue which was filtered through 900-1000 silica gel (gradient elution hexane-hexane: ethyl acetate 10: 1) affording 157 g of product (93%) which could be crystallized from hexanes: ethyl acetate to afford large white crystals- mp 86-87 ° C-

Example 3 3 (S) -4-cyclohexyl- (N-triphenylmethyl) amino-2-oxobutyl-4-sulfonamide. dimethyl.

N-BuLi (2.5 M, 800 mL, 2.0 mmol) was added to a -78 ° C solution of dimethyl methylphosphonate (272.59, 2.2 mol) in 1.6 L of THF and stirred for 45 minutes. The product of Example 2B (156 mg, 366 mmol) was then added dropwise in 40 mL of THF. The reaction mixture was stirred at -50 ° C for 3 h , then at -40 ° C for 6 h and finally at room temperature overnight. The reaction mixture was concentrated, taken up in ether, washed with 1M KHSO 4, saturated NaHCO 3 (2 times) and brine, dried and concentrated. The residue (200 g) was filtered through

and 1 g of silica gel (hexanes: ethyl acetate 1: 1) to give 135 g of beta-ketophosphonate (72%) as an oil.

Example 20

6 (S) -7-Chlorohexyl-2-hexylethyl-6- (trifluoromethyl) amino-5-oxohept-2-ene-3-

The product of Example 2C (117.2 g, 229 mol) was dissolved in 600 mL of THF and cooled to 0 ° C. To this solution was added NaH washed with hexanes (60%, 9.6 g (wet), 240 mmol) and the mixture was stirred for 30 min. Methyl 3-methyl-2-oxobutyrate (29.8 g, 229 mmol) was then added in 100 mL of THF and stirred at 0Â ° C for 4 h. The volatiles were removed under reduced pressure, the residue was dissolved in 1: 1 hexanes: ether (500 ml) and washed with water (100 ml), NaHCO3 (200 ml), brine (200 ml) (MgSO4) and concentrated to afford 129 g of the desired ester as an oil. This material (123 g) was taken up in 460 ml of THF, 229 ml of MeOH, cooled to 0Â ° C and then 18.86 g of H2 O-H20 in 229 ml of distilled water was added. This solution was allowed to warm to room temperature and stirred for 3 days. The volatiles were removed under reduced pressure and the resulting aqueous solution was washed with ether (100 ml x 2) then acidified to pH 3 with HCl or N. The aqueous solution was then extracted with EtOAc (300 mL x 2), washed with brine, dried (MgSO4) and concentrated to give 116 g of a yellow foam. This material was recrystallized from 525 ml of hot hexanes / EtOAc (12/1) to provide 72.4 g of a white solid (62% for three steps), m.p. 97-98Â ° C.

Example ..... 2E (Îμ, 5.3, 63) -6-Cyclohexylmethyl-3-isopropylidene-5-hydroxypiperidin-2-one

A solution of 3.06 g (6.0 mmol) of the product of Example 2D in 50 mL of THF was added to 6.8 g (60 mmol) of N-hydroxysuccinimide. This homogeneous solution was cooled to 0 ° C, then DCC (1.25 g, 12 mmol) in 5 mL of THF was added. The / 72500

, · 4805 η P3 · 01

The reaction mixture was stirred for 2 h at which time an additional 1.25 g of DCC was added. After 5 h total reaction time, the mixture was filtered, concentrated, and concentrated. dissolved in ether. The organic phases were washed with NaHC03 (aq., 50 ml x 2), brine, dried (MgSO4) and concentrated under reduced pressure to give 5.2 g of product as an oil which was dissolved in 20 ml of ether. 1N HCl / ether solution (30 ml) was added. A gummy solid was immediately precipitated from the solution; CH 2 Cl 2 (25 ml) was added and the clear reaction mixture stirred overnight. After 12 h, the product which precipitated from the mixture was collected by filtration and washed with ether to give, after drying, 1 g of a white solid in 87% yield in two steps, which was used in the next step.

Imidazole (204 mg, 3.0 mmol) was added to an o-paste of the above-mentioned white solid resulting from the first part of Example 2E (1.2 g, 3.0 mmol) in 20 mL of CH2 Cl2 The resulting reaction mixture was stirred for 1 h, then washed with 20 ml of KHSO 3, water, saturated NaHCO 3 and brine. The organic portion was dried over MgSO 4, filtered and cooled to -78 DEG L-Selectride K (Aldrich, 1.0 M, 5.0 mL, 5.0 mmol) was added to the cold solution and stirred for 10 min. The reaction mixture was then warmed to -40 ° C and quenched with 20% citric acid solution. The organic phases were washed with 20 ml of water, saturated NaHCO 3 solution, brine, dried over And concentrated to give a clear oil. This residue was purified on silica gel (50% hexanes / ethyl acetate) to give an oil which was triturated with ether to afford a white solid, 545 mg, yield of 72% from the active ester, mp 128 DEG-130 DEG C.

Example 2F, 2S, 4S. 53) -6-Cyclohexylmethyl-2-iodo-5-amin o-4-hexanolide

A solution of the product of Example 2E (24.7 g, 98.4 mmol) in 500 mL of ethyl acetate was treated with 2.5 g of dry Pd / C and 72500 4805 PO

(4 atm) for 4 h at ambient temperature. The reaction mixture was filtered and concentrated to a white foamy solid which was taken up without further purification. The resulting saturated lactam was dissolved in ethyl acetate. 200 ml of 1N HCl and 50 ml of ethanol and then heated at reflux for 14 h. The reaction mixture was concentrated under reduced pressure and azeotropically dried with toluene to give a pale oil. This material was taken up in water and extracted with hexane, then made basic by addition of a NaHCO3 solution. Extraction with ethyl acetate followed by drying (MgSO4) and removal of the volatiles gave a yellowish oil which solidified as a white solid upon standing. Crystallization from hexane gave 20.7 g (90% ) of product in the form of white needles, mp 49-50 ° C.

Example 2fâ

(S) - (4-Methoxymethoxy) pyridin-1-yl) carbonyl] -2-phenyl-ethoxyhexanoic acid of 3- (S) (4-morpholinyl) propyl-5 (S) -amin-6-cyclohexyl-4 (S) -hydroxy-2 (S) -isopropylhexanamide

The product of Example 2F was reacted with N- (benzyloxycarbonyloxy) succinimide to give the N-Cbz-protected amino lactone. The reaction of the N-Cbz-protected amino lactone with 3-amino-1- morpholinyl-4-yl) propane afforded 3- (4-morpholinyl) propyl-5 (8) -benzyloxycarbonylamino-6-cyclohexyl-4 (S) -hydroxy-2 (8) -isopropylhexanamide This product can be N-deprotected and coupled with the product of Example 1J according to the procedure of Example IK to give the desired compound.

Example ..... 3

(2S) -2-Benzyl-5- (1-methylpiperazin-4-yl) sulfonyl] propyl] - ( L) - (4-Aza-1-yl) amino] -2S-9,3RA4Slz2zAmih] [1,2,3] -hexahydroxy-6-methylheptane, 72500 4β-hydroxy-2-methylene-3-phenylpropionate of methylene

A mixture of benzaldehyde (82 mL, 0.81 mol), methyl acrylate (109.1 mL, 1.211 mol), 1,4-diazabicyclo (2,2,2) octane (13.6 g g, 0.12 mol) and acetic acid (1.4 ml, 0.024 mol) at 35 ° C for 60 h at which point the reaction was found to proceed to 70% completion by NMR. Methyl acrylate (20.9 mL, 0.23 mol) was then added and the solution allowed to react at 35 ° C for an additional 48 h. The mixture was diluted with diethyl ether (1.0 L) and washed with 2 200 ml portions of a phosphate buffer at pH 7. After concentration in. vacuum, the remaining mixture was distilled under reduced pressure (12 mm) to give 6.5 g of unreacted benzaldehyde and 130.0 g (90%) of the desired product as a colorless oil; bp 130 ° C (12 mm); IR (film) 1718, 1440 cm-1 '; NMR (CDCl 3) delta 3.67 (s, 3H), 5.52 (bs, 1H), 5.83-5.85 (m, 1H), 6.29-6.31 (m, 1H), 7.23-7.39 (m, 5H); 13 C NMR (75 MHz, CDCl 3) delta 51.8, 72.9, 125.8, 126.5, 127.7, 128.3, 141.2, 141.9, 166.6 "

Example ..... 3.B (2) -1-Bromo-2-carbomethoxy-3-phenyl-2-propene

The resulting compound of Example 3A (305.9 g, 1.585 mol) was added to a 3-necked Mortori flask of 21 equipped with a thermometer, mechanical stirrer and addition funnel followed by addition of HBr at 48% (505 ml, 4.46 mol) in one portion. The flask was immersed in an ice-water bath, when it was added dropwise, over 90 min. concentrated sulfuric acid (460 mL, 8.62 mol) and the internal temperature of the reaction mixture was maintained at 23-27øC during the addition process. After removal of the ice-water bath, the mixture was allowed to stir at room temperature overnight. The solution was then transferred to a separatory funnel and the organic layer was allowed to separate from the acid layer. The acids were drained and the organic layer was diluted with 2 L of a 1: 1 ethyl acetate / hexane solution, washed with saturated aqueous sodium bicarbonate solution (1 L), dried over sodium sulfate and concentrated to provide 400 g (99%) of the desired product as a light yellow oil, which was used without further purification: bp 180 ° C (12 mm) film) 1718, 712 cm -1; NMR (CDCl 3) delta 3 = 89 (s &gt; SH), 4 &gt; 40 &lt; -S'2H), 7.38-7.45 (m, 3H), 7.56-7.60 (m, 2H ), 7.83 (s, 1H); 13 C NMR (75 MHz, CDCl 3) delta 26.77, 52.47, 128.63, 128.87, 129.61, 134.20, 142.95, 166.62.

Example 3C

Sodium salt of the acid ..... (Z) -2-Carbomethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline

The product of Example 3B (400 g, 1.57 mol) and methanol (4 L) was added to a 3-necked round bottom flask equipped with a mechanical stirrer, a thermometer and a funnel of The mixture was heated to 50Â ° C and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4 L) was added over 75 min, while maintaining the internal temperature of the flask a 50 * 0. After the addition was complete, the clear solution was allowed to stir at 50 ° C for an additional 45 min. The reaction mixture was brought into solution for the next step without further purification. The compound by concentration to amorphous powder, which is. contaminated with one equivalent of sodium bromide: IR (KBr) 1711, 1628, 1215 cm &quot;1; 1H NMR (DMSO D-6) delta 3.70 (s, 3H), 3.77 (s, 2H), 7.33-7.41 (m, 3H) 7.48 (s, 1H) 87-7.89 (m, 2H); 13 C NMR (75 MHz, DMSO D-6) delta 49.88, 51.93, 127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60,

Example ..... 3D

Sodium salt of 2-carbomethoxy-3-phenylpropane-1-sulfonic acid

60 g of the nickel-raney W-24 were added to the mixture of Μ

72500 4805.Ρ8.01 74 methanol / ln water containing the compound resulting from Example 3C. The resulting suspension was pressurized under 50 psi of hydrogen and allowed to stir on a Parr shaker for 24 h, at which time an additional 20 g of nickel-raney catalyst was added. After 6 h under 345 kPa (50 psi) hydrogen, the catalyst was removed by filtration and the solution was concentrated to dryness. To the dry white solid was added ethyl acetate (61) and heptane (4 L) and the solution was stirred vigorously with a mechanical stirrer overnight. The white suspension was removed by filtration yielding 530 g (88%) of the desired product as an amorphous powder which was contaminated with approximately one equivalent of NaBr. The compound was used without further purification: IR (KBr) 1740, 1215, 1050 cm⠻¹. 1 H NMR (DM 80 D-δ) delta 2.48-2.54 (m, 1H), 2.74-2.87 (m, 2H), 2.91-3.04 (m, 2H) 48 (s, 3H), 7.12-7.32 (m, SH); 13 C NMR (75 MHz, DMSO-d6) delta 38.18, 44.80, 52.67, 52.82, 127.42, .129.13, 129.34, 138.14, 176.84 .

Example 5E

Chloride ..... of 2-Carbomethoxy-3-phenyl-1-propanesulfonyl chloride

The resulting compound of Example 30 (530 g, 1.39 mol) and toluene (520 ml) was added to a 3 L round bottom flask, followed by addition of PCI5 (317 g, 1.52 mol ). The mixture was heated at 50 ° C with stirring for 45 min. It was then diluted with toluene (11) and filtered through celite. After concentration in vacuo, 371 g (96%) of the desired product was obtained as a light brown oil: IR (film) 5 1740, 1380, 1170 at &quot;1; 1 H NMR (CDCl 3); δ 2.92 (dd, 1H, J = 8.1, 14.0), 3.17 (d, 1H, J = 6.6, 14.0), 3.41-3.50 (m, 1H ), 3.67 (dd, 1H, J = 3.3, 14.3), 3.72 (s, 3H), 4.20 (dd, 1H, 3 -8.8, , 15.78 (m, 2H), 7.25-7.35 (m, 3H); 13 C NMR (75 MHz, COCl 3) delta 37.26, 42.88, 52.65, 64.89, 127.49, 128.87, 128.92, 135.61, 171.79.

Example 3F 2-Benzyl-5- (1-methyl-piperazin-4-ylsulfonyl) propionate

The resultant compound of Example 3E (84.5 g, 72500 4805.PQ.01

0.305 mol) and dichloromethane (305 ml) were added to a 1 L round bottom flask. The mixture was cooled to 0 ° C in an ice-water bath and added dropwise with vigorous stirring for 90 min , a solution of N-methylpiperazine (35.5 ml, 32.1 g) dissolved in dichloromethane (305 ml). After the addition was complete, the ice-water bath was removed and the mixture was stirred for an additional of 4 h while heating to room temperature. The solution was then poured into a separatory funnel containing 11 of a 5% aqueous NaOH solution. Concentration in vacuo afforded an oil, which was filtered through 200 g of silica gel using 4: 1 hexane / ethyl acetate as the eluent, . Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1; 1 H NMR (CDCl 3) delta 2.30 (s, 3H) 2.42 (t, 4H, 3 ~ 4.8), 2.88 (dd, 1H, 3-7.7, 14.0) 93 (dd, 1H J &quot; 3.7, 14.0), 3.06 (dd, 1H, J = 7.0, 13.6), 3.18-3.27 (m, 5H), 3 , 43 (dd, 1H, J = 8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24,24-7.34 ( m, 3H); 13 C NMR (75 MHz, CDCl 3) delta 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129 , 06, 136, 79, 173,33-

Example ..... 3 (3

2 (S) -benzo [1,3-c] [1,4] -pyrrolidin-1-yl] oxy] propionic acid

The resulting racemic ester of Example 3F (135 g, 397 mmol) in acetone (300 mL) and water (900 mL) was suspended. While stirring vigorously at 35 ° C, a crude preparation of Subtilisin Carlsberg (10 ml, Alcalase 241, Novo Laboratories). Sodium hydroxide solution (6 M) was used to keep the reaction mixture at pH 7.5-8.0. After 3 days, the reaction mixture was removed. acetone under reduced pressure and the aqueous phase was extracted with CHCl3 (11) to remove the ester which had no reacted 72500 4805, Ρ0 η01. The aqueous phase was adjusted to pH 7 with 3 M HCl and was desalted, eluting through a column of Amberlite XAD-16 (2 kg, pre-washed sequentially with water, methanol and water) using a gradient of water to water / methanol. Evaporation of the solvent yielded 46 g (70%) of a white solid: mp 184.5 ° C; TLC (25% ethyl acetate / 25% water / 25% acetic acid / 25% n-butanol) Rf = 0.43; Anal. (c 5 H 22 N 2 O 4 S0.25H 2 O)

Calc'd: C, 54.44; H, 6.85; N, 8.47.

Found: C, 54.77; H, 6.53; N, 8.39.

Exemino 3H (2-Bromoallyl) acetami-

Sodium hydride (26.4 g, 1.1 mol) in several portions was added to a stirred mixture of diethyl acetaminomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in dry tetrahydrofuran (2.50 L) under nitrogen. The reaction mixture was stirred at room temperature for 30 min and then refluxed. After heating for 18 h, the resulting slurry was cooled to room temperature and suction filtered through a short pad of silica gel. The solid residue was washed with tetrahydrofuran (2 x 50 ml), and the filtrates were combined and concentrated. The residue was dissolved in ethyl acetate (2.0 L), washed with water and brine and then dried over MgSO4. Filtration and concentration yielding a yellow oil which solidified on drying. The resulting solid was recrystallized from a warm ethyl acetate / hexane mixture to give 301 g (89%) of the desired product: mp 85-87 ° C. »

Example 31 Diethyl (3-bromo-2-oxopropyl) acetamidomalonate

Solid N-bromosuccinimide (193 g, 1.08 mol) was added in three portions over a period of 15 min to a stirred (0 ° C) cold solution of the resulting compound of Example 3H (280 g, , 83

72500 4805.PQ-01

(Mol) in a 2: 1 mixture of acetonitrile / water (1.68 L). The resulting orange mixture was stirred at 0Â ° C for a further period of 1 h and then allowed to warm to room temperature. After 4 h, the reaction mixture was treated with 10% aqueous sodium thiosulfate, diluted with ethyl acetate and washed sequentially with water, 10% aqueous NaHSG4 (3 x), water and brine. Drying (H₂ QQ)) and concentration gave a yellow solid which was recrystallized from a mixture of ethyl acetate and hexane to provide 247 g (85%) of the desired compound as a white solid: mp 97 DEG- 98.5%.

Example 3Î ±, 4-Thiazolylmethylacetamide, diethyl ether.

A 3-necked round bottom flask of 5 1 equipped with a mechanical stirrer, a stopper and a drying tube was charged with the resulting compound of Example 31 (325 g, 0.92 mol). pass nitrogen. A freshly prepared solution of thioformamide in tetrahydrofuran (0.8 M, 1.25 L) was added in one portion. The reaction mixture was stirred at room temperature for 4 h. The resulting slurry was then diluted with ether (1.25 L) and cooled to 0 ° C. The solid was then collected by filtration with suction and washed with cold ether (3x) to give the title compound as the hydrochloride salt. This material was collected to a separatory funnel of 4 L, made into a slurry with ethyl acetate (2 L) and basified by careful addition of 2 M NaOH. The organic layer was separated, washed with water and brine and then dried over MgSO 4. Filtration and concentration afforded a pale yellow oil which solidified on drying to give 242 g of the desired compound. This material was recrystallized from a mixture of ethyl acetate / hexane to give 185.6 g (64%) of pure material: mp 104-106 ° C

Example 3K N-acetyl-S- (4-thiazolyl) -β-alanine ester

Aqueous LiQH 2 II (325 ml, 0.65 mol) was added dropwise to

A stirred solution of the compound resulting from Example 3J (185.6g, 0.59 mol) in a mixture of tetrahydrofuran (620ml) and ethanol (20ml) was added dropwise over 20 min. 310 ml). After stirring at room temperature for 2.5 h, the reaction mixture was concentrated and the resulting aqueous mixture was extracted with ether (3 x 200 ml), adjusted to pH 3 with 3N HCl and concentrated The residual water was removed by evaporation of toluene (2 x 200 ml). The residue was diluted with toluene (1.5 L) and the resulting slurry was heated at reflux with separation from the residue. water (Dean-Stark mousetrap). After 3 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate (1.5 L) and suction filtered through SiO 2 (60 g). The solids were washed with additional ethyl acetate (4 x 500 mL) and the combined organic phases were concentrated to afford a pale yellow oil which solidified with 66.6 Pa (0.5 torr) drying to afford 119.6 g (84%) of the desired compound: mp, 58-62 ° C-

N-Acetyl-3-C4-thiazolyl) -L-alanine and N-acetyl-3- (4-thiazolyl) -D-alanine ethyl ester

A 3-necked round bottom flask equipped with a mechanical stirrer was charged with the resulting compound of Example 3K (210 g, 0.87 mmol), distilled water (1.6 L) and aqueous KCl 1 M (0.8 1) The homogeneous solution was adjusted to pH 7.0 with 0.1 M NaOH and then treated with Carlsberg Subtilisin (1.8 g) dissolved in 0.1 M aqueous KCl (25 ml) The reaction mixture was stirred at room temperature with 1.0 L NaOH addition as necessary to maintain the pH at 6.25-7.25 After 4 h, 430 ml of base and the reaction was found to be complete. The reaction mixture was then extracted with chloroform (4 x 1.5 L), the aqueous phase was carefully acidified to pH 4 with HCl and then concentrated under reduced pressure. Residual water was removed by successive evaporation of portions of toluene (3 x 500 ml) and ethanol (3 x 500 ml). The residue was taken up in warm ethanol and filtered with suction.

to remove the warm ethanol (3x and filter the solids with the filtrates to give 1-L-alanine in the inorganic salts). The solids were washed with 400 ml). It resorted to the residue in warm ethanol suction to remove inorganic salts. Wash with warm ethanol (3.times.40 ml) and concentrate to afford 92.6 g (50%) of N-acetyl-3- (4-thiazole-form of a white solid m.p. 186Â ° C.

The combined chloroform fractions of the extractions were washed with saturated aqueous NaHCO3, water and brine and then dried over MgSO4. Filtration and concentration afforded 103 g (49%) of N-acetyl-3- (4-thiazolyl) -D-alanine ethyl ester. This material may further be purified by recrystallization from ethyl acetate / hexane, m.p. 79-80.5 ° C.

Example ..... 3M

Eimetry of the ethyl ester of H-acetyl-3- (4-methyl-2-oxazolyl)

A 2 L round bottom flask equipped with a magnetic stirrer, a reflux condenser and a nitrogen inlet was charged with sodium (0.96 g, 0.045 mol) and ethanol (900 ml) and allowed to the mixture was refluxed until sodium was consumed. The resulting solution of sodium ethoxide was cooled slightly and N-acetyl-3- (4-thiazolyl) -D-alanine ethyl ester of Example 3L (102 g, 0.42 mol) was added. The reaction mixture was then heated to reflux. After 3 h, the solution was cooled to room temperature, quenched with glacial acetic acid (0.045 mol) and concentrated to remove ethanol. The residue was diluted with ethyl acetate, washed with water and brine and dried over MgSO4. Filtration and concentration afforded a yellow oil which was purified by recrystallization from a mixture of hot ethyl acetate and hexane to give 89 g (87%) of material identical to that obtained in Example 3L. -80 "-80" • .Γ 7 2500 4805.P0.Q1

Example ..... 3N

Dihydrochloride ..... (3).

A 21 L round bottom flask equipped with a magnetic stirrer was charged with N-acetyl-3- (4-thiazolyl) -L-alanine from Example 3L (92.6 g, 0.43 mol) and HCl MW (11). The resulting solution was refluxed. After 3 h the mixture was allowed to cool to room temperature. The solution was then concentrated under reduced pressure, evaporated with toluene (3 x 200 mL) and dried under vacuum overnight to give 120 g of a slightly damp solid. This material was used in the next reaction without further purification. For example,

A Erlerimeyer flask of 4 L equipped with a mechanical stirrer was charged with the resultant compound of Example 3N (125.9 g) and tetrahydrofuran (1.5 L) and the mixture was adjusted to pH 6, 6 with saturated aqueous sodium bicarbonate. The resulting solution was then adjusted to pH 8.9 with 3.0 M NaOH and a solution of di-tert-butyl dicarbonate (117.8 g, 0.51 mol) in tetrahydrofuran ( 150 ml). The reaction mixture was stirred vigorously at room temperature for 40 h. The tetrahydrofuran was removed in vacuo, the pH of the residue was adjusted to 2.0 with 3.0 M HCl, and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined extracts were dried over MgSO 4, filtered and concentrated to give 150 g of a white solid. Recrystallization from warm 1: 1 ethyl acetate / hexane (1.06 L) yielded 107, 6 g (82% from the resultant compound of Example 3 M) of the desired compound mp H5e> C; Calfa / Wt = + 129.8 (c = 1.04, CHCl3).

Anai. (C 11 H 16 H 2 O 2).

Found: C, 48.53; H, 5.88; N, 10.29 Found C, 48.58; H, 5.91; N, 10.17.

7 2500 4805-PG3-01

Example ..... 3.Ρ

Boc-L- (4-Thiazolyl) Ala ..... of ...... (28. 4S) -2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

(2S, 3R, 4S) -2- (tert-butyloxycarbonyl) amino] -1-cyclohexyl-3,4-dihydroxy-6-methylheptane (5.05 g, 14 mmol) , 7 mmol, Luly et al., J. Org. Chem. 1988, 53, 6109) for 90 min in 4 M HCl in ethanol and then evaporated. Ether was added and evaporated 3 times and the residue was dried under high vacuum. To this residue was added 1-hydroxybenzotriazole (5.57 g, 41.2 mmol), the acid resulting from Example 30 (4.00 g, 14.7 mmol), dimethylformamide ( 60 ml) and H-methylmorpholine (3.40 ml, 30.9 mmol). The mixture was cooled to -23 ° C, treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 4.03 g, 21.0 mmol) After 2 h at -23 ° C and 21 h at room temperature, the mixture was poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The organic layer with water and brine, then dried over Na2 SO4 and evaporated to give a white solid which was recrystallized from methylene chloride / ether (v / v) (multiple crops) yielding 6.28 g (86%) of the desired product as a white flocculent solid, mp 159-160 ° C. TLC (15% CH3 OH / 85% CHCl3) Rf 0.63; NMR (CDCl3) delta 8.78 (1H, d), 7.14 (1H, d), 6.18 (2H, broad d), 4.44 (1H, dd), 4.27 (1H, m) (1H, dd), 3.30-3.12 (3H, m), 1.89 (1H, septet), 1.46 (9H, s) , 0.94 (3H, d), 0.88 (3H, d) -Anal - (ε'25Η43Ν3058) -Cals C, 60.33; H, 8.71; N, 8.44-Found C, 60.43; H, 8.68; N, 8.51

Example ..... 3.Q

Amide ..... Hâ,,Lâ, ... â, ... â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒTiazg.l.ll. 2-amino-cyclohexyl-3-4-dihydroxy-6-methyl-heptane

Trifluoroacetic acid (50 mL) was slowly added via cannula to a solution of the resultant compound of Example 3P (6.27 g, 12.6 mmol) in methylene chloride (50 mL) at 0 ° C. The reaction mixture was stirred for 3 h at 0 ° C and concentrated in vacuo. vaçuc &gt;. The residue was extracted with dichloromethane, dried over Na2SO4, filtered, and concentrated to give an oil. The product was extracted with chloroform, dried over Na2 CO4, filtered and concentrated. Recrystallization from methylene chloride / hexane 1: 4 (o / o) afforded 5.00 g (100%) of the desired product as a fluffy white solid: mp 111-112øC TLC (15% CH3 OH / 85% CHCl3) Rf = 0.46; NMR (CDCl3) delta 8.77 (1H, d), 7.40 (1H, broad d), 7.13 (1H, d), 4.54 (1H, m), 4.25 (1H, m) , 3.80 (1H, dd), 3.33 (1H, dd), 3.25-3.12 (3H, m), 0.95 (3H, d), 0.86 (3H, d)

Anal. (Â ±)

Calc'd: C, 60.42; H, 8.87; N, 10.57.

Determined; C, 60.05; H, 8.65; N, 10.42.

Example ..... 3R

Amide ...... (2S) -2-Benzyl-3- (4-methylpiperazin-1-ylsulphonyl) -propionyl-L - (4 &quot; Thiazolyl) Ala. ... (23,3R, 4S) -2-Amino-1-cyclohexyl. 1-3 .., 4-d] -1-hydroxy-6-methyl-heptane

N-methylmorpholine (0.35 mL, 3.2 mmol) was added to the resultant acid of Example 30 (1,000 g, 3.064 mmol), to the resultant amine of Example 3Q (1.110 g, 2.792 mmol) and 1-hydroxybenzotriazole ( The mixture was cooled to -23 ° and treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.760 g, 3.96 mmol) in dichloromethane After 2 h at -23 ° C and 14 h at ambient temperature, the reaction mixture was poured into saturated NaHCO 3 solution (100 ml) and extracted with ethyl acetate (2 x 50 ml) which washed with water (2 x 50 ml) and brine (50 ml) and then dried over Na2 SO4 and evaporated to give 1.94 g. Recrystallization from ethanol (15 ml) / hexane (90 ml. ) afforded 1.559 g (79%) of a white solid; 169-170 ° C; TLC (10% CH 3 OH / 90% CHCl 3) Rf = 0.40; δ-NMR (CDCl 3) delta 8> 73 C H 7 7.43 (1H, d), 7.37-7.16 (6H, m), 6.23 (1H, d), 4.63 (1H, dd), 2.30 (3H, s), 0.95 (3H, d), 0.87 (3H, d).

Anal. Anal. Calc'd (35%).

Calc; C, 58.43; H, 7.91; N, 9.73.

Determined; C, 58.51; H, 7.74; N, 9.60.

7 2500 4805.ΡΘ.01 "" 83 "imP ** '. *' ** &amp; * ρ00 *

Example ..... 4.

Alternative preparation of ..... N-Boc-3- (4-1-aza-1-yl) -L-alanine

To a solution of the product of Example 3H (3.36 g, 10.0 mmol) in dimethylformamide (10 mL) was added sodium chloride (586 mg, (360 microliters, 20 mmol) and 4N hydrochloric acid in dioxane (0.12 mL, 0.5 mmol), the reaction vessel was purged with Firestone three times and placed under a pressure of positive nitrogen. The reaction mixture was refluxed for 24 hours and then concentrated in vacuo, the obtained residue was diluted with water (5 ml) and extracted with ether (3 x 15 ml). The combined organic extracts were decolorized with charcoal (0.5 g), dried over magnesium sulfate, filtered and concentrated in vacuo. to give the title product (2.51 g, 95%) as a pale yellow oil, â € ƒâ € ƒâ € ƒ1 H NMR (300 MHz, COCl3) 1.29 (t, 3H), 2.04 (s, 3H) 2H), 4.22 (q, 2H), 4.79 (m, 1H), 5.53 (d, 1H), 5.68 (m, 1H), 6.44 (d, 1H); IR (film) 1195, 1220, 1370, 1540, 1660, 1740, 2990, 3050, 8,300 cm -1. MS (CDI / NH 3) m / e 264/266 (M + H) +, 281/283 (M + H + NH 3) Anal. Calc'd for C 9 H 14 NO 3 Br, C, 40.92; H, 5.34; N, 5.30, Found; C, 42.04; N, 5.48; N, 5.26.

Example 4B N-Boc- (2-Bromoallyl) glycine

A slurry of the product of Example 4A in 0.1N potassium chloride solution (300 ml) was treated with a solution of Subisylis Carlsberg (4 mg) in 0.1 N potassium chloride solution (3 ml) containing phosphate buffer 0.2 M, pH 7.0. The pH was maintained between 6.50 and 7.25 with addition of a 2.0 N sodium hydroxide solution, via pH-Stat. After 25 minutes, the rate of hydrolysis decreases noticeably; and the unreacted D-ester was extracted with methylene chloride (3 x 150 mL).

The resulting aqueous phase was treated with cobalt (II) acetate (6 mg) and Acylase I (80 mg). The reaction mixture was stirred for 4 hours and was determined complete. -84- -84- jff · F 3 * 7 2500 4805.PQ.01

The pH of the reaction mixture was adjusted to 10 with addition of solid sodium carbonate. The resulting solution was treated with di-tert-butyl dicarbonate (6.55 g, 30 mmol) dissolved in THF (100 ml). The aqueous solution was washed with hexane (200 ml) to remove any unreacted protective reagent. The aqueous layer was adjusted to pH 2.5 with the addition of solid potassium hydrogen sulfate and extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound (7.30 g, 81%) as a pale yellow crystalline solid-Calc'dp at 250 ° C = -9.86 ° (MeQH), c = 1.085-1.93 (m, 9H), 2.91 (m, 2H), 4.52 (m, 1H), 5.19 (d, G, SH), 5.53 (m, 1H), 5.71 (s, 1H), 6.79 (d, 0.5H), 11.3 (s, 1H); IR (COCl) 1150, 1250, 1400, 1500, 1620, 1640, 1710, 3000, 3350 83520 cm-1 (CDI / NH3) m / θ 311/313 (Μ + Η + ΝΗ ^) * Anal. Calc'd for C 16 H 16 ClN 6: H, 5.66; N, 4.91 Found C, 41.38; H, 5.59; N, 4.75.

Example ..... 4C

N-Bromosuccinimide (1.45 g, 8.16 mmol) was added in three portions over twenty minutes to a solution of (2R) -H-Boc-2-Amino-5-bromo-4-oxopentanoic acid of the product of Example 4B (2.00 g, 6.80 mmol) in water (30 ml) and tetrahydrofuran (15 ml) cooled to 0 ° C. After the addition was complete the bath was removed from ice-water and the solution was stirred for four hours. The tetrahydrofuran was removed in vacuo and the product was extracted with ethyl acetate (3 x 35 mL). The organic extracts were combined and washed with 5% sodium chloride solution (25 ml) and brine (25 ml), dried over magnesium sulfate, and concentrated in vacuo to afford the title compound (1.70 g, 81% ). 1 H NMR (300 NHz, CDCl 3) 1.45 (s, 9H), 3.30 (m, 2H), 3.93 (s, 2H), 4.61 (m, 1H), 5.51 (d, 1H). MS (DCI / NH 3) m / e 310/312 (M + H) +, 327/329 (M + H + NHS) +.

Example 4D

Acid ...... (2R) -N-Boc-2-Amino-3- (4-thiazole) propanediol

Thioformamide (17.7 mg, 0.29 mmol) was added to a solution

(91 mg, 0.293 mmol) in tetrahydrofuran (5 ml) was added dropwise. The thioformamide was prepared by reacting a slight excess of phosphorus pentasulfide with formamide in tetrahydrofuran. The resulting solution was diluted with hexanes and filtered through a plug &quot; of silica gel and stored at ~ 25 ° C. The resulting solution was allowed to stand for sixteen hours and then concentrated in vacuo to provide a residue which was partitioned between diethyl ether and aqueous sodium bicarbonate, The aqueous layer was washed with ether (2 x 10 ml) and methylene chloride (10 ml), adjusted to pH 2.3 with potassium hydrogen sulfate and extracted with ether (3 x 20 ml). The organic extracts The combined extracts were dried over magnesium sulfate and concentrated in vacuo. to provide the title compound as a white crystalline solid (55 mg, 71%). NMR (300 MHz, COCl3) 1.48 (.beta., 9H), 3.48 (m, 2H), 4.52 1H), 5.61 (m, 1H), 7.18 (d, 1H), 8.91 (d, 1H).

Example ..... 5.

Alternative Preparation of ..... Acid ...... (2R) -N-Boc &quot; 2 &quot; Amino-5-bromo-4-oxopentanoic acid

Example 5A (2-Chloro-1-yl) acetamidomalonate of ..... Diethyl. To a suspension of 95% sodium hydride (17.2 g, 680 mmol) in tetrahydrofuran (1.2 L) was added 2,3-dichloropropene (100 g, 900 mmol), diethyl acetamidomalonate (146 The resulting slurry was heated at reflux under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the resulting residue was (200 ml) and a mixture of ether (300 ml) and methylene chloride (100 ml). The organic phase was washed with 5% sodium chloride solution (200 ml) and brine (200 ml) ), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid (195 g) was dissolved in hot hexanes (1300 ml) and allowed to cool to room temperature and allowed to stand for to give the title compound as a crystalline solid (157 g, 80%): mp 76.3 Â ° C NMR (300 MHz, CDCl3) 1.29 (t, 6H), 2.05 ( s, 3H), 3.48-86.750 (M, 4H), 5.18 (m, 1H), 5.9 (m, 1H), 6.92 (bs, 1H) CDCl3): 1140 "1180" 1200 "1240" 1270 "1300, 1500" 1630 "1740, 2950" 2990 and 3300 cm "EM (CDI / NH3) m / e 292/294 (M + H) 309/311 (MH + NH4): Anal. Calc'd for C: c = 49.41; 1H, 6.22; Found: C, 49.18; H-6-29; N, 4.75.

Example ..... 5B (2-chloro-1-yl) acetamide. t ethyl

The product of Example 5A (137 g, 500 mmol) was hydrolyzed and decarboxylated by the procedure described in Example 4A to provide the title compound (105.4 g, 96%) as a pale yellow oil which crystallized from â € ƒâ € ƒâ € ƒ1 H-NMR (300 MHz, CDCl3): Î'31 (t, 3H), 2.00 (s, 3H), 2.79 (m, 2H), 4.22 (q "2H), 4.79 (m, 1H), 5.29 (m, 1H), 6.61 (m, 1H); IV 1200 "1220" 1280 "1300" 1370 "1440" 1550 "1638" 1659 "1740" 2890 "2990" 3050 and 3300 cm &quot; 1. MS (CDCl3 / NH3) m / e 220/222 (M + H) +, 237/239 (M + H + NH3). Anal. Calc'd for C 24 H 22 NO 4 Cl. H, 6.42; N, 6.38. Found: C, 46.58; H, 6.05; N, 6.02.

Example 5C

Amino-5-bromo-4-oxopentanoic acid The product of Example SB is treated according to the procedure of Examples 4B and 4C to provide the desired product.

Example ..... 6

Alternative Preparation of ..... (2S) -2-benzyl-3- (4-methyl-piperazin-1-ylsulfonyl) propionic acid

Example ..... 6 ..... A

Sodium salt of ..... Acid ..... 2-Carbomethoxy-3-phenylpropane To a 0-3 M ethanolic solution of the product of Example 3B (Z) -1-bromo-2- 3-phenylpiperazinecarboxylate (0.88 molar equivalents) was added aqueous solution of sodium sulfide (1.0 g molar equivalent) for one hour at 50Â ° C. stirred for 10 hours at 50 ° C, and then the ethanol was removed under reduced pressure at 50 ° C. Ethyl acetate (3 kg per kg of bromide) was added and the mixture was stirred for an additional 15 minutes, resting for 10 minutes. The layers were separated

And the aqueous layer was washed as above with two additional aliquots of ethyl acetate (1 kg per 1 kg of bromide)

Raney nickel (1 kg per 10 kg of aqueous solution) was added to an aqueous solution which was then subjected to vacuum and purged with nitrogen followed by hydrogen (3x) and placed under 40 psi of hydrogen for 6.5 to 9, 5 hours »0 Raney nickel was removed &quot; was added dropwise by filtration using nitrogen pressure and the filtrate was concentrated under reduced pressure at 55 ° C. A 10% aqueous solution of acetone (0.3 kg per 1 kg of starting bromide) was added to the residue obtained and the mixture was heated at 50 ° C for 30 minutes. Additional acetone (3 kg per 1 kg initial bromide) was added slowly for one hour to effect crystallization of the product. After stirring for one hour, the product was removed by filtration and washed with acetone to give the title compound in SOâ,, 65%. â € ƒâ € ƒâ € ƒ255 DEG C. The 300 MHz NMR spectrum was found to be consistent with the proposed structure. second harvest by adding additional acetone (2.5 kg per 1 kg initial bromide) and cooling to -20 ° C for 10-12 hours and the second crop removed by filtration. In this way an additional yield of 13-40% of the title compound.

Example 6B

Methyl 2-benzyl-3- (4-methyl-plperazin-1-ylsulfonyl) propionate The product of Example 6A (1 molar equivalent) was mixed with phosphorous peritylchloride (1.5 mol equivalents) and heated to 70- The reaction mixture was warmed to room temperature and then diluted with toluene (16.7 molar equivalents) and added to a solution of aqueous sodium chloride (4 kg per 1 kg of phosphorus pentachloride), maintaining the temperature below 40Â ° C. The mixture was stirred 5 minutes, allowed to settle for 15 minutes and then the phases were separated. The sodium chloride wash was repeated as described above. The toluene phase was cooled to 5 ° C and N-methylpiperazine (3 molar equivalents in 3 molar equivalents of toluene) was added, keeping the temperature below 15 ° C

The mixture was stirred for 4-6 hours and then washed with 8% aqueous sodium hydroxide (2.times.3.4 kg per kg of phosphorus pentachloride). The combined basic washings were reextracted with toluene (0.25 kg per 1 kg of solution of sodium hydroxide). The combined toluene extracts were washed with water (1 kg per 1 kg of phosphorus pentachloride) and the toluene was removed by distillation under reduced pressure to provide the title compound (65-70%) as a viscous oil which crystallized At rest, the 300 MHz NMR spectrum was found consistent with the proposed structure. MS (DCI / NH 3) m / e 341 (M + H) +.

The product from Example 6B (69 kg, 20 mol) in acetone (420 kg) / water (2 x) (960 kg) was adjusted to pH 8.0 using sodium hydroxide XN. Alkalase R (Subtilisa) was added and the pH was maintained between 7.9 and 8.4 by the addition of 1N sodium hydroxide. When 80% of the theoretical amount of sodium hydroxide had been consumed, the reaction was quenched by the addition of ethyl acetate. The reaction mixture was concentrated to half the original volume under reduced pressure and then washed with ethyl acetate (2 x 700 kg), the volume of the aqueous phase was concentrated to half and the pH adjusted to 5.2. The reaction mixture was treated with XAD-16 resin (50 kg), stirred for 18 hours and applied to a column of XAD-16 resin (50 kg). The column was eluted with water (500 kg) and then with 35% ethanol in water (1000 kg) to provide a residue which was treated with isopropanol (270 kg) and heated to 75 ° C. After cooling to room temperature and subsequently at-5Â ° C, crystalline material was obtained. The solid was collected by filtration, washed with cold isopropanol (30 kg) and dried at 50 ° C to provide the title compound (13 kg, 49%). It was found that the 300 MHz NMR spectrum was consistent with the proposed structure. MS (DCI / NH 3) m / e 327 (M + H) + This compound can be recrystallized from isopropanol / water 1:

Alternative Preparation of ..... Amide ..... 2 (S) -2-Benzoyl-3- (4-methylpiperazin-1-ylsulphonylpropionyl-L-thiazolyl) 2-Amino-1-Cyclohexyl-4,4-dihydroxy-6-methyl-heptane

Example ..... 7A

trimethylsilyloxyphenyl) -2-amino-1-cyclohexyl-5,4-dihydroxy-6-methylheptone A solution of 3.5% of 23-Boc-amino-1-cyclohexyl-3R, 4-dihydro-6-methylheptane in 4N hydrochloric acid gas in anhydrous ethanol. After 4 hours at 0-5 ° C, bubble nitrogen through the reaction mixture to remove dissolved gaseous hydrochloric acid. The solvent was removed under reduced pressure at 30 ° C to provide a solid which was dissolved in ethyl acetate and water. Potassium carbonate was added to bring the pH of the mixture to a value between 10 and 11 and the layers were separated. The aqueous layer was extracted with additional portions of ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to 50 ° C. ° C to give a solid. The solid was crystallized by dissolving in a minimum amount of ethanol at 40 ° C and water was added slowly until the ratio of ethanol to water was 40/60 (w / w). The solution was cooled to 0-5 ° C at a ratio of S ° C per hour. The cooled mixture was stirred for a period of not less than 2 hours before removal of the solid by filtration. The solid was dried in a vacuum oven at 45 ° C until the loss on drying was less than 0.1%. The title compound was obtained as a white crystalline solid in 65-72% yield. mp. 106-108 ° C. The 300 MHz NMR spectrum was found consistent with the proposed structure. MS (GDI / NH 3) m / e 244 (M + H) +.

Example 7B

(2S, 3R, 4S) -2-Amino-1-cyclohex-1-one To a solution of the product of Example 7A (14.25 g, 58.5 mmol), N-Boc-L- (4-thiazolyl) alanine (17.45 mmol) 64.4 mmol) and 1-hydroxybenzotriazole hydrate (HOBT) (9.86 g, 64.4 mmol) dissolved in dimethylformamide (DMF) (33 mL) and cooled to 0-5 ° C in a

(DCC) (14.5 g, 70.3 mmol) dissolved in DMF (27 ml) was added dropwise over 30 minutes of 1,3-dicyclohexylcarbodiimide (DCC) ). After 1 hour the reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. The reaction was quenched by addition of citric acid (1.14 g, 6.0 mmol) and ethanol (1.31 mL, , 5.0 g, 22.0 mmol). The mixture was stirred for 1 hour and then ethyl acetate (285 ml) was added. After an additional 30 minutes, the solid by-product was removed by filtration and washed with ethyl acetate (48 ml). Additional ethyl acetate (1.9 L) was added and the organic phase was washed with 1% sodium chloride (713 ml), 5% citric acid containing 1% sodium chloride (2 x 713 ml), sodium bicarbonate (2x713 ml) and 20% sodium chloride (2x713 ml) and concentrated under reduced pressure to provide a white solid. The solid was dissolved in isopropanol (200 ml) with heating, treated with decolorizing carbon at 50 C. The filtrate was diluted with isopropanol (50 ml) and stirred at room temperature with a mechanical stirrer for 15 hours. The suspension of the solid was cooled to 0-5 ° C in an ice bath and stirred at this temperature for 3 hours. The solid was removed by cold filtration, washed with cold 1: 1 isoproparol / heptane (100 ml) and dried in a vacuum oven at 500 ° C for 48 hours to provide the title compound as a white solid in a yield of 85% %. mp 156-158 ° C. The 300 MHz NMR spectrum was found consistent with the proposed structure. EI (DCI / NH4) m / e 498 (M + H) +.

Example 7C

(2 S, 3 R, 4 S) -2-Amino-1-cyclohexyl-1,3,4- dihydroxy-6-methyl-heptane

A 12% solution of the product of Example 7B was prepared at 15-25øC in 3N hydrochloric acid. After 4 hours at 15-25 ° C, the reaction mixture was quenched, poured into a mixture of 4% sodium hydroxide / 15% sodium chloride / ethyl acetate. The pH of the mixture was brought to 10-12 by the addition of sodium hydroxide. The layers were separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organic extracts were: &quot; 72500 4805.Pfâ-01 washed with 25% sodium chloride (2x), dried over magnesium sulfate, treated with activated carbon at 50Â ° C for 1 hour and filtered through ethyl acetate. The filtrate was concentrated to a solid , under reduced pressure at 45 ° C. The solid was crystallized by dissolution in a minimum amount of ethyl acetate (5x by weight) and trituration with heptane until the ratio of ethyl acetate to heptane was 30/70 (w / w). The solution was cooled to 0-5 And stirred for two hours and then filtered. The solid was dried in a vacuum oven at 45 ° C for 60 hours or until the loss on drying was less than 0.1%. The title compound was obtained as a white crystalline solid in a yield of 70-82 %. mp 109-112 ° C. The 300 MHz NMR spectrum was found to be consistent with the proposed structure-MS (DCI / NH 4) m / e 398 (M + H) +. .70

(4-methoxyphenyl) -propionyl-L- (4-thiazolyl) Ala ..... from (2S-tetrazolyl) 5R-4S) -2-Amino-1-cyclohexyl-5-4-dihydroxy-6-methylheptane The product of Example 7C (3.00 g, The product of Example 6C, 2S-benzyl-3- (4-methyl-piperazin-1-ylsulfonyl) propionic acid (2.59 g, 7.9 mmol) and HOBT (1.27 g, 8 mmol) , 3 mmol). After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0-5 ° C in an ice bath and treated with dropwise addition over a 30 minute period of a solution of OCC ( The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was quenched with citric acid (0.15 g, 8.3 mmol) , 0.26 mmol) and ethanol (0.17 mL, 3.04 mmol) and stirred for 1 hour. Ethyl acetate (60 mL) was added and the mixture was stirred for an additional hour. filtered and washed with ethyl acetate (10 ml). The filtrate was diluted with ethyl acetate (400 ml) and washed with 5% sodium bicarbonate solution (2 x 100 ml), 1% sodium chloride solution (100 mL) and 20% sodium chloride solution (100 mL), the solvent was removed under reduced pressure to provide a white solid. The solid was dissolved in isoproparol (80 mL)

Treated with deodorizing carbon at 55 DEG C. for 1 hour, filtered through Celite and stirred at room temperature with a mechanical stirrer for 12 hours. The white solid suspension was cooled to 0 DEG- The solid obtained was washed with cold heptane / isopropanol (25 ml) and dried in a vacuum oven at 55 ° for 48 hours to give the title compound ( 4.32 g, 81%) as a white solid: mp 169-170 ° C â € ƒâ € ƒâ € ƒThe 300 MHz NMR spectrum was found to be consistent with the proposed structure MS (DGI / NH2) m / e 706 (M + H) + -

Example ..... 8 "

N- (4-Morpholinylsulfonyl) -L-phenylalanyl] - (2-amino-4-thiazole) Alanine hydrochloride (2 S, 3 R, 4 S) -2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane The title compound can be prepared according to the procedure disclosed in the patent application European patent EP 399 556 published 28 November 1990. The ability of a renin inhibitor to treat psoriasis is demonstrated as follows. A 62-year-old female patient with confirmed psoriasis received 0.1 mg / kg enalhirene ( (S) -amino-1-cyclohexyl-3 (R), 4 (R) -hexahydro-benzoic acid salt S-dihydroxy-6-methyl-heptane-acetic acid) (enaleren 5.0 mg / 5 ml (concentration 0.1%), glacial acetic acid 0.91 mg / 5 ml and sodium chloride 43, 9 mg / 5 ml in water for injection) intravenously over a period of 5 minutes, followed 40 minutes later by administration of an additional 0.3 mg / kg enalvenum intravenously over a period of The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1 72500 4805 - Pfâ "01 -93 '

JL

Sraduaçap ..... da .... Lfôsao .... a .... se.aui.r: ..... §a ..... treatmen.to ..... com .. Enalquireno

Elbow injuries Treatment + 2 Days +4 Days +7 Days 4 3 ò 4 3 3 4 3 3 right. Day desquamation 4 erythema 4 severity of the 4 lesion

Lesions of the face 2 erythema 3 3 Skin lesions, hairy erythema 4433

DescamacaQ 0 1

O 3 4

None Minimal: poorly defined scales, possibly dusty appearance Moderate: flat-edged scales Severe: well defined, raised and loose scales possible yellow / brown color possible Extreme: scales completely covered by raised plaques may be pigmented, possible cracks may be present with &quot; crust &quot;

Sr.lt.ema 0 1 2 3 4

none

Very soft: red / light pink Moderate: red but still no dark texture Strong: very red, possibly dark Extremity: bright red

Sovereignty, of. 0 Complete disappearance 1 Minimal severity 2 Moderately severe 3 Severe 4 Severe The data provided in Table 1 indicates that the renin inhibitor -94- 72500 4805 "PG.01 improved patient psoriasis"

The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids. These salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, pierate, pivalate, propionate, succinate, tartarate, thiocyanoate, tosylate and undecanoate. Basic nitrogen-containing groups may also be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and ferethyl bromides and other 'Soluble or dispersible products are thus obtained in water or oil'

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid. salts include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium or with organic bases

The compounds of the present invention may also be used in the form of prodrugs including esters. Examples of such esters include a hydroxyl-substituted compound of the invention which may be acylated with a blocked or unblocked aminoacyl residue, a phosphate function, or a hemisuccinate residue. The amino acid esters of particular interest are those of

However, other amino acid residues may also be used. Other esters include compounds of the invention where a carboxylic acid group has been esterified to provide esters which include, but are not limited to, methyl, ethyl or benzyl esters. These esters serve as prodrugs of the compounds of the present invention. The prodrugs are metabolically converted in vivo into the parent compound of the invention. The preparation of the prodrug esters is carried out by reacting an inhibitor of hydroxyl-substituted renin, with an aminoclucyl, phosphoryl or activated hemisuccinyl derivative. The resulting product is then deprotected to provide the desired prodrug ester. Prodrugs which are esters of renin inhibitors containing the carboxylic acid group are prepared by processes known in the art. The novel process of the present invention is directed to the use of a renin inhibitor for the treatment of psoriasis in a human or other mammal.

This invention is also directed to the process of preparing compositions of renin inhibitors useful for the treatment of psoriasis. The total daily dose administered to a host in a single dose or in individual doses may be in amounts, for example, between 0.001 mg / kg body weight and, more usually, 0.01 to 1 mg / kg. The dosage unit compositions may contain these amounts or their sub-multiples to make up the daily dose. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend on a variety of

Including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the particular disease in therapy. The renin inhibitor may be administered orally, parenterally, by inhalation spray, nasally, rectally, or topically in dosage unit formulations containing as necessary carriers, adjuvants and conventional, non-toxic and pharmaceutically acceptable carriers.

Topical compositions comprising the rerine inhibitor may be in the form of shampoos, ointments, powders, sprays, ointments, lotions, creams, solutions, suspensions and the like. These topical compositions may be prepared by mixing the renin inhibitor with solid or liquid carriers , inert and non-toxic which are suitable for topical administration. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral, used in the present invention, includes subcutaneous injections, intravenous injection, injection intramuscular injection, intrasternal irgection, intra-lesional injection or infusion techniques'

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable carriers and solvents which may be The use of water, dextrose solution, mannitol solution, Ringer's solution and sodium chloride solution

7 2500 4805-PS.01 -97 "isotonic. In addition, sterile fixed oils are conventionally employed as a solvent or suspending agent. For this purpose any fixed light oil may be employed, including synthetic morowane or di-glycerides. In addition, fatty acids such as The injectable preparations may be in ready to use form or may be reconstituted from a freeze-dried powder,

Suppositories for rectal administration of the drug may be prepared by mixing the drug with a suitable non-irritating exciperite such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug,

Solid dosage forms for oral administration may include capsules, tablets, films, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms may also comprise, as is normal practice, additional substances in addition to inert diluents, eg, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may , also, comprise buffering agents. Tablets and pills may additionally be prepared with enteric coatings. Solid dosage forms may also comprise agents for enhancing oral absorption. Solid dosage forms may also comprise liquid filled capsules, for example solutions of PEG of the active compound in a soft elastic gelatin capsule.

A typical tablet dosage form comprises the active ingredient (not more than 3% by weight of the tablet), citric acid (5-15% by weight tablet), a filler such as microcrystalline cellulose (for example, Avieel® PH101 ), a disintegrant (8-12% by weight of the tablet, for example crospovidone) and a lubricant ¢ 0.5-1.5% by weight of the tablet, for example magnesium stearate.

72300 4805 "PO, 01 plus surf actarites (for example, Tween 80, BrijR 35 Emulphor 719 to the like) the total amount of surfactarites being 2-3% by weight of tablet- The tablet dosage form is prepared by mixing the 50% of citric acid and Avicel® ethanol (200 degrees) is added and the mixture is granulated. If surfactants are included they are added as a solution in the ethanol during the granulation step. The granules are dried during The remaining 50% of citric acid, crospovidone and magnesium stearate are mixed with the granules and then compressed to form tablets. The composition of two typical tablet dosage forms (100 mg of active ingredient) is shown below.

COMPOSITION OF TABLET A

Ingredient.

Hydrochloride salt of the compound of Example 3

Citric acid

AvieelR PH101

Crospovidone

Amount per, tablet mg% 107.2 30;, 6 50.1 14 * 3 150.0 42 * 8 o Xi or 11 * 4

Magnesium stearate 3.0 0.9

72500 4805 η Pfâ η 01 -99-

COMPOSITION OF TABLET B

Ingredient Amount per tablet Cp Hydrochloride salt of the compound of Example 3 11.1, Î'107.2 ° 30.3 Citric acid 49.9 14.1 Avicel® PH101 150.7 42.6 BríjR35 2.5 0.7 Tween 80 0.7 0.2 Crospovidone 40.0 11.3 Magnesium stearate 2.8 0.8

A typical capsule dosage form comprises a soft elastic gelatin capsule filled with a solution comprising the active ingredient dissolved in a solvent comprising a blend of PEQ 400 (98% v / v) and glycerol (2% v / v)

A soft elastic gelatin capsule has a composition comprising MF gelatin (38.3 wt%), glycerin (96% active, 29.0 wt%) and water (32.7%). The capsule dosage form is prepared by mixing appropriate volumes of ΡΕΘ 400 and glycerin to give a mixture which is 98% of ΡΕΘ 400 and 2% by volume of glycerin-nitrogen is bubbled into the mixture for several hours. Keeping the mixture under a nitrogen atmosphere, the mixture is heated to about 40 ° C and then the desired amount of the active ingredient is dissolved. The solution of the active ingredient is then filled into the soft elastic gelatin capsules. The filling operation is conducted under an atmosphere of nitrogen- 100%

100 "JL 72500 4805-ΡΘ-01

Using the method described above, soft elastic gelatin capsules containing 0.1 ml of a solution of PEfâ "¢ 400 / glycerin (98% / 2% by volume) of the compound of Example 3 (hydrochloride) can be prepared at concentrations of 0 , 7 mg / ml, 7mg / ml and 21mg / ml,

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents commonly used in the art, such as water. These compositions may also comprise adjuvants, such as wetting agents, emulsifying or suspending agents, and sweetening, flavoring and perfuming agents,

In addition to being used as the sole active ingredient in the treatment of psoriasis, a renin inhibitor may be administered in combination with one or more agents known to be useful for the treatment of psoriasis. These agents include anthralin, (dihydroxyantraline), azarabine, colchicine, fluorouracil, methotrexate, methoxsalen (8-methoxypsoralen), resorcinol, retinoids (e.g. retinoic acid), corticosteroids (e.g. clobetasol propionate, triamcinolone- acetonide and the like), cyclosporin, lipoxygenase inhibitors, cyclooxygenase inhibitors, leukotriene synthesis inhibitors, odocloxyhydroxyquinoline, salicylic acid, vitamin D, dapsone, somatostatin, sulfur, tars, zinc oxide, ultraviolet light treatment UVA or UVB) and PUVA treatment. The renin inhibitor and the other psoriasis treatment agent may be administered as part of the same composition or separately, which is described is merely illustrative of the invention and is not intended to limit the invention. It is intended that variations and changes which are obvious to those skilled in the art are included within the scope and nature of the invention which are defined in the appended claims.

Claims (7)

72500 4805-PO-01-R-I-V I. N. D. I. C. A. O. A process for the preparation of a pharmaceutical composition for the treatment of psoriasis, characterized in that a pharmaceutical carrier is combined with a renin inhibitor, said dosage unit comprising 0.001 to 10 mg / kg body weight. A process for the preparation of a pharmaceutical composition comprising the combination of a pharmaceutical carrier with a renin inhibitor of the formula: in which is hydrogen, lower alkyl, arylalkyl, -OR4 or R4 is hydrogen, lower alkyl or aminoalkyl, -NR4 R4, and R4 is independently selected from alkylamino, carboxyalkyl, alkoxycarbonylalkyl, (amino) carboxyalkyl, (amino (N-protected) carboxyalkyl, (alkylamino) carboxyalkyl, (N-protected) alkynyl) carboxyalkyl, (dialkylamino) carboxyalkyl, (amino) alkoxycarbonylalkyl, (amino (N-protected)) alkoxycarbonylalkyl, (alkylamino) alkoxycarbonylalkyl, (N-protected) alkylamino) alkoxycarbonylalkyl, (dialkylamino) alkoxycarbonylalkyls or Af is Wherein R6 is lower alkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino (alkyl) amino, (dihydroxyalkyl) (alkyl) amino, aminoalkyl, N-protected aminoalkyl, (C 1 -C 4) alkylamino, alkylaminoalkyl, (N-protected) aminoalkyl, di-aminoalkylamino, carboxyalkoxyalkyl, (alkoxycarbonyl) alkoxyalkyl, carboxyalkyl, carboxyalkylamino, alkoxycarbonylalkyl, alkoxycarbonylalkylamine, (amine) carboxyalkyl, (amino) carboxyalkylamino, carboxyalkylamino) (carboxylalkyl) carboxyalkylamino) (carboxylalkyl) carboxyalkylamino, (alkylamino) carboxyalkylamino, (alkylamino) carboxyalkylamino, (dialkylamino) carboxyalkyl "(dialkylamino) carboxyalkylamino" (amino) alkoxycarbonyl alkoxycarbonylalkylamino (N-protected) alkoxycarbonylalkylamino (alkylamino) alkoxycarbonylalkylamino (alkylamino) alkoxycarbonylalkylamino, alkylamino (alkylamino) Alkylcarbonylalkyl, (dialkylamino) alkoxycarbonylalkylamino, aminocycloalkyl, aminoalkylamino, dialkylaminoalkyl (alkyl) amino, arylalkylamino, arylalkyl (alkyl) amino, (polyalkoxy) alkyl, amino, di- (alkoxyalkyl) amino, di- (hydroxyalkyl) amino, di - ((polyalkoxy) alkyl) amino, polyalkoxy, ( polyalkoxy) alkyl, (heterocyclic) alkyl or a substituted or unsubstituted heterocycle, the saturated hetero-cyclic being unsubstituted, mono-substituted or di-substituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or lower alkyl and heterocycles do not are unsubstituted or mono-substituted with hydroxy, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or lower alkyl; W f is -CONH OR CHOH; U | ' R 2 is lower alkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl) methyl (2-naphthyl) methyl, ( (Alpha, alpha,) -dimethylbenzyl, 1-benzyloxyethyl, phenylethyl, phenoxy, thiophenoxy or anilines provided that, when it is fanoxy, thiophenoxy or anilino, is CH2 or CHOH or Af is hydrogen? (lower alkenyl), lower alkenyl, (alkoxy) alkoxy) lower alkyl, (thioalkoxy) alkyl, benzoyl or methyl substituted by a heterocyclic ring; R R1 is lower alkyl, cycloalkyl or benzyl; R5 is vinyl, formyl, hydroxymethyl or hydrogen; is hydrogen or lower alkyl; and R6 are independently selected from OH and NH2, and R8 is hydrogen, lower alkyl, vinyl or arylalkyl, or a pharmaceutically acceptable salt, ester or prodrug thereof, 3. A process according to claim 1, wherein the renin inhibitor is a compound of formula Wherein A 1 is (I) R 5 'C (O) -CH 2) w' '' wherein 1) W &quot; is 0 to 4 and 2) P5i is i) hydroxy (ii) alkoxy iii) thioalkoxy, iv) amino or v) amino substituted (II) alkylsulfonyl, (aryl) sulfonyl or (heterocyclic) sulfonyl; (III) aryl, arylalkyl, heterocyclic or (heterocyclic) alkyls, or (IV) R90i or R90i is a straight or branched C1 to C4 carbon chain substituted by a substituent selected from ) carboxy, 2) alkoxycarbonyl, "104" "72500 4805.Pfâ- 01 3) alkylsulfonyl, 4) aryl, 5) arylsulfonyl, 6) heterocyclic or 7) (heterocyclic) sulfonyl); (IV) arylalkoxyalkyl, (IX) arylthioalkoxyalkyl, (VI) aryloxyalkyl, (VI) aryloxyalkyl, (VI) aryloxyalkyl, a carbon chain of C1 to C3, lin®3 · 1 &quot; or branched alkyl substituted by a substituent selected from 1) alkoxy, 2) thioalkoxy, 3) aryl and 4) heterocyclyl (I) CH 2, (II) CHOH, (III) s, (VII) 8 (O), (VIII) so2, (IX) H (O) or (X) - P (O) -; (VI) (VII) (VII) cycloalkylalkyl, cycloalkenylalkyl, alkoxyalkyl, thioalkoxyalkyl (VIII) ( alkoxyalkoxy) alkyl, (IX) hydroxyalkyl, (X) - (CH2) eeNHR121 wherein 1) and e is 1 to 3 and R12i is 1) hydrogen, ii) lower alkyl or iii) a protecting group of N (XI) ) arylalkyl or (heterocyclic) alkyl; and Ti is R41 -nh and OH in which is (I) (II) (III) (IV) lower alkyl, cycloalkylalkyl cycloalkenylalkyl or arylalkyl; and Di is (I) Γ &gt; Η73, wherein R733; is lower alkyl, (II) &quot; wherein: (i) is (i) i) iii) iv) V) S or NH; O or S; O, wherein Rg é is lower alkyl, C CH ,H?, or. R18-j is a) hydrogen, b) lower alkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g) alkylamino; and 4. A process as claimed in claim 1, wherein the renin inhibitor is the excipient. A process according to claim 1 wherein the renin inhibitor is 2 (S) - (1 (S) - (4 "'- (methoxymethoxy) piperidin-1-yl) carbonyl) -2- (S) -hydroxy-2 (S) -isopropylhexanamide or a pharmaceutically acceptable salt thereof, may be prepared by reacting the compound of formula salt, ester or prodrug pharmaceutically acceptable. (III) is absent, is CH2 or is RR -): wherein R19 is hydrogen or lower alkyl, with the proviso that when G1 is NR19, then R1 is lower alkyl or hydroxyalkyl (III) in which 1) II is 0 or 2) R 21i is i) NH, ii) 0, iii) S or iv) "107" (Iv) a substituted methylene group or a pharmaceutically acceptable salt, ester or prodrug thereof; A process according to claim 1, characterized in that the renin inhibitor is 2- (S) -2-benzyl-3- (1-methylpiperidino) -4-ylsulfonyl) propionyl- (L) (2S, 3R, 4S) -2-Amino-1-Cyclohexyl-3,4-dihydroxy-6-methyl-heptylamide, or a salt, ester or pharmaceutically acceptable prodrug- A process according to claim 1, characterized in that the renin inhibitor is N- (4-morpholinylsulfonyl) (L) -phonylalanyl- (L) - (2-amino-4-thiazolyl) (2S, 3S, 4S) -2-Amino-1-Cyclohexyl-3,4-dihydroxy-6-methyl-heptane or a pharmaceutically acceptable salt, ester or prodrug thereof , 991 By ABBOTT LABORATORIES - 0 OFFICIAL AGENT ~