AU651390B2 - Novel cholecystokinin antagonists, their preparation and therapeutic use - Google Patents

Description

OPI DATE 30/03/92 AOJP DATE 14/05/92 APPLN. ID 87492 91 PCT NUMBER PCT/IS91/06180 INTERNA1 A i i'REATY(PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/04045 A61K 37/02, C07K 5/08, 5/10 Al (43) International Publication Date: 19 March 1992 (19.03.92) (21) International Application Number: PCT/US91/06180 (74) Agents: ANDERSON, Elizabeth, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, MI 48105 (22) International Filing DIte: 29 August 1991 (29.08.91) (US) et al.

Priority data: (81) Designated States: AT (European patent), AU, BE (Euro- 576,628 31 August 1990 (31.08.90) US pean patent), CA, CH (European patent), DE (Euro- 726,655 12 July 1991 (12.07.91) US pean patent), DK (European patent), ES (European patent), FI, FR (European patent), GB (European patent), GR (European pitent), IT (European patent), JP, KR, (71) Applicant: WARNER-LAMBERT COMPANY [US/US]; LU (European patent), NL (European patent), NO, SE 2800 Plymouth Road, Ann Arbor, MI 48105 (European patent).

(72) Inventors: HORWELL, David, Christopher 8 West Hill, Foxton, Cambridge KLEINSCHROTH, JOrgen Published Ricarda-Huch-Str. 11, D-7819 Denzlingen REES, With international search report.

David, Charles 33 Norwich Street, Cambridge CB2 2JB RICHARDSON, Reginald, Stewart 9 Rockall Close, Haverhill, Suffolk CB9 OLV ROARK, Wil- liam, Howard 2810 Gladstone Avenue, Ann Arbor, MI 48104 ROBERTS, Edward Wilow Tree Cottage, High Street, Ditton Green, Wood Ditton, Newmarket .7 CB8 9SQ ROTH, Bruce, David 6089 White Swan A Lane, Ann Arbor, MI 48108 TRIVEDI, Bharat, Kalidas 21515 Green Hill Road, Apt. 160, Farmington Hills, MI 48335 HOLMES, Ann 4641 Wylie Road, Dexter, MI 48130 PADIA, Janak, Khimchand 3566 Greenbrier Blvd., Apt. 393-B, Ann Arbor, Ml 48105 (US).

(54)Title: NOVEL CHOLECYSTOKININ ANTAGONISTS, THEIR PREPARATION AND THERAPEUTIC USE (57) Abstract Novel cholecystokinin antagonists useful as agents in the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as antipsychotics are disclosed. Further, the compounds are antianxiety agents and antiulcer agents.

They are agents useful for preventing the response to the withdrawal from chronic treatment with use of nicotine, diazepam, alcohol, cocaine, coffee, or opioids. The compounds of the invention are also useful in treating and/or preventing panic. Also disclosed are pharmaceutical compositions and methods of treatment using the antagonists as well as processes for preparing them and novel intermediates useful in their preparation. An additional feature of the invention is the use of the subject compounds in diagnostic compositions.

A

i NOVEL CHOLECYSTOKININ ANTAGONISTS, THEIR PREPARATION AND THERAPEUTIC USE BACKGROUND OF THE INVENTION Agents acting at central cholecystokinin (CCK) rectntors may induce satiety (Schick, Yaksh, and Go, Requlatorv Peptides 14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughes, and Pitta.tay, Neuropharmacolor 26:289-300, 1987), and as anticonvulsants (MacVicar, Kerrin, and Davison, Brain Research 406:130-135, 1987).

Reduced levels of CCK-peptides have been found ii the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak ax.t Bloom, Brain Research 288:199-211, 1983). It has been proposed that changes in the activity of CCK neurones projecting to the nucleus accumbens may play a role in 15 schizophrenic processes by influencing dopaminergic function (Totterdell and Smith, Neuroscience 19:181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, 20 Tanzer, and Ettenberg, Pharmacolovy, Biochemistry and Behaviour 30:309-317, 1988; Schneider, Allpert and Iversen, Peptides 4:749-753, 1983). It may therefore be expected that agents modifying CCK receptor activity he i File: 16173.80 SHELSTON WATERS CLARENCE STREET, SYDNEY, AUSTRALIA lcl II r' i: 1, WO 92/04045 11 ICT/US91/06180 -2-

I

may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's disease.

CCK and gastrin peptides share a common carboxy terminal pentapeptide sequence and CCK peptides can bind to the gastrin receptor of the stomach mucosa and elicit acid secretion in many species including human (Konurek, Gastrointestinal Hormones, Ch. 23, pp 529- 564, 1980, ed. G. B. J. Glass, Raven Press, NY).

Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gastrin receptor and this would also be of value for conditions involving excessive acid secretion.

CCK and gastrin peptides have trophic effects cn the pancreas and various tissues of the gastrointestinal tract (Johnson, ibid., pp 507-527), actions which are associated with increased DNA and RNA synthesis. Moreover, gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp 729- 739), and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend, and Thompson, Cancer Research 46:1612, 1986; Smith, J. P., Gastroenteroloqg 95:15421 1988). Antagonists of CCK/gastrin receptors could therefore be of therapeutic value as antitumor agents.

The CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems.

Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl-terminus fragments of this peptide the L R^ is a cyclo or polycycloalkyl hydrocarbon or mono- or polyheterocyclic moiety wherein the hetero /2 I I WO 92/04045 PCT/US91/06130 -3octapeptide CCK26-33 and the tetrapeptide CCK30-33) J. Dockray, Br. Med. Bull. 38(3):253-258, 1982).

The various CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions and other behavioral effects.

(Cholecystokinin: Isolation, Structure and Functions, G. B. J. Glass, Ed., Raven Press, New York, 1980, pp 169-221; J. E. Morley, Life Sciences 27:355-368, 1980; Cholecvstokinin in the Nervous System, J. de Belleroche and G. J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp 110-127.) The high concentratio: of CCK peptides in many brain areas also indicate major brain functions for these peptides Dockray, Br. Med. Bull.

38(3):253-258, 1982). The most abundant form of brain CCK found is CCK26-33, although small quantities of CCK30-33 exist (Rehfeld and Gotterman, J. Neurochem.

32:1339-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473, 1979).

Currently available appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as thyroxine), or in some other 30 manner (such as the biguanides), or act by exerting a central effect on appetite or satiety.

Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence serotonergic pathways (for example, fenfluramine).

/3 -4 Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.

CCK is known to be present in some cortical interneurones which also contain gamma-aminobutyric acid (GABA)(H. Demeulemeester et al, J. Neuroscience 8:988-1000, 1988). Agents that modify GABA action may have utility as anxiolytic or hypnotic agents (S.C.

Harvey, The Pharmacological Basis of Therapeutics (7th Ed.) 1985, pp 339-371, MacMillan). Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities. The role of CCK in anxiety is disclosed in TIPS 11:271-273, 1990.

SUMMARY OF THE INVENTION The invention relates to novel compounds of the formula R2 1+

R

1

-A-E-(C

2 m-C-(CH 2 q-(CHR 3

-(CHR

4

-(C

2

R

1 2 )u-(CHR 13 -Ar I 1 (CR'R) Ar 2 1 20 "and the pharmaceutically acceptable salts thereof wherein 1 2 3 4 5 6 1 2 1 3 2 0 SR,R,R,R,R,R,R R ,R 1 2 A, X, Y, E, Ar Ar n, m, p, q, r, s, t, u, and v are as defined hereinbelow.

EL -ec-i

'S

-CONH-,

I iI in-i-na 5 In PCT publications W092/04025, W092/04322, W092/04038, W092/04320 and W092/04348, the disclosures of which are incorporated herein by reference, CCK antagonists are disclosed.

In like manner, the present invention relates to a pharmaceutical composition containing an effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.

The compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behaviour, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility.

Compounds of the invention are also useful as analgesics, and they potentiate the effect of morphine.

They can be used as an adjunct to morphine and other 20 opioids in the treatment of severe pain such as cancer pain, and reduce the dosage of morphine required in the ~treatment of pain where morphine is contraindicated.

An additional use for compounds of the invention is that a suitable radiolabeled isotope gives an agent suitable for treatment of gastrin dependent tumors such as those found in colonic cancers. 1-125 radiolabeled compounds of the invention can also be used as diagnostic agents by localization of gastrin WO 92/04045 PCr/US91/06180 -6and CCK-B receptors in peripheral and central tissue.

The invention further relates to a method of appetite suppression in mammals which comprises admiLnistering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition for reducing gastric acid secretion containing an effective amount of a compound of formula I in combination with a pharmaceutwically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.

The invention also relates to a method for reducing gastric acid secretion in mammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage !orm, effective for reducing anxiety.

The invention also relates to a method for reducing anxiety in mammals which comprises administering an amount effective for anxiety reduction of the composition described above to a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating gastrointestinal ulcers.

The invention further relates to a method for treating gastrointestinal ulcers in mammals which~ WO 92/04045 PCT/US91/06180 -7comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.

The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating psychosis, schizophrenia.

The invention further relates to a method for treating psychosis in mammals which comprises administering an amount effective for treating psychoses of a composition as described above to a mammal in need of such treatment.

The invention also relates to pharmaceutical compositions effective for stimulating or blocking CCK or gastrin receptors, for altering the activity of brain neurons, for schizophrenia, for treating disorders of the extrapyramidal motor system, for blocking the trophic and growth stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.

The invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment for abuse of drugs or alcohol.

The invention further relates to a method for treating the withdrawal response produced by withdrawal from chronic treatment or withdrawal from abuse of drugs or alcohol. Such drugs include benzodiazepines, especially diazepam, cocaine, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the invention.

The invention also relates to a pharmaceutical composition containing an effective amount of a 8 compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating and/or preventing panic.

The invention also relates to a method for treating and/or preventing panic in mammals which comprises administering an amount effective for panic treatment and/or prevention of the composition described above to a mammal in need of such treatment.

The invention further relates to the use of the compounds of formula I to prepare pharmaceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above.

The invention further provides processes for the preparation of compounds of formula I.

The invention further provides novel intermediates useful in the preparation of compounds of formula I and also provides processes for the preparation of the intermediates.

DETAILED DESCRIPTION 20 The compounds of the present invention are i represented by the formula

R

2

(CH

2 C 2 )p q-(CHR 3

,-(CHR

4

-(CR

2 0

R

l 2

-(CHR

1 3 -A1r I

(CR

S

R

6 Ar 2 or a pharmaceutically acceptable salt thereof wherein:

LL-

l t 9 S9 R is a cyclo or polycycloalkyl hydrocarbon or mono- or polyheterocyclic moiety wherein the hetero atom(s) can be N, 0, and/or S, of from 3 to 12 carbon atoms with from 0 to 4 substituents each independently selected from a straight or branched alkyl of from 1 to 6 carbon atoms, halogen, CN, OR*, SR*, CO 2

CF

3 6 or (CH 2 OR5 wherein R 5 and R 6 are each independently hydrogen or a straight or branched alkyl of from 1 to 6 carbon atoms or R is (PhCH 2 2 N (I'll

Q]

i, tj t r o 0, Mej j 1 i i 1 r io k ul

I',

0 3

C

orQ~j~) mn r st, IU, ar-. v~ aeac 4deppenden. an 1= 4nzscer o:f frcm 0 to m- h rvsc that a, r and. S are aot all I when p, u and v are all 0 except when- X is not CONP. 9or A-2 Is not (CH 2) aCONEa- -SON-0 CO-, or -HEC=c:-EcCNE- whe-rein a is as 20 above,

Q*

A 4S a bond, 0, -z, -S-z,

CY

11 0 -(CH 2 )n-OC-Z provided that n is not 0, SCO- Z, -0-(CI*I 2 )n C0-Zi

-HC=CHCO-Z,

wherein Z is a bond, oxygen, sulphur, or -NR*wherein R* is as defined above; E is a bond, an amino acid residue, -(CH.3.r- -(CHR 3) r'.(CHR 4)S-

-NHCO-,

-OCO-,

-coo-, -CH 2 N (R -CH 2 0-, 2'

-CH=CS-,

3

-C-NR

-so 2 NR.3 -NR 3so 2

-NHCONH-

i -12-

S

S

N-N

N-0

X"~

N

4

N-N

N

N

wherein r and s are independently as de:Fned above and R3 and R are as defined belcw; R2 and R20 are each indenendentl hydroen, a straight or branched alk-yl of from 1 to 6 carbon atcms, -C=CH 21 -CZ, (cH 2 C H CH 2 (cH 2 C=-CH 7r (C -(CH 5 6 2 )nCO R* 2 NR R wherein n, R*, R 5 and R are ab defined above, and Ar and Ax 2 are as defined below; X and Y are each independently:

-CONK-,

9 -CON9 -HC0-,

-OCO-,

-coo-,

-CH

2

N(R

3

C

i I L~I 13

-CH

2

S-,

-OCH

2

-SCH

2

-H=CH-,

S

3

-C-NR

S

II

-NR 3-C- 3

-SO

2

NR

3 -NR SO 2

-NHCONH-,

-CH(OR*)CH2- 2 -COCH 2 -CH 2 Co-, -NR3CH2- N-0 25 'N

N-N

N

I or

N-N

N

14 wherein Q is 0, S, or NRP9; R and R 4 are each independently the same as RP2 or (CH 2)n wherein n' is an integer of from 0 to 3 or R 3is -CH 2 COCH=CC 2H B is abond, -OCO (CH 2 n' -o (OH 2 n-I -NHCO (CH -CONH(CH 2 )n-I

-NHCOCH=CH-,

-COO(CH 2 )11-, -CO (OH 2 n'- -SO(C -S (OH 2

NHCO-C=C-,

H H

NHOO-O-O-,

CONH-C=C-, or R 7 15

HH

I I

R

7

R

8 wherein R? and R8 are each independently selected from hydrogen and r2 or together form a ring (CH 2 )m wherein m is an integer of from 1 to D is -COOR*,

-CH

2

OOR*,

2 -CHR OR*,

-CH

2

SR*I

-CHR

2

SR*,

-CONR R5 6

-CN,

-NR R

-OH,

and acid replacements selected from tetrazole; 0 joA RIO R 0 i H *R10 is OH, NH 2

CH

3 or C1 I IHOMS 0 0" 1 k-P0 3

H

2 .000 101,2,4 oxadiazole :cnr]N-N n 9 n% RII is CN, C02H, OZ CF3 N H 14 N N*pN H HH

HH

NINH PhS 0 2 NH C0-k H0 .114)

F

3 CONHCOA

CF

3

SO

2 NHCO- N

C

H H 2

NS

2 -A ,0 0 3

L

MI

HO

SO-b( H0 NH (0Ob wherein b is an integer of frcm 0 to 2, wherein 20 R, P 5 adP 6 ae as defi4ned above; R 9 is or a straight or branched alky of from cne to si.x carbon atoms, -(CE 2 2 V, (CH 2 r,OAr (CH 2 n~rlI (CH 2 YR-R 6 wherein n, R*, R 5 and R 6 are as dej-fined above or taken from 3 and Ar 1 iss as defined below;

P.

1 2 and R 2 3 are each indeuendently hydrogen or taken together f orm a double bond, or are-(CA2n D as defined above; and Ar 1 I and Ar 2 are each iinde-cendently a monocyclic unsubstituted or substituted carbocyclic aromatic moiety, a polycyclic unsubstituted or substi tuted carbocyclic aromatic moiety, a monocyclic unsubstituted or substituted heterocyclic aromatic moiety, a polycyclic unsubstituted or substituted heterocyclic aromatic moiety, a monocyclic unsubstituted or substituted carboaromatic moiety, a polycyclic unsubstituted or substituted carboaromatic moiety, a monocy.clic 16la unsubstituted or substituted heteroaromatic moiety, or a polycycli4c unsubstituted or substituted heteroaromatic moiety; or a compound selected from: 5,13-dioxa-2,8-diazatetradec-10-enoic acid, 3- (1H-indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7-phenyl-, tricycloC3.3.l.1 3 7 ldec-2-yl ester, 5, 13-dioxa-2, 8-diazatetradecanoic acid, 3- (IT.I-indol-3-ylmethvl) -3-methyl-4, 9, 12-trioxo-7-phenryl-, tricyclocr 1.1 3 7 dec-2-y. ester, 6,12-dioxa-2,4,8-triazatridec-9-enoic acid, 3- (1E-indol-3-yl)ethyll -3-methyl-7,ll-dioxo-5-phenyl-, tricyclo[3.3.1.1 3 7 )dec-2-yl ester, glycine, N- IN- ta-methyl-N- £(tricyclo[3.3.1.1 3, 7 1 is dec-2-yloxy) carbonyl] -D-tryptoohy1I -D-phenylalanyl] or 2,4-heptadienoic acid, 6- I£3-(1H-indol-3-yl) carbonyll amino] propyll amino] -7-phenyl, with the proviso that when R 1is cycloalky. or polycycloalkyl; A-E is (CH 2 )n CONHi -SO 2 NH, -SON., -NHCONH, (CH 2 )n OCONH~,-SCON1Ii-0(CH 2 )n CONH,

HC=CHCONH;

m 0; R2is other than hydrogen;

(CR

5 R 6 )n is CH 2 p is 0; 0 0 X CNTIT, or CNR 9 t 0 and two of r, S, u, v 1,or

I

16b 0 0 Y CNH, or CNR 9 q 0, r and s are 0, t 1, and u, v 1 2 then Ar cannot be 3 *I Preferred Ar 1 is substituted phenyl, fused aryl, heterocycle, fused heterocycle, or perhydroaryl.

Preferred Arl is 2 or 3-thienyl, 2 or 3-furanyl, 2, 3 or 4-pyridinyl or an unsubstituted or substituted benzene ring wherein El and F are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH 2

OCF

3

NHCOCH

2

CH

2O H, or CH 2

CH

2 CO H.

Preferred cycloalkyl or polycycloalkyl substituents have from six to ten carbon atoms.

Preferred compounds of the instant invention are those wherein cycloalkyl is a substituted or unsubstituted and wherein polycycloalkyl is selected from x- Z wherein W, X, Y and Z are each independently hydrogen, a 16 straight or branched alkyl of from one to six carbon atoms, CF, R R -(CH 2 )nCO 2 or CN, F, C1, Br, OR*, SR*, wherein R* is hydrogen or a straight or branched alkyl of from one to six carbon atoms and R and R 6 are as defined above and n is an integer of from 1 to 3.

Preferred mono- or polyheterocyclic moieties wherein the heteroatom can be N, 0, and/or mono- and polycyclic hydrocarbons include compounds wherein e* Ic- 4-r

-/I

I

4077% I i 3c or

II

I

18 Other preferred compounds of the instant invention are those wherein

R

1 is 2-adamantyl or 1-(S)-2-endobornyl; A is -NHCO-, -OCO-, -SO 2 or -CH 2

CO-;

R

2 is -CH 3

-CH

2

CO

2

CH

3 or -CH 2

C=CH;

R

3 is -(CH 2 or H; and 4

R

4 is -(CH 2 or H.

More preferred compounds of the instant invention are those wherein R is 2-adamantyl or 1-(S)-2-endobornyl,

O

II

A is R is -CH 3 3 R is H, -CH 2 OH, -CH20COCH 2

CH

2 C02H, -CH20OCOCH=CHC02H, -CH 2 CO 2H, -CH2SCH 2 C0 2

H,

-CH

2

SCH

2

CH

2 CO 2

H,

-CH

2

NHCOCH

2 H2CH 2

CO

2 H, or

-CH

2

NHCOCH=CHCO

2 H and

R

4 is H, -NHCOCH 2

CH

2

CO

2 H configuration) or

-NHCOCH=CHCO

2 H configuration).

The D and the L configurations are possible at the chiral centers and are included in the scope of the invention: 1. Preferred is when R 2 is -CH 3

[D

configuration; 2. Preferred is when R 3 is 2

CH

2 C02H or -CH 2

NHCOCH

2

CH

2 CO2H i- -18awith the ED] configuration at the Trp carbon atom and the EL] configuration at the Phe---carbon atom; and 3. Preferred is when R 4 is -HOH2 CH2 O 2 H[ED] configuration or NHCOCH=CHCO 2HED] configuration with the ED] configuration at the Trp carbon atom.

Most preferred compounds of the instant invention are: Carbamic acid, E2- [El-(hydroxymethyl) -2-phenylethyl] amino] (H-indol-3-ylmethyl) ethyl]-, tricycloE3.3.1 3 7 ]dec-2-yl ester, -19- Carbamic acid, (hydroxymethyl) -2phenyl ethyl] amino] 1- (1H-indol1-3 -ylmethyl1) ethyl] tricyclo[3.3.1.1 3 7 ]dec-2-yl ester, Tricyclo dec-2-yl [1-hydroxymethyl) -2-phenylethyl] carbonyl] amino] (lH-indol-3yl) ethyl] carbamate, Carbamic acid, [2-[:(2-hydroxy-2-phenylethyl) amino] -1-(lH-indol-3-ylmethyl) -1-methylethyl] tricyclo[3.3.1.1 3 7 ]dec-2-yl ester (hydroxy center is RS, other center is R), Carbamic acid, (hydroxymethyl) -2-phenylethyl] amino] (H-in'dol-3-ylmethyl) -1-methylethyl] tricyclo[3.3.l.1 3 7 ]dec-2-yl ester, 4methylbenzenesulfonate f(1:1) (salt), Benzenepropanol,B- (11-indol-3-yl) -2- [tricyclo 71 dec-2-yloxy) carbonyl] amino] propyl]amino]-, acetate (ester), methylbenzenesulfonate (salt), Carbamic acid, [acetyl [1-(hydroxymethyl) -2phenylethyllamino)-l- (lH-indol-3-ylmethyl) -1-methyl]ethyl]-, tricyclo[3.3.1.1 3 7 3dec-2-yl ester, 13-Dioxo-2, 8-diazatetradec-10-enoic acid, 3- (lH-indol-3-ylmethvl) -3-methyl-4, 9, 12-trioxo-7phenyl-, tricyclo[3.3.l.1 3 ,7]dec-2-yl ester, [sR,3Dixo 2 ,8-diazatetradecanoic acid, 3- (lH indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7-phenyl-, tricyclo[3.3.1.1 3 7 ]dec-2-yl ester, 2-, Carbamic acid, [1-(1H-indol-3-ylmethyl)-l-methyl- 2-:(l-oxo--4-phenylbutyl) amino) ethyl]-, tricyclo]3.3.1.1 3 7 ]dec-2-y1 ester Carbamic acid, (benzoylamino) (H-indol-3ylmethyl) -1-methylethyl]-, tricyclo 1 3 7 ]dec-2-yl ester, WO 92/04045 PCFr/US. x/06180 Carbamic acid, (1H-indol-3-ylmethyl) -1-methyl- 2-f (1-oxo-3-phenylpropyl) amino] ethyl]-, tricyclo[3.3.l.1 3 7 )dec-2-yl ester, Carbamic acid, (lHi-indol-3-ylmeth'.yl) -1-methyl- 2-f (2-phenylacetyl) axinolethyl)-, tricyclof3.3.l.1 3 7 3dec-2-yl ester, Carbamic acid, [2-f (hydroxymethyl) -2phenylethyl] amino] -3-oxopropyl] amino (lH-indol-3ylmethyl) -l-methyl-2-oxoethy-]-, Carbamic acid, (lH-indol-3-ylmethyl) -2-f [3- [1-(hydroxymethyl) -2-phenylethyl] amino) -3oxopropyl) amino] -1-methyl-2-oxoethyll tricyclo- [3.3.1.1 3 7 3dec-2-y. ester, D-Phenylalaninamide, cx-methyl-Nf (tricyclo[3.3 .1.1 3 7 3dec-2-yloxy%,carbonyll-Dtryptophyl-B-alanyl-, L-Phenylalaninamide, C-methyl-N- (tricyclo[3.3.l.1 3 7 3dec-2-yloxy)carbonyl]-Dtryptophyl-h-alanyl-, L-Phenylalaninamide, a-methyl-N- (tricyclo 3. 1. 13,'7dec-2-yloxy) carbonyl3-Ltryptophyl-IB-alanyl-, D-Phenylalaninamide, a-methyl-N- [tricyclo 1. dec-2-yloxy) carbonyl]3 -Ltryptophyl-B-alanyl-, 12-Oxo-2, 5, 9-triazatridecanoic acid, 3- (lH-indol- 3-ylmethyl) -3-methyl-4, B, l-trioxo-10- (phenylmethyl) tricyclo[3.3.l.1 3 7 ]dec-2-yl ester, 1-, L-Phenylalanine, N-[fN- fcX-methyl-Nf(tricyclo [3.3.1.1 3 7 dec-2-yloxy) carbonyl3-Dtryptophyl] -f-alanyl] phenylmethy. ester, Propanoic acid, 2-f [3-f (lH-indol-3-yl) -2methyl-1-oxo-2-[ [(tricyclo[3. 3.l.1 3 7 ]dec-2yloxy) carbonyl] amino] propyl] amino) -1-oxopropyl] amino]-3-phenyl-, phenylmethyl ester, WO 92/04045 WO 9204045PCT/S9 1/06180 -21- D-Phenylalanine, N-[N-[a~y-methyl-N- ((tricyclo 1. 1 3 7 J]dec-2-vyJoxy) carbonylj]-Dtryptophy.)-13-alanyl] L-Phenylalanine, N- [a-methyl-Nf(tricyclof(3.3.1.1 3 7 ]Jdec-2-yJloxy) carbonyl] -Dtryptophyl] B-alanyl) L-Phenylalanine, N-EN- [a-methyl-N- (tricyclo 3 7 J]dec-2-yloxy) carbonyl J-Ltryptophyl) -1-alanyl] Benzenepropanoic acid, a-f [3-f [3-f (1H-indol-3yl) -2-methyl-1-oxo-2- f (tricyclo 3. 3. 1 13, 7 J] dec-2yloxy) carbony.)amino] propyl] amino) -l-oxopropyl) Glycine, N-[2-methyl-N-f (tricyclof3.3.1.l 3 ,,]dec- 2-yloxy) carbonyl] -D-tryptophyl]-, phenylmethyl ester, Carbamic acid, (1E-indol-3-ylmethyl) dioxo-1- (2-phenylethyl) -3-pryrrolidinyl] tricyclo[3.3.l.1 3 7 ]dec-2-yl ester,()- Carb.±mic acid, (1H-imidazol-4-ylmethyl) -1methyl-2-oxo-2-f (2-phenylethyl) aminolethyl]-, 1,1dimethylethy. ester,(±- [(2-phenylethyl) amino] carbonyl~propyl) tricyclof3.3.l.1 3 7 Jdec-2-yl ester,()- Carbamic acid, [1-f f[l-hydroxymethyl) -2phenylethyl] amino] carbonyl) (lH-indol-3-yl) -1methyipropyl]-, tricyclo l 3 7 dec-2-yl ester (hydroxymethyl center is S, other center is RS), 12-Oxa-2, 5, 1-triazatetradec-lO-enoic acid, 3-f[2- (1H-indol-3-yl) ethyl)-3-methyl-4,5,12-trioxo-7phenyl-, tricyclo[3.3.1.1 3 7 jdec-2-yl ester [TPUP center is R/S mixture, other center is R], L-Phenylalaninamide, N-f 1-dimethylethoxy) carbonyl] -a-methyl) -L-tryptophyl] -L-methionyl-L-axaspartyl-, WO 92/04045 PCT/US91/06180 -22- Glycine, N-[2-methyl-N-[(tricyclo[3.3..11 3 7 dec- 2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-, Carbamic acid, (hydroxymethyl) 2phenylethyl]amino]carbonyl]-2- (lH-indol-3-yl)propyl]-, tricyclo[3.3.1.1 3 7dec-2-yl ester (hydroxymethyl center S, other centers RS), 2,4-Heptadienoic acid, 6-[[3-(lH-indol-3-yl)-2methyl-l-oxo-2-[[(tricyclo[3.3.1.1 3 7 ]dec-2-yloxy)carbonyl]amino]propyl]amino]-7-phenyl-, and Glycine, N-[2-methyl-N-[(tricyclo[3.3.1.1 3 7 ]dec- 2-yloxy)carbonyl]-D-tryptophyl]-, phenylmethyl ester.

Table I, below, illustrates representative compounds of the invention. The numbers on the left-hand column in Table I correspond to the compound numbers given above. All of the compounds shown in Table I have their stereochemical configurations shown.

In addition to the compounds shown in Table I, the compounds of the present invention include compounds of formula I wherein the indole moiety is a 2-indolyl.

The compounds of the invention include solvates and hydrates and pharmaceutically acceptable salts of the compounds of formula I.

i i j,4

I

TABLE I 1+ +f

,CR

5 Ar2 Ex.

R

No.

A E m Rt 2 OCOHH Null 0 H OCONH NuH ItH OCOHi Null 0 H X q R 3 NH 1 CH 2 0H r R 4 3 y t Ft 20

R

1 2

R

1 3 u v Ar 1 P15 R0 n Ar 2 1 H I Hull 0 Null Null H 0 1 Ph H H 1 1 Nit 1 CHOH 1 It 1 Null 0 Null Null H 0 1 Ph H H 1 o 1 Ph H Ht 1 i-iis

N

0 NHico X.OHi I Ht 1 Null 0 Null Null It

U)-

TABLE I Ex.

R

No.

A E m R P X q R r

R

3 y t R 20 R 1 2

R

1 3 U v Ar 1

R

5

R

6 n Null 0 6OCONH Null 0 7OCONH Null 0 a OCONH Null 0 1 Null 1 H 1 OH 1 Null 0 Null Null H Me I NH 1 C1,014 1 Null 0 Null 0 Null Null H 0 1 Ph Ht H 1

N

o 1. Ph H H 1 52NH o 1 H H I 0 1 Ph H H 1 I 1 NH 1 1:' 2 OAc 1 Null 0 Null 0 Null Null N MAC I CHOH 1 Null 0 Null 0 Null Null Ht

I

I.

~UIJi1dJL I WV. if TABLE I U. v Ar 1

R

5 Iw' n ArC 2 R' A E m p2 P x q F3 r RO 3 y t R 2 0 k 12

R,

13 11~ 12&f 19 OCONH Null 0 Me OCOPIH Null 0 He OCONH Null 0 Me o coo 1 H 1 Ph I NHtCO 1 Ht coo I H I Ph 1 NHCO 1 H H 1 NHCO 1 H 1 Hf 1 Null 0 Null 0 1 1 COZMe H R Ht 1 1 C0 2 Me It H I jm Ht 0 1 Ph H H 1 OCONH Null 0 Me OH Nl 0 Me 1 NfICO 1 Null 0 Null 0 Null 0 Null Null Null 0 0 Ph H H 1 "If I I TABLE I Ex. R A E m R p P X q R3 r R s y t R 2 C RIZ R 13 u v Ar 1

R

5

R

6 n Ar 2 Ho.

21 OCONH Null 0 Me I NHCO H 1 Null 0 Null 0 Null 0 H 0 1 Ph H H 1 22 23 24 OCONH Null 0 Me OCONH Hull 0 Me CONH Hull 0 Me 1 NHCO 1 C0O4H 1 o CH 1 H 1 Hull 0 Hull 0 Hull Hull H 0 1 Ph H H 1 Ht 1 d 1 CONN 1 CH 2 ,01 H H 1 1 Ph H H 1 H 1 H 1 CONH 1 CH 2 OH Ht H I I Ph H H 1

NJH

I!

TABLE

I

4 RFO k12 13 v AI

R

5

R

6 n r AC H uU o M CO H 1 It H 1 CO NNI 1 COlIH 2 it H 1 1 Ph H H 1I H 1H I COVH I COVH2

H

26 OCOun. Hull 0 Me 27 OCOHH Null 0 Me 28 OCONH Null 0 Me o

CONHH

0

CONHH

H I

H

1 IH 1 CONH 1 CO131 2

H

1 H CONH 1 CO"H 2

H

H 1 1 Ph H 1 Ph H H 1 6

H

It H 1 5

H

C)

TABLE I Ex 1 A E m R2 P x q R 3 r R4 y t R 20 p.

1 2

R

1 3 u v Ar 1 R R n Ar 2 No.

29 OCONH Null 0 Me 0 NH I H H 1 CONH 1 CO 2 Me H H 1 1 Ph S S 1

I

31 32 OCONH Null 0 Me OCONH Null 0 Me 0 CONH 1 H 1 Ht 1 CONH 1 C010 2

H

0 CONH 1 H 1 H 1 CONH 1 CO 2 8Z Hf Ht 1 1 P h H H 1 i H 1 1 Ph H H 1 Nil I OCONH Null 0 He 0 CONH I H 1 H 1 CONH 1 CO 2 H H 1 1 P h H H TABLE I Ex. F A E m R2 P X q R 3 r R4 y t R20 R 1 2

R

13 u v Ar t

R

5 R' n Ar 2 No.

33 OCONH Null 0 Me 0 CON 1 H 1 N 1 CONH C0 2 H N N 1 Ph N It 1 it 34 OCONN Null 0 Me OCONH Null 0 Me 36 OCONH Null 0 Me

CONN

2 1 o CONH 1 o COH 1 N N 1 COH 1 CO 2 i It Nt 1 N 1 CONI I CON H N 1 Null 0 coo I Null 0 N 1 1 Ph N it 1 N 1 1 Ph N N 1 N 0 1 Ph N N I it

V

30 TABLE I FRy. R 1 A E m R2 P X q R 3 r R4 s y t Z~ 2 0 R12 R 1 3 u v Ar 1

R

5

R

6 n Ar 2 No.

37 E~ OCONII Null 0 1 CON 1 1 0 CON~II H 1 Null 0 1 Null 0 Null Null 0 Null Null 0 Null Null H 0 1 Ph H 0 1 Ph H H I H If 2 39 OCONII Null 0 Me fIJ0 Nit Null 0 Me 0 41 H1 0 Me 0 0 CONHI 1 C0 2 0O1 1 Null 0 Null 0 0-C-NIl 11 0 Null Null H 0 1 Ph H H 2 1 11 CO 2 Me H 11 2 0 NH 1 Ph I1- 1 If

-I

TABLE I Ex A E m R2 P x q R? r R4 y t R 2 0

R

1 2

R

1 3 u v Ar 1

R

5

R

6 n Ar 2 Ho.

43 OCONH Null 0 Me 0 COH 1 CftPh I Null 0 C0OH 1 Null Null H 0 1 C0 2 H H H 1

NH

44 OCONH Null 0 Null 0 46g OCONI Null 0 H 0 CON" 1 CHOH 1 Null 0 Null 0 Null Null H 0 1 Ph Me H 1 Me 0 CONH 1 CHPh 1 Null 0 Null 0

CA

2 H -1 1 CM 2 H H I COH INH Me 0 COH 1 H 1 Null 0 coo Null Null H 0 1 Ph H H 1 WO 92/ 04045 PCr/US9I/06180 -32- Other examples of compounds of the invention include: Tricyclo[3.3.11 3 7 dec-2-ylcarbamic acid, hydroxy-1- (hydroxymethyl) -2-phenylethyl) amino) (H- 3-ylmethyl) -1-methyl-2-oxoethyl ester, N- [2-Hydroxy-l- (hydroxymethyl) -2-phenylethyl) -amethyl-ax- (2-oxo-2-tricyclof3 13 7 dec-2-ylethoxy) 1H-indole-3-propanamide, N- f2-hydroxy-l- (hydroxymethyl) -2--phenylethyl) -a- (2-hydroxy-2-tricyclo [3.3.1.1 3 7 1]dec-2-ylethozy) -amethyl-1H-indole-3-propanamide, (Tricyclo [3.3.1.1 3 7 ]Jdec-2-ylamino) carbonyl] sulfamic acid, 2- ff2- (hydroxy-1- (hydroxymethyl) -2phenylethylJ amino) (H-indol-3-ylmethyl) -1-methyl-2oxoethy. ester, (Tricyclo [3 .3.1.13,7)j dec-2-ylamino) sulf onyl] carbamic acid, 2-f f2-hydroxy-1- (hydroxymethyl) -2phenylethyl) amino) (H-indol-3-ylmethyl) -l-methyl-2oxoethyl ester, ff2-f f2-Hydroxy-l- (hydroxymethyl) -2phenylethyl] amino) (1-indol-3-ylmethyl) -1-methyl-2oxoethoxyjsulfonyljcarbamic acid, tricyclof3.3.l.1 3 7 idec-2-yl ester, N- f2-Hydroxy-1- (hydroxymethyl) -2-phenylethyl) methyl-f f2-oxo-2-(tricyclo[3.3.1.1 3 7Jdec-2-ylamino)ethyl) amino) -1H-indole-3-propanamide, N- f2-Hydroxy-1- (hydroxymethyl) -2-phenylethyl) -amethyl-aX-f (tricyclo[3.3.1.1 3 7 ]dec-2-ylamino)acetyl)amino) -1H-indole-3-propanamide, N- f2-Hydroxy-l- (hydroxymethyl) -2-phenylethyl) -amethyl-aX-f (2-oxo-2-tricyclof3.3.1.1 3 7 ]dec-2ylethyl) amino) -lH-indole-3-propanamide, N- f2-Hydroxy-1- (hydroxymethyl) -2-phenylethyl] -a- (2-hydroxy-2-tricyclof[3.3.1.1 3 7 1 dec-2-ylethyl) amino) aX-methyl-1H-indole-3-propanamide, WO 92/04045 PC/US91/06180 -33- N- [2-Hydroxy-1- (hydroxymethyl) -2-phenylethyl] -amethyl-x-[ ((tricyclo[3.3.l.1 3 7 dec-2-ylamino) carbonyl] amino] sulfonyl] amino] -lH-indole-3propanamide, N- (2-Hydroxy-l- (hydroxymethyl) -2-phenylethyl) -amethyl--: [EL(tricyclo[3.3.1.1 3 7 )]dec-2-ylaninosulfonyl) amino] carbonyl) amino] -lH-indole-3propanamide, ([2-[[2-Hydroxy-l- (hydroxymethyl) -2-phenylethyl] amino] (H-indol-3-ylmethyl) -l-methyl-2oxoethyl] amino] sulfonyl] carbamic acid, tricyclo[3.3.1. 1 3 7 dec-2-yl ester, EL (2-Hydroxy-l- (hydroxymethyl) -2phenylethyl] amino) -1-(lH-indol-3-ylmethyl] -l-methyl-2oxoethyl] amino] carbonyl] sulfamic acid, tricyclo[3.3. 1.1 3 7 )]dec-2-yl ester, N- E2-Hydroxy-1- (hydroxymethyl) -2-phenylethyl] -amethyl-aX-[ (tricyclo (3.3.1.1 3 7 ]Idec-2-ylamino)sulfonyl] amino] -lH-indole-3-propanamide, N- (2-Hydroxy-l- (hvdroxymethyl) -2-phenylethyl] -2- (lH-indol-3-ylmethyl) -2-methyl-N' -(tricyclo- 1 3 7 ]dec-2-ylmethyl)propanediamide, N- (2-Hydroxy-l- (hydroxymethyl) -2-phenylethyl) -2dec-2-ylpropanediamide, N- (2-Hydroxy-l- (hydroxymethyl) -2-phenylethyl) -c- [imino (tricyclo 3. 3 1. dec-2-ylamino) methyl) amino) -a-methyl-lE-indole-3-propanamide, (Cyanoimino) (tricyclo[3.3.1 .1 3 7 ])dec-2ylamino) methyl) amino] (2-hydroxy-1- (hydroxymethyl) 2-phenylethyl] -a-methyl-lE-indole-3-propanamide, N- [2-Hydroxy-1- (hydroxymethyl) -2-phenylethyl] -cmethyl-aX-E[L (nitroimino) (tricyclo [3.3.1.1 3 7 )]dec-2ylamino) methyl) amino] -lH-indole-3-propanamide, 1- WO 92/04045 PCT/US91/06180 -34- [2-[[2-Hydroxy-1-(hydroxymethyl)-2phenylethyl amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2oxoethyl]phosphoramidic acid, phenyl tricyclot3.3.1.1 3 7 *]dec-2-yl ester, N-[2-[[2-Hydroxy-1-(hydroxymethyl)-2phenylethyl] amino) -1-(1H-indol-3-ylmethyl)-1-methyl-2oxoethyl]-N-tricyclo[3.3.1.13' 7dec-2ylphosphorodiamidic acid phenyl ester, Tricyclo[3.3.1. 13 7) dec-2-ylphosphoramidic acid, 2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl] amino]- 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl phenyl ester, and Phosphoric acid, 2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethylamino]-1-(1H-indol-3-ylmethyl)- 1-methyl-2-oxoethyl phenyl tricyclo 3.3.1. 13, ]dec-2-yl ester.

The compounds of the present invention can have multiple chiral centers including those designated in the above formula I by the symbol t, depending on their structures. For example, when R 3 taken with R 4 and R 1 2 taken with R 13 form double bonds to their carbon atoms, they are no longer chiral. In addition, centers of asymmetry may exist on the other substituents. In particular, the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers. The present invention contemplates all such forms of the compounds. The mixtures of diastereomers are typically obtained as a result of the reactions described more fully below.

Individual diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography or repet4tive recrystallizations. Individual enantiomers may be separated by convention method well known in the art 6. WO 92/04045 PCT/US9 1/06180 such as conversion to a salt with an optically active compound, followed by separation by chromatography or recrystallization and reconversion to the nonsalt form.

The compounds of the present invention can be formed by coupling individual substituted o-amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise "The Peptides, Analysis, Synthesis, Biology," by Gross and Meienhofer, Academic Press, New York.) The individual substituted alpha amino acid starting materials are generally known or, if not known, may be synthesized and, if desired, resolved by methods within the skill of the art.

(Synthesis of racemic [DL]-c-methyl tryptophan methyl ester see Brata, M. et al, J. Heterocvclic Chem., 1980, 17:829.) A key intermediate in the preparation of compounds of formula I is a compound of formula

H

II

ROCONH COOH Me wherein R is selected from R 1 9-fluorenylmethyl, Bz and other suitable N-blocking groups. These are useful as intermediates in the preparation of compounds of formula I. The compounds wherein R is 1adamantyl, 2-adamantyl, 4-protoadamantyl, exo-bornyl, enc4-bornyl, exo-norbornyl, endo-norbornyl, 2methylcyclohexyl, 2-chlorocyclohexyl, or camphoryl are novel and are preferred.

WO 92/04045 PCT/US91/06180 -36- The disclosure of U.S. 4,757,151 is hereby incorporated by reference. It describes the 9fluorenylmethyl blocking group.

Compounds of foriula II are prepared by reacting ROH III wherein R is as defined above, with phosgene or a phosgene substitute to produce a corresponding compound of formula ROCOC1 IV and then reacting a compound of formula IV with ocmethyltryptophan to produce the desired compound of formula II above.

Alternatively, a compound of formula IV can be reacted with an o-methyltryptophan methyl ester to produce

H

ROCONH COOMe Me which can be converted to a compound of formula II by known means such as hydrolysis with aqueous lithium hydroxide.

The schemes below illustrate procedures for preparing intermediates useful in producing final products of formula I.

L WO 92/04045 PCT/US91/06180 -37- Scheme I below illustrates preparative steps in the process of making compounds of the instant invention. Treatment of 2-adamantyloxycarbonyltryptophan 1 with N-methylmorpholine followed by isobutylchloroformate gave an intermediary mixed anhydride, this when mixed with N,O-dimethylhydroacylamine hydrochloride gave the hydroxamate 2 which yielded the aldehyde 3 on reduction with LiAlH 4 Reductive amination of 3 with S-phenylalaninol and NaCNBH 3 gave the amino methylene 4 (Example 1).

Example 2 (compound 5) was prepared in an exactly analogots manner. The intermediate mixed anhydride described above was treated with Me3SiN 3 to make the acid azide which then reacted with a-nitrobenzyl alcohol in the presence of DABCO to give the bis urethane 6. Hydrogenation using Pearlman's catalyst to the monourethane, and treatment of the amine with the HOBT ester of 2-(acetoxymethyl)-3-phenylpropionic acid gave the compound 7, Example 3 after saponification of the ester with LiOH in aqueous THF.

Example 4, compound 10 was prepared in three steps from 1. Here the mixed anhydride of 1 was treated with diazomethane to give the diazoketone 8. Reaction with HC1 to the chloro ketone followed by reaction with sodium diethylbenzyl malonate gave a diester which, upon saponification, decarboxylated to the acid Example 4.

I.

WO 92/04045 PCT/US91 /06 180 -38- SCHEME 2.

H

2-AdOCOHN COH

R

2-AdOCOHN' Me 2-AdOCOHH ,COCIN, 2-dCH1CCiC 8 9

H

2-AdOCOFNlCCH-.C P

HOO

\i- ii

HH

2-AdOCOHN NHcoocH-- 2-AdOCOH2; CHO H -H i

I

2 Example 3 A Ex.wnple 1 R P 5 -xa.,rple 2 -S ifi Example 4 KEY i) isobutyichiorofornate, N-methyl morpholine,

CH

3 0NH (CE 3 HCl; ii) LiAlR 4 i) S-phenylalaninol, NaCNBH 3 iv) isobutylchloroformate, N-nrthylmornholine, Me 3 SiN' 3 then 400 C then para-N0 2 -CgH 4

CH,

2 Ol, LDABCO; 2, 4-diazabicycloE[2. 2. 2)octane (DABCO) v) Pd (OH) 2

H

2 then

RS-HO

2 )CCCH (CH 2 Ph) CH 2 OAC; then LiOH, THF; vi) is obutyl chloro format e, N-nmethylmorpholine, CH 2

N

2 vii) HCl-dioxane; viii) HaI, NaDME, then sodiodiethylbenzyJlmalonate, then HaQH, then HC1, then heat.

WO 92/04045 PCT/US91/06180 -39- Scheme 2 Example 5, compound 12 was prepared by reduction of the amide in 11 using LiBH 4 and Me 3 SiCl.

Similarly, Example 6, compound 14 was prepared from 13. 14 was treated with acetylchloride to give Example 7, in the presence of base. The major product was compound 15a, which was hydrolyzed to Example 8, compound 16, on treatment with lithium hydroxide. The thiazoline 17, Example 9, was prepared by heating 13 with Lawesson's reagent.

~~1 PCr/US91/06180 WO 92/04045 SCHME 2

H

IN N 2-AdOCOHN MeCONH Ph iii

H

N

R OH 2-AdOCOHN CONI,,A Me R,S Ph i

H

N

2-AdOCOHN CO h HI 22 Example 16

H

N N 2-AdOCOHN4c P A e 11 H

S

2.2 Examrple 9

H

R OH 2-AdOCOHN MeCH 2 NN Ph 12 Example

H

2-AdOCOHN CR' 2 NH S M e m P h .UA Example 6

H

NN

2-AdOCOAM'N CH 2 N S P R

OR

2 11 Example 7 R 1 H, R 2 Ac 16 FxaMPle 6 R' 1 Ac, R 2 Hi

R

1 Ac, R 2 Ac i KEY i) LiBH 4 Me 3 SiC. ii) CH 3 COCI (E:axnP~e ,O CH 3 COC1, Et'N then LiOH (Example iii) Laweason's Reagent.

Ar WO 92/04045 PCT/US91/06180 -41- Scheme 3 shows the synthesis of examples of ester isosteres. Monomethylfumarate was condensed with R-phenylglycinol via its HOBT ester to give 18.

Further condensation of this with R- or S 2-Adoc-a-MeTrpOH in the presence of N,N'-carbonyldiimidazole gave Examples (compound 19) and 11 (compound 20), respectively. In an exactly analogous way Example 12 (compound 22) was made except using monomethyl succinate.

WO 92/04045 PCr/US91/06180 -42- SCHME 3 H01 2 Me NCO Cz" 44 H% 4 .Ph N NiHco COMe 2-AdOCONR M Coo

P

Example 101 2-Q Example 1.1 =R-conficuration -S-configuration H0C-,.C0 2 Me NHCO^'Nc2Me

H

N N R ~NHCO 0M 2-AdOCONH MeCOO

-RP

22 Example 12 1 KEY i) HOST, DCCI; ii) R-phenylalaninol; iii) R- or S~- 2-Adoc-clMeTrp-OH (Compound 23).

WO 92/04045 PCT/US9]/06180 -4 3- Scheme 4 Reduction of 23a to the primary alcohol 24 with LiAlH 4 followed by treatment with phenyll acet4ic acid and N,N.'-carbonyldiimidazole gave the ezter 'z~r 25, Example 13. Oxidation of 24 to the provided a very versatile intermediate.

26 was treated with Wittig reagents tc, (Example 14) and 29. Compound 219 wa, to 30, Example 16 by hydrolysis of th subsequent condensation with arn.iline h aldehyde 26 with the Grignard reagent magnesium bromide afforded the secondary (Example NJ H WO 92/04045 PCr/US91/06180 -44- SCHEE 4

R

2-AdOCOHN-1 CO,,Et Me

R

OH

2-AdOCOH Me

N

2-AdOCOHN CHO Me 2-AdOCOHN4

OCOCH

2 Ph Me Example 23

N

2-AdOCOHN

P

Me

V

22 Example 14 2.a Example KEY i) LiAJ.H 4 ii) PhCH 2 Co 2 H; carbonyldiimidazo2.e; iii) Tetravropylammonium perruthenate; iv) PhCH 2

CH

2 PPh 3 r-, NaH; v) PhCH 2

CH

2

CH

2 MgBr.

-I

WO 92/04045 PCT/US91/06180 Scheme 5 shows the synthetic routes to some examples of homologated a-methyltryptophans, and their reverse amide isosteres. *The mixed anhydride of 23b prepared by using isobutylchloroformate and N-methylmorpholine was treated with diazomethane to give the diazoketone 31, this as a solution in benzyl alcohol was treated with silver benzoate and Et 3 N to yield the homologated benzyl ester 32. Hydrogenation afforded the acid 33 which was condensed in the usual way via the pentafluorophenyl ester with S-phenyl alaninol to give 34 (Example 18).

The amide of 23b, 35 was prepared by bubbling ammonia gas through a solution of the pentafluorophenyl ester. This amide was reduced to the amine 36 with Me 3 SiCl/LiBH 4 in THF. This amine was subsequently reacted with phenyl acyl chlorides to give Examples 19-22 inclusive.

a

I

SCHEME R g If

N

R

ROCOIIN MeCOCIN 2

R

PROCOIlN MeCl 2 CO2C" 2 Ph

N

ROCONM CO 2 32 Example 17 R

IN

ROCOHN Me HCONI[2'h iv 1 2 C0 2 .11 2 Example 18 v.vii NN N ROCOHiN CoR 2 PCN C1N1 OCOEEN4 Ci jiN j ICo( Cll) Me Co"2Me "2'2Me 12p M Ekf 31a 0 J2 1 22 F- 2 21 -d 3 19 KEY Reagents: i) isobutyichiloroformiate, NMM, TIIF; ii) C11 2

N

2 1 EtOAc; iii) Ag -OCOL1h, Et 3 N, PhCII 2

OH-;

iv) l- 2 /pdIC; V) PEP, DCC, H 2 14CH (C11 2 011) C11 2 Ph, EtOAc; vi) PFP, DCC, EtOAc; vii) Nff3 THfF; viii) TI-IS--C1, LiB11V TfIl; ix) Ph (Cu 2 nCOC1, pyridine, EtOAc- WO 92/04045 PCT/US91/06180 -47- Scheme 6 illustrates the synthesis of a-methyltryptophyl---alanine derivatives. The 2-adamantyl oxycarbonyl a-methyltryptophan 23b (R isomer) or 38 (S isomer) is condensed with 8-alanine ester in the usual manner. This ester can then be hydrolyzed using standard methods aqueous LiOH, etc) to afford the carboxylic acid 41 or 42. Either of these two isomers may be condensed with an appropriate amine to give Examples 23 and 24 (using S-phenyl alaninol), Examples 25-28 inclusive (using R and S phenyl alaninamide) and.Examples 29-31 inclusive (using phenylalanine ester. Examples 29-31 and compound 52 may then be hydrolyzed using known methods to afford the products Examples 32-35 inclusive.

i L- vk, PCr/US9I /06 180 WO 92/04045 -48- ROCOHN C0 2

H

Me SCHEE 6 i ROCOHN CN ,-0M Me .u

R

H

N

I OH ROCOHN C*JN Me iii.

H

N

ROCOHN4 CONH,-% ,CO2H Me .A ExN' R S 23 Al S s 2 4 i v

CONH,

~Ph ROCOIN' CONHIN CONHI Me AExN* R R 25 -4-kR s 26 A7 S S 27 A.U S R 28

H

N

CO

2

R

ROCOHN CN _CN Me Al R R 29 R S S S 31 Si R C0 2

H

JPh .U R 32 .5 Rs 33 Ss 34 S K~EY Reaaents: i) PFP, DCC, B-Alanine Me ester, EtOAc; ii) LiCH, aq dioxan; iii) DCC, -2-amino-3-phenl-.propanoJ. EtOAc; iv) PFP, DCC, (R)-phenyla2.aninamide, EtOAc; v) PFP, DCC, (S)-phenylalanine benzyJ. ester, EtOAc or PFP, DCC, (R)-phenylaJlanine methyl ester, EtOAc; vi) H 2 Pd/C, EtOH.

WO 92/04045 PCT/US91/06180 -49- Scheme 7 describes synthetic steps towards derivatives of a-methyl tryptophyl glycine. As an illustration, 2-Adoc-a-methyltryptophan 23b may be easily condensed with glycine benzyl ester via the pentafluorophenyl ester of 23b. Hydrogenation of this ester using 10% palladium on carbon in an ethanol solution affords the carboxylic acid 58 in high yield.

Treatment of this acid with N,N'dicyclohexylcarbodiimide and pentafluorophenol gives the active ester which undergoes reaction with phenylalaninol readily to give the product compound 59, Example 37.

Ii -i WO 92/04045 PCr/US91/06180 SCHEME 7 2AdOCHN CO 2

H

i

H

Me

Z

2AdOCHN CONH 2

CH

2 Ph 572 Example 36 1 ii

H

I I 0O i Me -C 2AdOCHNX CONH CONH

P

RZ

H

N

2AdOCHN~ CO'P -"C 2

I'

R

.2Examtple 37 KErY Reaaerits: i) PFP, DCC, glycine benzyl ester hydrochloride, Et 3 N, EtOAc; ii) H 2 Pd/C, EtCH; iii) PFP, DCC, sE-phenylalaninol, EtOAc.

I

WO 92/04045 PC'/US91/06180 -51- Scheme 8 describes synthetic steps towards derivatives of a-methyltryptophyl-y-aminobutyric acids. As an illustration, the carboxylic acid 23b may be condensed with y-aminobutyric acid methyl ester to give 60, hydrolysis of this with LiOH affords acid 61. The product 62, Example 39 is produced when 61 is condense- with phenylalaninol via an active pentafluorophenyl ester.

z WO 92/04045 WO 9204045PCr/US9I/06180 -52- SCHEME 8

H

me 2AdOCHN C0 2

H

B

i

H

2AdOCHN CONH- 2 Me I ii

H

M e 2AdOCHN< CONH" C2 La-Exanple 39 KEY PReaaents: i) PFP, DCC, gaxruna-axiobutyric acid mnw: hylester hydrochloride, Et3N, E OAc; ii) LiCH, aq 1,4-dioxan; iii4) PFP, DCC, s-phenylalaninol, EtOAc.

i WO 92/04045 PCT/US91/06180 -53- Scheme 9 outlines the synthesis of a-substituted tryptophanylphenethylamides and their intramolecular cyclizations to compound 68, Example 40. The isonitrile 63 (prepared by the method described in Synthesis 465, 1990) in ethanol at -5 0 C was treated with ethanolic HC1 to give the amine 64. This underwent coupling with 2-adamantylchloroformate to the urethane 65. Hydrogenation of 65 using palladium on charcoal at 45 psi yielded the mono acid mono ester 66 which was condensed in the usual way to 2-phenethylamine giving 67. The product was formed by treatment of 67 with LiOH which abstracts the amide NH proton and cyclizes onto the ester group, liberating methoxide.

jJ\

I

WO 92/04045 PCT/US9 1/06180 -54- SCHEME 9 coocH 2 ph I.-COOCH3 Boc

COOCH

2 Ph

COOCH

3 H O o i iii

COOCH

2 Ph N. COOCH 3 I ii N NH

COCH

'N

COOCH

3 i

N

H 0 C ONH CH 2C H 2Ph NH COOCH3

()N

H 0 0

/-JQ

_6a Example REY Reaaents: i) EtOH'HCI, 67%; ii) 2-adaxnantyl-OCOCI, Et.,N, EtOAc, 58%; iii) Pd/H 2 EtOH, 88%; iv) H2NCH 2

CH

2 Ph, PFP, DCC, DMAP, EtOAc, 73%; v) LiOH(0.OlM), 0 0 C, THF/H 2 0, 79%.

L WO 92/04045 PCT/US91/06180 Scheme 10 outlines the synthetic steps towards -substituted tryptophan derivatives. Isopropylamine, when added to acetaldehyde and treated with KOH, gives 69 which reacts with indole in glacial acetic acid over 5 days to produce 70. The isopropylamino ethylidene 70 then reacts with 71 in the presence of NaOMe in hot toluene, yielding 72. Saponification and decarboxylation affords 74 as a mixture of separable diastereoisomers.

The amide 74 is dissolved in 4N sulphuric acid at reflux, then cooled to ambient temperature, and treated with 0.4N barium hydroxide until a pH of 8 is obtained, yielding the free amine 75 which reacts with 2-adamantyl chloroformate 75, yielding the urethane 77. This is then condensed with phenyl alaninol in the normal manner to give the product 78, Example 89.

^i WO 92/04045 PCr/US91/06180 -56- SCHiEME H3C

H

3 C -CHO

HC

HC -CH=-R

H

CH-

AcOH

H

CR

3

CH

3

NH-K

N

H

CH

3 COBz __C02Bz

H

ACNH-<

OB

CO,Bz

CH,

CO,R

CR

3 0 C02H N1,

CE

3 yC0 2

H

N IIC NHY 0

N

H

Cl 0 726

OR

Ph

OR

CR

3 0 N Ph

HH

Example 89 WO 92/04045 PCT/US91/06180 -57- GENERAL PROCESS FOR REACTION SCHEMES Scheme Cyano acetic esters or substituted derivatives 1 are alkylated with gramine and a base, NaOH in toluene, to compounds 2 in analogy to known methods.

Compounds 2 are hydrogenated catalytically with Raney nickel alloy to the amino esters 3, which are reacted with chloro- or fluoroformates to the carbamic acid esters 4. The esters 4 are hydrolyzed to the acids which are converted to activated esters, with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluorophenyl esters. The activated esters are reacted with an appropriate amine to an amide of formula 6. Further conversions at the amide part of the molecules are done in analogy to known methods.

ComDounds of aeneral formula R2 I a R -0-CO-NH- CH 2 CO -NH-(CHR 3 c--CHR 4 Ar Ia

CH

2

N

H

where R 1 1-adamantyl, 2-adamantyl, 1 (1S)-2-endo-bornyl

CH

2

R

2 H or Me c 0 or 1

H

H

R

3 H, -CH20H, -CH20-CO-(CH 2 2 C0 2

H

WO 92/04045 PCr/US9I /06180 -58- H, -NH-C0 2 -t-Bu,

-NH-CO-CH

2

-CH

2

-CO

2 Bz, -NH-CO-CH,-CH 2

O,

2

H

-NH-CO-CH-=CH--CO

2 Me, -NH-CO-CH=CH-CO 2

H

are prepared according to Synthetic Scheme WO 92/04045 PCT/US9I /06180 -59- SYNTHETIC SCHEME

R

2

R

Igramine IH 2 NC( -Ch-CO 2 Et NC;-C-COL; 2 Et analog to Raney-Ni4 J. Org. Chem.

1 1953, 18, 1440, 1447

N

2

H

R2

R

2 I R 1 -O-CO-ClI

H

2

N-CH

2

-UC-C

2 Et R 1

-O-CO-NH-CHU'

2

CO

2 Et N

HH

R

2 LiOH I 1

O-ON-C

2

CC

2 N 0

H

R

1 -0-CO -NH-CH 2 -C -CO-N4H-(CHR 3

-CHR

4

-C

6

H

Uf1 2 N S H

I

I- WO 92/04045 PCT/US91/06180 Scheme Compounds of general formula la, where R 2

R

3 and R 4 are H are also prepared according to Synthetic Scheme 15b. Cyano acetic esters 7 are reacted with appropriate amines to the cyano acetamides 8, which are condensed with indole-3-carboxaldehyde and catalytic amounts of piperidine to compounds 9 in analogy to known methods, and thereafter hydrogenated catalytically with Raney nickel alloy to the 3-indolylmethyl substituted 5-aminopropionamides Reaction with chloro- or fluoroformates yields the carbamic acid ester derivatives 11.

L WO 92/04045 WO 92/04045PCr/!US9 1/06180 -61- SYNTHETIC SCHEvM

NC-CH

2

-CO

2 Et C 6

H

5

-CH

2

(CH

2

),-NH

2 7

NC-CH

2

-CO-NH-(CH

2 c-CH 2

-C

6

H

analog to JACS 22Z, 2982 (1950)

H

2 indole-3 carboxaldehyde analog to J. Org. Chem.

19.53., 2-4, 1165 NC-C -CO-NH-(CH 2 c-CH 2 11 N -O

HI

Raney-Ni

H

2

N-CH

2 -CH-CO-NH- (CH 2 c-CH 2

C

6

H

H 1

R

1 -0-CO-NH-CH 2 -CH-CO-NH- (CH 2 c-CH 2

-C

6

H,

H

WO 92/04045 PCT/US91/06180 -62- Scheme Compounds of general formula Ia, where R 2 H or -CH 2

H

and R 3 and R 4 are H are also prepared according to Synthetic Scheme Cyano acetamides 8 are alkylated with gramine and a base, NaOH in toluene, to compounds 12 and 13, which are hydrogenated catalytically with Raney nickel alloy to the mono- or bis-(3-indolylmethyl) substituted 8-aminopropionamides 10 and 16. Reaction with chloro- or fluoroformates yields the carbamic acid ester derivatives 11 and 17.

-WMNWM

AL

pCT/Us9i /06 180 WO 92/04045 -63- SYNTHETIC SCHEME NC-CO 2 OoNH(CH2) C-4-CH gramidne ,,,CH-ooNHi(H2) -C

H

2 C6 OH1 2 l a

H

Raney-Ni-

H

2 N CH-OON4-(CH2) -HC6

OHM

2

N

H

OH

2 N OOO1O-0 NH(C2) C-CH2

O

6

+I

UrH 2

HH

iRaney-Ni

OH

2 HZOONH(2) -C~H2zO6H5 OH1 2 P'l O-~NHO-H2 1 -ONi

(OH

2 C-CH 2 -CGH5

OH

2

H

HI0coc

H

OH

2 I 7 6H ai--C-Ni-H2 C- C -H-(C2)C-HH WO 92/04045 PCT/US91/06180 -64- Scheme 16: Compounds of the general formula Ib,

R

2

I

R -CO-NH-CH 2 -C -CO-NH-(CHR 3 c--CHR 4 -Ar Ib

CH

2

H

where R 1

R

2

R

3

R

4 and c are as defined above are prepared according to Synthetic Scheme 16.

Aminoesters 3 are reacted with carboxylic acid chlorides to give the amides 18. The ester groups of compounds 18 are hydrolyzed with lithium hydroxide to the carboxylic acids 19, which are converted to activated esters, with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluorophenyl esters. The activated esters are reacted with an appropriate amine to an amide of formula 20. Further conversions at R 3 and R 4 are done in analogy to known methods.

c-_ WO 92/04045 WO 9204045Pcr/US91/06180 SYNTHETIC SCHEMEZ 16 R 1 -CO-C1

H

2 N -CH 2 -C -CO 2 Et

N

H

R

1 -CO -NH-CH7 -C -CO 2 Et 2CH

N

H

LiOH

R

1 -CO -NH--CH 2 C -COU 2

H

CR

2

N

H

K CO -NH--CR 2 -C O -NH-(CHP.

3 CHR -Ar 2CHa

N

H

IL

WO 92/04045 PCT/US91/06180 -66- Scheme 17 Compounds of general formula Ic, R:-0-CO--NH--C-CO-NH-(CHR3) c-CHR 4 -Ar I Ic

CH

H

are prepared to Synthetic Scheme 17.

1-(3'-indolyl)-butan-3-one is converted with potassium cyanide and ammonium carbonate in a Bucherer synthesis to the hydantoin 21, which is hydrolyzed with aqueous sodium hydroxide to the amino acid 22, which is consequently esterified with methanol and hydrogen chloride to 23. Compound 23 is reacted with chloroor fluoroformates to the carbamic acid esters 24. The ester groups of compounds 24 are hydrolyzed with lithium hydroxide to the carbuxylic acids Acids 25 are converted to activated esters, with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluoro phenyl esters. The activated esters are reacted with an appropriate amine to an amide of formula 26. Further conversions at R 3 or R 4 are done in analogy to known methods.

PCr/US91/06180 WO 92/04045 -67- SYNTHETIC SCHEME 17

CH-CH

2 -CO-CH3

H

Tetrahedron Lott. 1OP 2577 Me h 2

-CO

2

H

I MeOH,

(CH

2 2 Me RI -O-CO-NhCk

-O

2 Me

(CH

2 2 2- KcN

(NH

4 2 C0 3

CH

2

-CH

2 Me H H NaOH Me (Cli 2 2

H

IRI-o-co-C., Me LIOH R -0-CO-NHC1--C2n

(CH

2 2 Hi Me R -0OCO NHC CONH(CHR3 c -CHR 4

C

6

(CH

2 2

H

WO 92/04045 PCT/US91/06180 -68- Scheme 18 Compounds of general formula Id,

SR

2 R1-O-CO-NH-(CH 2 2

-C-CO-NH-(CHR

3 c-CHR 4

CH

2 Id I s

H

where R 1

R

3

R

4 and c are as defined above and R 2 Me are prepared according to Synthetic Scheme 18.

Diethyl methylmalonate 27 is alkylated with gramine and a base, NaOH in toluene, to compound 28 by known methods. The diester 28 is hydrolyzed with potassium hydroxide to the mono acid 29. The ester group of 29 is selectively reduced with borane methyl sulfide complex to compound 30, which is esterified with methanol and sulfuric acid to the methyl ester 31. The hydroxy compound 31 is reacted with p-toluene-sulfonyl chloride and pyridine to the tosylate 32. Nucleophilic substitution with potassium cyanide gives the cyanoester 33, which is hydrogenated catalytically with Raney nickel alloy to the amino ester 34. The amino ester 34 is reacted with chloroor fluoroformates to the carbamic acid esters 35. The ester groups of compounds 35 are hydrolyzed with lithium hydroxide to the carboxylic acids 36, which are converted to activated esters, with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluorophenyl esters. The activated esters are reacted with an appropriate amine to an amide of formula 37. Further conversions at R 3 and R 4 are done in analogy to known methods.

i _1_ WO 92/04045 PCT/US9 1/06180 -69- SYNTHETIC SCHEME 18 gramine EtO 2

-CH-O

2 E: analog to 3. Org. Chein 22) 1Mai, 22, 14 40, 144 7 n2 21 2

H

Me

CH

2 h

BH

3

V

2

S

HCH--CO

2

H

2z 2

H

CH30O H.

TsCI py ridine Me

H

2

N-CH

2

-CH

2 -C -O 2 Me tCH 2 R'-O-CO-Cl, Me I LiOH RI -O--CO-N1H-(h 2 2 -C -O, 2 Me

CH

2

H

R' -O0- CO NH-(C H 2 2

-CUC

2 Hr

H

R

2

H

EL

WO 92/04045 rCr/US91/0618o SYNTHETIC SCHEME 19 1,2 MG 4 OCONH/ CH2CO 2 H COtlHX CH 2

CO

2 CH2Ph

H

Me YNM CO CH 2 CONH -COM "'OCO CRCON 1 4 Ph Reagents: 1) N-Methylmnorpholine, iBuOCOC1; 2) CH 2

N

2 3) AgOCOPh, HOCH 2 Ph, AgOCH 2 Ph, 4) H 2 Pd/C; 5) DPP, DCCi, Phenyiglycine Methy2.ester; 6) CiOH PCT/US91/06180 WO 92/04045 -71- SYNTHETIC SCHEME 1 2N

H

~C0 2

H

H

Me OCONH' ON H,\\C2 CB N a Ph Reaaents: 1) DCCi, DMF; 2) Phenyiglycile,

DMF'

WO 92/04045 PCI'IUS91/0618o -72- SYNTHETIC SCHEME 21 Me -3-ind 2-Ad-OCON COQH

H

Me A-3-ind 2-AdOCON CONH~r~

H

1) LiBH 4 Me 3 SiCl

THF

2) pTsOH Ac Cl Me ~\3-ind 2-AdOCON

CH

2 N FP

HI

COCH

3 Me ~3-ind 2-AdOCON

CH

2 NH Ph H Tosvlate based on rec. SM) SEt 3

N

Me -3-ind 2-AdOCON

CH

2 N P

HI

C C ON~t LiOH 2-AdOCON

XCH

2 N _P H

I

CO

COOH

1d (81%) Ifw

I

WO 92/04045 PCr/US9I /06 180 -73- SYNTHETIC SCHEM 22 1) pentafluorophenol ,,3-ind 2-AdOCON RCO

H

;-ind 2) (S)-Phe-o.

2-AdOCON

H

NPh 0-

H

1 (71 1) t-BuMe 2 SiCl 2) Lawesson's Reagent I(21%) 3-ind

S

2-AdOCON

H

N Ph WO 92/04045 PCT/US9I /06180 -74- SYNTHETIC SCHEME 23 (See Examples 97-102)

HH

E)

0Na o CH o Hc e H 3 3 Gramine methiodide

CH

3 I C0 2 CH 2 CHi 3 N c C 2

CH

2

CH

3

H

.a OH /H 2 0

OH

3 0 I COOH N I Co 2

CH

2

CH

3

H

CH

3 t C

ONH

9NH2

A

IDCC

fHC1 /H 2 0 MeOH

CH

3 0 I CONH 1 N C0 2 CH 2

CH

CONH

DCC

H

H

WO 92/04045 PCTr/US9I/06180 SYNTHETIC SCHEME 23 (cont)

H

2 0

CH

3 CH 3

N

CO

2

CH

2

CH

3 o0C2H COOH

N

H

OH H 2 0 0 0 I COOH

NH

N

H

NH

2 0

DCC

0 NH @N 71 HO0 la1 NH 4

H

2 /HC1 1 0 WO 92/04045 PCT/US91/06180 -76- SYNTHETIC SCHEE 23 (cont)

NH

2

CH

3 C1H R NH Q NOC4 DCC NH Na o I H-CL fCH 2 C1 2 0 2) K 2 C0 3 0 N0H 0 R 0 NH NHCN H N HN N 0 H H 0 0 a, b WO 92/04045 PCT/US9I /06180 -77- SYNTHETIC SCHEME 23 (cant) 0 oA (OH 0

NH

a=C a a S

NH.

NH

2

F

N"H2

CH

3

H

DCC

HC1 (g)

CH

2 CI1 2

E)

OH/H

2 0 0

H.CH

3 NHI -'COOH 0 0i INEt 3 Q9 NH 2

C

a WO 92/04045 PCT/US91/06180 -78- The biological activity of compounds of the present invention was evaluated employing an initial screening test which rapidly and accurately measured the binding of the tested compound to known CCK receptor sites. Specific CCK receptors have been shown to exist in the central nervous system. (See Hays et al, Neuropeptides 1:53-62, 1980; and Satuer et al, Science 208:1155-1156, 1980).

In this screening test, the cerebral cortices taken from male CFLP mice weighing between 30-40 g were dissected on ice, weighed, and homogenized in volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0-40C).

The resulting suspension was centrifuged, the supernate was discarded, and the pellet was washed by resuspension in Tris-HCl buffer followed by recentrifugation. The final pellet was resuspended in volumes of 10 nM Hepes buffer (pH 7.2 at 23 0

C)

containing 130 mM NaCI, 4.7 nM KC1, 5 nM MgC12, 1 nM EDTA, 5 mg/mL bovine albumin, and bacitracin (0.25 mg/mL).

In saturation studies, cerebral cortical membranes were incubated at 230C for 120 minutes in a final volume of 500 p.L of Hepes incubation buffer (pH 7.2) together with 0.2-20 nM tritiatedpentagastrin (Amersham International, England).

In the displacement experiments, membranes were incubated with a single concentration (2 nM) of ligand, together with increasing concentrations (10 11 to 10- 14 M) of competitive test compound. In each case, the nonspecific binding was defined as that persisting in the presence of the unlabeled octapeptide CCK 26 33 6

M).

Following incubation, radioactivity bound to membranes was separated from that free in solution by rapid filtration through Whatman GF/B filters and I- WO 92/04045 PCT/US91/06180 -79washed three times with 4 mL of ice cold Tris-HCl buffer. Filters from samples incubated with tritiated-pentagastrin were placed in polyethylene vials wi'h 4 mL of scintillation cocktail, and the radioactivity was estimated by liquid scintillation spectrometry (efficiency 47-52%).

The specific binding to CCK receptor sites was defined as the total bound tritiated-pentagastrin minus the amount of tritiated-pentagastrin bound in the presence of 10- 6 octapeptide, CCK 26 -3 3 Saturation curves for specific tritiatedpentagastrin binding to mouse cortical membranes were analyzed by the methods of Scatchard (Ann. New York Acad. Sci. 51:660-672, 1949, and Hill Physiol.

40:IV-VIII, 1910), to provide estimates for the maximum number of binding sites 3 ma,) and the equilibrium dissociation constant (Ka).

In displacement experiments, inhibition curves were analyzed by either logit-log plots or the iterative curve fitting computer program ALLFIT (DeLean, Munson and Redbard, 1978) to provide estimates of the IC 50 and nH (apparent Hill coefficient) values). (IC 50 values were defined as the concentration of test compound required to produce 50% inhibition of specific binding.) The inhibition constant (Ki) of the test compound was then calculated according to the Cheng-Prusoff equation: ICo K ic 50 1 [L]/K where is the concentration of radiolabel and Ka is the equilibrium dissociation constant.

WO 92/04045 PCT/US91/06180 The K i values for several representative compounds of the present invention are present in Table III.

The utility of the compounds of the present invention as appetite suppressants is tested according to the procedure described hereinbelow.

In the Palatable Diet Feeding assay, adult male Hooded Lister rats weighing between 200-400 g are housed individually and trained to eat a palatable diet. This diet consists of Nestles sweetened condensed milk, powdered rat food and rat water which when blended together set to a firm consistency. Each rat is presented with 20-30 g of the palatable diet for 30 minutes per day during the light phase of the light-dark cycle over a training period of five days.

The intake of palatable diet is measured by weighing the food container before and after the access period (limits of accuracy 0.1 Care is taken to collect and correct for any spillage of the diet. Rats are given free access to pellet food and water except during the 30-minute test period.

After the training period, dose-response curves are constructed for CCK8 and several representative compounds of the present invention (n 8-10 rats per dose level). MPEs 0 values confidence limits) are obtained for the anorectic effects of these compounds and are shown in Table III.

In therapeutic use as appetite suppression Sagents, the compounds of the instant invention are administered to the patient at dosage levels of from about 200 to about 2800 mg per day.

Table III below shows the binding data for SPC /US9 0 WO 92/04045 PCT/US91/06180 WO 92/04045 I WO 92/04045 PCT/US91/06180 -81- TABLE III Binding Data on Cerebral Cortexes Taken From Male CFLP Mice Example Number 1 Isomer 1 Isomer 2 6 7 8 14 9 Binding to Central CCK Receptors Ki (nM) 11500 1230 780 220 200 374 318

NT

808 260 39 1120

NT

353 493 >100 704 540 560 103 92 1100 1200 910 1400 240 >104 550 22 800

NT

NT

17 NT Not tested 1-q~ 1~ WO 92/04045 PCT/US91/06180 -82- Male Hooded Lister rats (175-250 g) are housed individually and are caused to fast overnight (free access to water). They are anesthetized with urethane g/kg IP) and the trachea cannulated to aid spontaneous respiration. The stomach is perfused continuously using a modification of the original method of Ghosh Schild in "Continuous recording of acid secretion in the rat", Brit. J. Pharmac. 13:54- 61, 1956 as described by Parsons in "Quantitative studies of drug-induced gastric acid secretion".

(Ph.D. Thesis, University of London, 1969). The cavity of the stomach is perfused at a rate of 3 mL/min with 5.4% w/v glucose solution through both the esophageal and body cannula. The fluid is propelled by a roller pump (Gilson, Minipuls 2), through heating coils to bring its temperature to 37 loC. The perfusion fluid is collected by the fundic collecting funnel and passed to a pH electrode connected to a Jenway pH meter (PHM6). An output is taken from the pH meter to a Rikadenki chart recorder for the on-line recording of the pH of the gastric perfusate.

Pentagastrin is stored as a frozen aliquot and diluted to the required concentrations with sterile 0.9% w/v NaC1. Novel compounds are dissolved in sterile 0.9% w/v NaC1 on the day of the experiment.

Drugs are administered IV through a cannulated jugular vein as a bolus in a dose volume of 1 mL/kg washed in with 0.15 mL 0.9% w/v NaCl. Basal pH is allowed to stabilize before administration of compounds is begun.

Typically 30 minutes elapses between surgery and the first compound administration.

The compounds of the instant invention are also useful as antiulcer agents as discussed hereinbelow.

I i c 1~ WO 92/04045 PCT/US91/06180 -83- Aspirin-induced gastric damage is assessed in groups of 10 rats each.

All animals are made to fast for 24 hours before and during the experiment. Drug or vehicle is given 10 minutes before an oral dose of 1 mL of a suspension of aspirin in 0.5% carboxymethylcellulose

(CMC).

The animals are sacrificed 5 hours after aspirin administration and the stomachs removed and opened for examination.

Gastric damage is scored as follows: Score 1 Small hemorrhage 2 Large hemorrhage 3 Small ulcer 4 Large ulcer Perforated ulcer The specific dosages may, however, be varied depending upon the patient, the severity of the condition being treated, and the activity of the compound employed. Determination of optimum dosages is within the skill of the art.

The compounds of the instant invention are also useful as anxiolytic agents as described and discussed below. Anxiolytic activity is assessed in the light/dark exploration test in the mouse J. Jones, et al, Brit. J. Pharmac. 93:985-993, 1988).

The apparatus used is an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small area and a large area by a partition that extended 20 cm above the walls. There is a x 7.5 cm opening in the partition at floor level.

The small compartment is painted black and the large compartment white. The floor of each compartment is marked into 9 cm squares. The white compartment is i j WO 92/04045 PC/US91/06180 -84illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb. The laboratory is illuminated with red light.

All tests are performed between 13 hundred hours, 0 minutes and 18 hundred hours, 0 minutes. Each mouse is tested by placing it in the center of the white area and allowing it to explore the novel environment for five minutes. Its behavior is recorded on videotape and the behavioral analysis is performed subsequently from the recording. Five parameters are measured: the latency to entry into the dark compartment, the time spent in each area, the number of transitions between compartments, the number of lines crossed in each compartment, and the number of rears in each compartment.

In this test an increase in the time spent in the light area is a sensitive measure of, that is directly related to, the anxiolytic effects of several standard anxiolytic drugs. Drugs were dissolved in water or saline and administered either subcutaneously, intraperitoneally, or by mouth (PO) via a stomach needle.

The compounds of the instant invention are useful as antipsychotic agents and can be tested for their ability to reduce the effects of intra-accumbens amphetamine in the rat as described hereinafter.

Male Sprague Dawley (CD) Bradford strain rats are used. The rats are housed in groups of five at a temperature of 21 20C on a 12 hour light-dark cycle of lights-on between 07 hours 00 minutes and hours 00 minutes. Rats are fed CRM diet (Labsure) and allowed water ad libitum.

Rats are anesthetized with chloral hydrate (400 mg/kg SC) and placed in a Kopf stereotaxic frame.

WO 92/04045 PCT/US91/06180 -98-

J

WO 92/04045 PCT/USl/06180 Chronically indwelling guide cannulae (constructed of stainless steel tubing 0.65 mm diameter held bilaterally in Parspex holders) are implanted using standard stereotaxic techniques to terminate 3.5 mm above the center of the nucleus accumbens (Ant. 9.4, Vert. 0.0, Lat. 1.6) or 5.0 mm above the central nucleus of the amygdala (Ant. 5.8, Vert. -1.8, Lat. (atlas of De Groot, 1959). The guides are kept patent during a 14-day recovery period using stainless steel stylets, 0.3 mm diameter, which extended 0.5 mm beyond the guide tips.

Rats are manually restrained and the stylets removed. Intracerebral injection cannulae, 0.3 mm diameter, are inserted and drugs delivered in a volume of 0.5 ILL over 5 seconds (a further 55 seconds was allowed for deposition) from Hamilton syringes attached via polythene tubing to the injection units.

Animals Are used on a single occasion only.

Behavioral experiments are conducted between 07 hours 30 minutes and 21 hours 30 minutes in a quiet room maintained at 22 t 20C. Rats are taken from the holding room and allowed 1 hour to adapt to the new environment. Locomotor activity is assessed in individual screened Perspex cages (25 x 15 x 15 cm (high) (banked in groups of 30) each fitted with one photocell unit along the longer axis 3.5 cm from the side; this position has been found to minimize spurious activity counts due to, for example, preening and head movements when the animal is stationary.

Interruptions of the light beam are recorded every minutes. At this time animals are also observed for the presence of any nonspecific change in locomotor activity, sedation, prostration, stereotyped movements, that could interfere with the recording of locomotor activity.

L

WO 92/04045 PCT/US9g/06180 -86- The abilities of the compounds of the invention to inhibit the hyperactivity caused by the injection of amphetamine into the nucleus accumbens of the rat are measured.

An increase in locomotor activity followed the bilateral injection of amphetamine (20 gg) into the nucleus accumbens; peak hyperactivity (50 to 60 counts minutes 1) occurs 20 to 40 minutes after injection.

This test is known to be predictive of antipsychotic activity (Costall, Domeney Naylor Tyers, Brit. J. Pharmac. 92:881-894).

The compounds o: the instant invention prevent and treat the withdrawal response produced when chronic treatment by a drug is stopped or when alcohol abuse is stopped. These compounds are therefore useful as therapeutic agents in the treatment of chronic drug or alcohol abuse as discussed and described below.

The effect of the compounds of the instant invention is illustrated, for example, in the mouse "light/dark box" test wherein five animals are given nicotine, in a range of 0.1 to 100 mg/kg i.p. b.d. for 14 days. After a 24-hour withdrawal period, compound (20) is given at 1.0 mg/kg i.p. b.d. The increased time spent in the light area is a sensitive measure of the effect of compound (20) as an agent to treat withdrawal effects from nicotine.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid.

Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, -WIMMM-dftw WO 92/04045 PCT/US91/06180 -87or tablet disintegrating agents; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository preparations, a lowmelting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

The powders and tablets preferably contain 5% to about 70% of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

Preferred pharmaceutically acceptable salts are the N-methyl glucamine salt and sodium.

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, WO 92/04045 PCT/US91/06180 -88phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannata, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.

The term "preparation" is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or waterpropylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.

Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Preferably the pharmaceutical preparation is in unit dosage form. In such form, the preparation is

I

WO 92/04045 PCT/US91/06180 -89divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

EXAMPLES

EXAMPLE 1 Tricyclo r3.3.1.1 3 7 1 dec-2-vl (lH-indol-3-vlmethyl)-2-(methoxymethylamino)-2-oxoethvllcarbamate 121 To a solution of acid (859 mg, 2.25 mmol) in dichloromethane (8 mL) was added N-methylmorpholine (495 L, 4.50 mmol). The mixture was cooled to -15 0

C

(C0 2 /benzyl alcohol) and isobutylchloroformate (292 L, 2.25 mmol) was added. The mixture was stirred at -15°C for 15 minutes followed by the addition of NO-dimethylhydroxylemine hydrochloride (219 mg, 2.25 mmol). The reaction mixture was stirred at -15 0 C for 1 hour, then warmed to room temperature and stirred for a further 15 hours. The mixture was filtered and the filtrate washed sequentially with sodium hydrogen carbonate, water, 10% citric acid and brine, dried (MgS04) and evaporated to dryness. The crude material was purified by column chromatography to give hydroxamate (694 mg, 73%) as a white foam; m.p. 72-80 0 C. (Found: C, 67.4; H, 7.35; N, 9.8%.

C

2 4

H

3 1

N

3 0 4 requires C, 67.7; H, 7.3; N, [a] 2 0 (C 0.3, CHC13); (S-ISOMER) [a] 2 0 (C 0.3, CHC1 3 *max (film); 1 695 (CO urethane), 1 657 (CO amide) 741 cm 1 (disubstituted Ph); H (CHC13), 6 1 i c WO 92/04045 PCT/US91/06180 1.30-2.01 (14H, m, adamantyl), 2.99-3.24 (5H, m, indole CH 2

NCH

3 3.58 (3H, s, OCH 3 4.7 (1H, s, adamantyl 5.00 (1H, br d, CH (NHR)CON-), 5.36 (1H br d, urethane NH), 6.92-7.17 (3H, m, indole 7.27 (1H, d, J 8 Hz, indole 7.53 (1H, d, J 8 Hz, indole 7.99 (1H, s, indole NH).

Tricvclo 3.3.1.13 '7 dec-2-vl l-formyl-2- (H-indol- 3-vl)ethvl carbamate (3) Lithium aluminum hydride (45 mg, 1.2 mmol) was added portionwise over a period of 30 minutes to a solution of the hydroxamate (197 mg, 0.460 mmol) in THF (3 mL) at 0°C. The mixture was stirred for a further 30 minutes, then ether (30 mL) was added followed by an ice cold solution of 10% citric acid (40 mL). The mixture was stirred vigorously for minutes, then the layers were separated and the aqueous layer extracted with ether (5 x 10 mL). The ether extracts were combined and sequentially washed with saturated sodium hydrogen carbonate (25 mL), water (25 mL), 10% citric acid (25 mL), and brine mL), dried (Na 2

SO

4 and concentrated in vacuo to give aldehyde (140 mg, 83%) as a white foam; ,)ma (film) 1 725 sh (aldehyde C=O) and 1 693 cm i (urethane H (300 M Hz; CDC1 3 '01.47-2.13 (14H, m, adamantyl), 3.26 (2H, d of d, J 15 and 7 Hz, indCH 2 4.58 (1H, br d, CH(NHR)CHO), 4.84 (1H, s, adamantyl 6.98-7.26 (3H, 7.35 (1H, d, J 8 Hz, indole 7.60 (1H, br d, J 8 Hz, indole 8.24 (1H, br s, indole NH), 9.64 (1H, s, CHO).

WO 92/04045 PCT/US91/06180 -91- Tricyclo[3.3.1.1 3 7 1dec-2-vlS-(R)-2-K[1-(hydroxVmethyl)-2-phenvylethyllamino-1-(1H-indol- 3-ylmethyl)ethyllcarbamate Example 1 Sodium cyanoborohydride (37 mg, 0.59 mmol) was added pcrtionwise over a period of 15 minutes to a solution of aldehyde (136 mg, 0.370 mmol) and (S)-2-amino-3-phenyl propanol (61 mg, 0.40 mmol) in methanol-acetic acid (99:1) (5 mL). The mixture was stirred for 2 hours at room temperature then chilled (:ce bath). Saturated sodium hydrogen carbonate mL) was added with stirring, followed by ethyl acetate (45 mL). The organic layer was separated, washed with brine (5 mL), dried (Na 2

SO

4 and evaporated to dryness. The crude product was purified by column chromatography (Si02:dichloromethanemethanol (95:5) as eluant] to give amino alcohol (4) mg, 32%) as a beige foam; m.p. 59-61 0 C. (Found: C, 73.7; H, 7.8; N, C 31

H

3 9N 3 0 3 -0.2 H 2 0 requires C, 73.7; H, 7.9; N, Umax (film) 3 325 (OH), 1 690 (CO urethane), 1 496 i 266 1 148 740 and 701 cm- 1 (monosubstituted Ph); H (CDC1 3 8 1.31-2.04 (16H, m, adamantyl NH OH), 2.44-3.01 (7H, m, indCH 2

-CH

2 NH-, CH 2 Ph, NH-CH(CH 2 0H)CH 2 Ph), 3.21 (1H, dd, J 11 and 6 Hz, CH of CH 2 0H), 3.47 (1H, dd, J 11 and 4 Hz, CH of CH 2 0H), 3.97 (1H, m,

-CH

2

CH(NCO

2 R) CH 2 4.66 (1H, br d, urethane NH), 4.73 (1H, s, adamantyl 6.87 (1H, d, J 2 Hz, indole 6.96-7.24 (7H, m, indole 5,6-H Ph), 7.29 (1H, d, J 8Hz, indole 7.55 (1H, d, J 7 Hz, indole 7.97 (1H, brs, indole NH).

L

WO 92/04045 PCT/US9 1/06180 -92- EXAMPLE 2 Tricyclo[ .3.1.1 3 7 ]dec-2-vltS-(S)]-2--ttlihvdroxVmethyl) -2-phenylethyllamino] -l-(lH-indol-3-ylmethyl) ethyllcarbamate Example 2 Compound 5 (253 mg, 23%) was synthesized using the same procedure as that described above for compound White foam, m.p. 62-63 0 C. (Found: C, 73.3; H, 7.8; N, C 3 1

H

3 9

N

3 03*0.4 H 2 0 requires C, 73.2; H, 7.9; N, (film) 3 331 1 692 (CO urethane) 1 513 1360 1048 739 and 701 cm- 1 (monosubstituted Ph); H (CDCl 3 8 1.47-2.10 (16H, m, adamantyl NH OH), ').54-3.04 (7H, m, CH 2 indole, CH 2 NH, CH 2 Ph CH 2 CH (CH 2 OH) CH 9 ,Ph), 3.30 (lH, dd, 1 11 and 6 Hz, CH of CH 2 OH) 3.59 (1H, dd, J 11 and 4 Hz, CH of CHOH), 4.06 (lH, m,

-CH

2

CH(NHCO

2 R) CH 2 NH-) 4. 81 (2H, br s, adamantyl 2-H urethane NH), 6.86 (lH, brs, indole 7.06-7.32 (7H, m, indole 5,6-H Ph), 7.35 (lH, d, J 8 Hz, indole 7.59 (1H, d, J 8 Hz, indole 8.03 (lH, br s, indole NH) EXAMPLE 3 Tricyclo r3.3.1.1 3 7 ldec-2-yl-r2- (lH-indol-3-yvl) 1- F F F(4-nitrophenyl) methoxy] carbonvl] amino] ethylcarbamate (6) To a solution of acid (3.62 9.74 nunol) in anhydrous THF (36 inL) at -101C was :ied N-methylmorpholine (1.15 mL, 10.4 r .ol)I and n-isobutyl chloroformate (1.35 mL, 10.4 minol) This mixture was stirred for 20 minutes at -10 0 C then filtered.

Trimethylsilyl azide [Aldrich] (1.869 mL, 14.2 minol) was added to the filtrate and the resulting solution stirred at -10'C for 1 hour. The solvent was thlen removed in vacuo at 25'C and the residue partitioned between ethyl acetate (100 mL) and saturated sodium WO 92/04045 PCT/US9I/06180 -93hydrogen carbonate (100 mL). The layers were separated and the organic phase was washed with brine, dried (MgSO 4 and concentrated in vacuo at ?5 0 C, The residue was taken up in toluene (100 mL) and treated at 40 0 C until rearrangement to the isocyanate was complete. (IR: Vma. N 3 2139, m. NCO 2249 cm-1).

p-Nitrobenzylalcohol (2.20 g, 14.3 mmol) and DABCO (149 mg, 1.33 mmol) were added and the mixture left at 0 C for 15 hours. The solvent was removed in vacuo and the crude product purified by column chromatography tSiO 2 :ether-hexane as eluant) to give (2.12 g, 42%) as a yellow solid which was recrystallized from ether/hexane, m.p. 148-149 0 C. 1H NMR (300 m Hz), 81.39-2.03 (m 14H, adamantyl), 3.07 (brs, 12H, CH 2 ind H 2 0/HOD), 4.64 1H, adamantyl 5.14 2H, CH 2 Ph), 5.37 1H, C&

(NHCO,)-NHCO

2 6.90-7.29 4H, indole H-2, H-6, and NH), 7.34 1 8 Hz, 2H, H-subst. Ph), 7.46-7.62 3H, ind H-4, ind H-7, NH), 8.16 J 8 Hz, 2H, 4-subst. Ph), 10.61 1H, ind NH); IR (film): 2908 2855 (adamantyl), 1703 (br, CO urethane), 1520 (NO 2 1347 (NO 2 Anal. C 2 9

H

3 2

N

4 0 6 requires C, 65.40; H, 6.06; N, 10.52.

Found: C, 65.25; H, 6.03; N, 10.50.

Tricyclof3.3.1.1 3 7 ldec-2-vl i-r r 1-hvdroxvmethyL)- 2-Dhenvylethyllcabonyllaminol-2-(1H-indol-3-vl)ethyllcarbamate Comnound Example 3 The urethane (190 mg, 0.357 mmol) in ethyl acetate (36 mit) was hydrogenated over palladium hydroxide on carbon (Pearlman's catalyst) at 45 psi and 30 0 C for 1 hour. The mixture was filtered through celite to remove the catalyst into a flask containing f IPIIC- i- WO 92/04045 PCT/US91/06180 -94the HOBT ester of 2-(acetoxymethyl)-3-phenylpropionic acid [the latter was generated via the reaction of 2-(acetoxymethyl)-3-phenylpropionic acid (81 mg, 0.36 mmol) in ethyl acetate (5 mL) with 1-hydroxybenzotriazole (57.5 mg, 0.426 mmol) and DCCI (85.9 mg, 0.416 mmol) at 0°C for 30 minutes]. The resulting mixt'ure was stirred at room temperature for 18 hours. The solution was co:.centrated in vacuo, chilled (ice-bath), filtered, and evaporated to dryness. the residue was taken up in THF:MeOH:H 2 0 (6 mL), lithium hydroxide monohydrate (28 mg, 0.67 mmol) added, and the mixture stirred at room temperature for 18 hours. The reaction mixture was poured into 2N HC1 (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was washed with saturated NaC1, dried (MgSO 4 filtered, and evaporated to dryness. The crude product was purified by column chromatography [Si02: dichloromethanemethanol (95:5) as eluant] to given an approximately 50:50 mixture of diastereomeric alcohols (16 mg total, as yellow oils. Isomer I: TLC Rf 0.24

(CH

2 Cl 2 -MeOH 1 H NMR (300 M Hz): 51.43-2.04 (br m, 17H, adamantyl H 2 2.42 1H, NHCO, CH), 2.67-3.22 (br m, 5H, CH 2 ind CH 2 Ph OH), 3.67 (m, 2H, CH 2 OH), 4.78 1H, adamantyl 5.40 (brs, 1H), 5.58 (brs, 1H), 6.26 (brs, 1H, amide NH), 6.82 1H, ind 7.02-7.37 9H, Ph ind H-5, ind H-6, ind H-7, CHC13), 7.44 J 8 Hz, ind H-4), 8.16 1H, ind NH); IR (film): 3540-3140 (br, OH), 2910 2855 (adamantyl), 1695 (urethane Co), 1660 (amide CO); Isomer II: TLC Rf 0.19 [CH 2 C12-MeOH 1H NMR (300 M Hz): 61.47-2.08 17H, adamantyl H 2 2.42 1H, NHCO'CH), 2.61-2.97 (m, 3H, CH 2 OH), 3.19 J 7 Hz, CH 2 4.68 (brs, 2H,

CH

2 OH), 4.75 1H, adamantyl 5.18 (brs, 1H), i WO 92/04045 PCT/US91/06180 5.49 (brs, 1H), 6.30 (brs, 1H, amide NH), 6.96 1H, ind 7.02-7.30 9H, Ph ind H-5, ind H-6 CHC1 3 7.37 J 8 Hz, 1H, ind 7.57 J 8 Hz, 1H, ind 8.12 1H, ind NH); IR (film): 3520-3160 (br, OH), 2907 2855 (adamantyl), 1696 (urethane CO), 1660 (amide CO).

EXAMPLE 4 2-Adamantvloxycarbonvltrvptophandiazoketone (8) Preparation of diazomethane. CAUTION! DIAZOMETHANE IS HIGHLY TOXIC AND EXPLOSIVE (NO GROUND GLASS JOIP"" HANDLE WITH CARE IN A FUME HOOD.

n-METHYLNITROSUREA IS HIGHLY TOXIC AND CARCINOGENIC.

HANDLE IN A FUME HOOD USING A FULL FACE MASK AND

GLOVES.

A solution of 40% potassium hydroxide (4.5 mL, 32 mmol) was added dropwise to a suspension of N-methylnitrosurea (1.5 g, 15 mmol) in ether (25 mL), cooled in an ice-salt bath. After all the solid had dissolved (additional base is added if necessary), the ZO ethereal solution of diazomethane was dried over solid potassium hydroxide. This drying process was repeated twice more and the diazomethane used immediately.

To a solution of 2-adamantyloxycarbonyltryptophan (1.77 g, 4.61 mmol) in THF (25 mL) at 0°C was added N-methylmorpholine (557 ILL, 5.07 mmol) and isobutylchloroformate (658 p.L, 5.07 mmol). The mixture was stirred for 20 minutes at 0 C, then filtered. To the filtrate was added a solution of diaaomethane (10 mmoL) in ether (produced from N-methylnitrosurea (1.0 g, 10 mmol)). The resulting solution was stirred for 15 minutes at 0°C, then for hours at room temperature. The solvent was removed in vacuo and the residue taken up in ethyl acetate (100 mL). This solution was washed with water WO 92/04045 PCT/US91/06180 -96- (2 x 10 mL), 5% citric acid (2 x 10 mL), 1N NaHC03 mL), and brine (10 mL). It was dried (MgSO 4 and the solvent removed in vacuo. The crude product was purified by column chromatography [SiO 2 :hexane-ethyl acetate as eluant] to give diazoketone (8) (1.35 g, 72%) as a yellow foam, m.p. 72-75°C. v ma (CDC13 film) 2 109 (N 2 1 697 (CO) and 740 cm (disubstituted Ph); H (dg-acetone), 61.39-2.02 (14H, m, adamantyl), 3.13 (1H, dd, J 15 and 8 Hz, CH of CH 2 indole), 3.29 (1H, dd, J 15 and 5 Hz, CH of

CH

2 indole), 4.51 (1H, m, CH 2 CH(NHR)CO), 4.69 (1H, S, adamantyl 5.90 (1H, brs, CHN 2 6.41 (1H, s, NH CO); 7.01 (1H, t, J 7 Hz, indole 5 or 7.09 (1H, t, J, 7 Hz, indole 7.61 (1H, d, J 9 Hz, indole 10.05 (1H, brs, indole NH).

2-Adamantyloxvcarbonvltrvptophanyl Chloromethvl Ketone (9) Hydrochloric acid (11.1 mL of a 0.30 M solution in dioxane) was added dropwise with stirring to a solution of diazoketone (1.35 g, 3.32 mmol) in THF (100 mL) at 0°C. The reaction was monitored by infrared for the disappearance of the N 2 peak (2 109 cm 1 in the starting material. When all the diazoketone had gone (ca 60 minutes) the reaction mixture was quenched with saturated sodium hydrogen carbonate (20 mL). The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate (1090 mL). The layers were separated and the aqueous extracted further with ethyl acetate (2 x 100 mL). The combined ethyl acetate fraction was washed with brine (50 mL), dried (MgSO 4 and the solvent removed in vacuo. The crude product was recrystallized from ethyl acetate-hexane to give ;i7 X i 1--i_ WO 92/04045 PCT/US91/06180 -97chloroketone (1.29 g, m.p. 138-140 0

C.

(Found: C, 66.6; H, 6.7; Cl, 8.3; N, 6.9%.

C

2 3

H

2 7

CIN

2 0 3 requires C, 66,6; H, 6.6; Cl, 8.5; N, uma) (CDC13 film), 1 740 (CO a chloroketone), 1 698 (CO urethane), and 736 cm 1 (disubstituted Ph); H (CDC1 3 81.45-2.06 (14H, m, adamantyl), 3.27 (2H, m,

CH

2 ind), 3.96 (1H, d, J 16 Hz, CH of CH 2 Cl), 4.11 (1H, d, J 16 Hz, CH of CH 2 C1), 4.83 (2H, m, CH 2 CHCO and adamantyl 5.35 (1H, d, J 7 Hz, NH), 7.00 (1H, d, J 2 Hz, indole 7.14 (1H, t, 6 Hz, indole 5 or 7.22 (1H, t, J 6 Hz, indole 5 or 7.37 (1H, d, J 8 Hz, indole 7.61 (1H, d J 8 Hz, indole 8.20 (1H, s, indole NH).

a-r4-(1H-indole-3-vl)-2-oxo-3-F[(tricvclo[3.3.1.1 3 7 1dec-2-vloxy)carbonyl]aminolbutvllbenzene propanoic acid, Compound Example 4 Sodium iodide (Aldrich) (51 mg, 0.34 mmol) was added to a solution of chloroketone (126) (112 mg, 0.27 mmol) in anhydrous DME (5 mL) at room temperature. This mixture was stirred at room temperature for 15 minutes, then an aliquot (800 0.30 mmol) of an anion solution [generated by the reaction of sodium hydride (60% dispersion in oil) (88 mg, 2.2 mmol) in anhydrous DME (5 mL) with diethylbenzylmalonate (950 pL, 4.0 mmol) at room temperature] was added. The resulting solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo, the residue taken up in dichloromethane (50 mL), washed with brine, dried (MgSO 4 and evaporated under reduced pressure. The crude material was purified by column chromatography [Si02:hexane-ethyl acetate as eluant] to yield ketodiester (100 mg, m.p. 49-540C. (Found: C, 70.8; H, 7.2; N, C 37

H

44

N

2 0 7 requires C, 70.7; H, 0 ~1 WO 92/04045 PCT/US91/06180 -98- 7.05; N, Uma, (CH 2 C1 2 film) 1 728 cm- 1

H

(CDC1 3 61.42-2.08 (14H, m, adamantyl), 2.98 (1H, d, J 19 Hz), 3.18 (1H, dd, J 15 and 6 Hz, CH 2 ind), 3.24 (1H, dd, J 15, and 6 Hz), CH 2 ind), 3.34 (2H, s, CH 2 4.18 (4H, m, 2 x CH 2 4.62 (1H, m, CH 2 CH(CO)NH), 4.79 (1H, s, adamantyl 5.30 (1H, d, J 8 Hz, NH), 6.84 (2H, d, J 7 Hz, Ph 6.92 (1H, d, J 2 Hz, indole 7.07-7.25 (5H, m, indole 5, 6-H, Ph 3,4,5-H), 7.34 (1H, d, J 8 Hz, ind 7.62 (1H, d, J 8 Hz, indole 8.07 (1H, s, indole NH).

A solution of the keto diester (1.19 g: 1.89 mmol) in ethanol (5 mL), and 6N NaOH (946 5.67 mmol) was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue diluted with H 2 0 (10 mL). This aqueous solution was acidified to pH 2 with concentrated HC1, then extracted with ethyl acetate (3 x 50 mL). The organic extract was washed with saturated sodium chloride solution, dried (MgSO 4 and concentrated in vacuo. The residue was taken up in dioxane (30 mL) and refluxed for 18 hours. The solvent was removed in vacuo and the crude material purified by column chromatography [Si02: toluene-acetic acid as eluant] to give ketoacid (783 mg, 78%) as a yellow foam, m.p. 66-80 0 C. 1

H

NMR (300 m Hz): 71.

3 8 2 2 2 16H, adamantyl H 2 0), 2.55-3.25 (vbr m, 12H, CH 2 ind, CH 2 Ph CO, CH 2 CH

H

2 0/HoD), 4.26 1H, NHCHCO), 4.57 1H, adamantyl 6.95-7.37 10H, Ph ind 2-H, ind 5-H, ind 6H, ind 7-H NH), 7.49 J 8 Hz, 1H, ind 4-H), 10.58 1H, ind NH). IR (film): 3460-3200 (br, OH), /920 2856 (adamantyl) 1707 (br, ester ketone CO, acid CO, urethane CO) Anal. C 3 2

H

3 6

N

2 0 5 requires C, 72.70; H, 6.86; N, 5.30%. Found C, 73.18; H, 6.98; N, 5.05%.

i i i WO 92/04045 PCT/US91/06180 -99- EXAMPLE Tricyclof3.3.1.1 3 ,71dec-2-l fl-f (2-hydroxy-2-phenvlethyl)aminol-3-(1H-indol-3-vl)-2-methvlprop-2-vl)carbamate (12) This compound was prepared by a route similar to that used to make compound (14) (Example 6) except that compound(11) was used. Recovered 0.42 g m.p. 78-80 0 C; IR (neat) 2910, 1694 0 urethane) cm-1 N1M (CDC 3 8 8.1 (1H, br s, indole NH), 7.6 (1H, d, J 8 Hz, indole 7.4-7.1 (8H, m, Ph indole H-5, H-6, 7.0 (1H, m, indole 4.6 (3H, m, adamantane H-2 urethane NH CHOH), 2.6 (6H, m, 3 x CH 2 2.1-1.5 (15H, m, adamantane OH) 1.4 (3H, s, CH 3 [C]3 180 (CHC1 3 22*C, c FABMS (mn/e)502 anal C 3 1H 39 N30 3 0.5 H 2 0; requires C 72.91%, H 7.90%, N 8.23%; found: C 72.56%, H 7.84%, N 7.95%.

EXAMPLE 6 Tricyclof3.3.1.13 7 dec-2-vl[R-(R*,S*) 1-1- fl-(hvdroxvmethyl)-2-vhenvlethvll aminol -3-(1H-indol-3-yl)-2methylproo-2-vylcarbamate (14) To a solution of lithium borohydride (4 mL, 2M solution, 8 mmol) in dry tetrahydrofuran under nitrogen was added a solution of chlorotrimethylsilane (1.75 g, 16.0 mmol) in dry tetrahydrofuran (5 mi). A white ppt of lithium chloride was observed. After 2 minutes a solution of Compound (1 g, 2 mmol) in tetrahydrofuran (15 mL) was added slowly (over 3 to 4 minute period) and the reaction was stirred for 20 hours at ambient temperature. The reaction was treated cautiously with methanol (5 mL) and the volatiles were removed in vacuo (40 0 The residue was purified by flash chromatography on normal phase silica gel using hexane/ethyl acetate eluant (a WO 92/04045 PCT/US9]/06180 -100gradient elution technique was employed, ranging from hexane:20% ethyl acetate to 100% ethyl acetate).

Recovered 0.60 g starting material and 0.26 g (27%) desired product (14) as a white foam; IR (neat) 2900, 1694 (C 0 urethane) cm- 1 NMR (CDCl 3 8 8.1 (1H1, br s, indole NH), 7.6 (1Hi, d, g 8 Hz, indole 11-4), 7.4- 7.1 (8H1, in, Ph indole H1-5, IH-61 6.9 (lH, d, !Z 2 Hz, indole H1-2), 4.9 (1H, s, urethane NH), 4.8 (1H1, s, adamantane H1-2), 3.6-3.3 (2H1, mn, CH 2 3.1 (2H1, m, CE 2 -indole), 3.0-2.6 (5H1, mn, 2 x CH 2 1 X CH), 2.1-1.5 (15H1, m, adainantane 0OH), 1.25 (311, s, CE 3 A mono-4-toluenesulphonate salt was prepared by dissolving (14) (0.2 g, 0.4 mmol) and 4-toluenesulphonic acid ionohydrate (0.074 g, 0.40 minol) in acetone (10 mL) and subsequent removal of solvent in vacuo to give a white solid; in.p. 110-113 0 C. IR (neat) 2915, 1790 (C=O urethane) cra- 1 ra3D 200 (CHCl 3 23 0 C, c1l) k FAB MS 516 (mn+ H1); anal: C 32

E

4 jN 3 0 3 *C7 8 S0 3 *0-51 2

O

Requires: C, 67.22; H, 7.23; N, 6.03; S, 4.60.

Found: C, 67.23; H, 7.26; N, 5.84; S, 4.36.

EXAMPLE 7 rR- S) 1-5- 2- lEH-indol-3-vlmeth 2. tricy clor3.3.1.13,"71 dec-2-yloxycarbonyll aminolpropyll aminol benzeriepropanol acetate To a solution of (14) (0.05 g, 0.10 nunol) in dichioroinethane (10 mLs) at ambient temperature was 3) added acetyl chloride (0.10 inL, 1.4 mmxol) and the reactants were stirred for 1 hour, the volatiles were removed in vacuo (400C) and the residue purified by flash chromatography using 80% hexane 20% ethyl acetate as eluant. Recovered 0.024 g, of (88) as an amorphous white solid. IR (neat) 2910, 1739 (C 0 ester) 17 00 (C =0 urethane) cm-1 NYR (CDC1l 3 8 WO 92/040:5 PCT/US91/06180 -101- 8.2 (1H, s, indole NH), 7.6 (1H, d, J 8 Hz, indole H- 7.4-7.0 (8H, m, Ph indole H-5, H-6, 6.9 (1H, d, J 2 Hz, indole 5.1 (1H, s, urethane NH), 4.8 (1H, s, adamantane 3.9 (2H, d, J 4 Hz,

CH

2 0CO), 3.1 (2H, m, CH 2 -indole), 3.0-2.5 (4H, m, CH 2 Ph

CH

2 2.1-1.4 (17H, m, CH 3 CO adamantane), 1.3 (3H, s, CH 3 A mono-4-toluenesulphonate salt was prepared by dissolving (15) (0.02 g, 0.04 mmol) and 4-toluenesulphonic acid monohydrate (0.007 g, 0.04 mmol) in acetone (5 mL) and subsequent removal of solvent in vacuo to give a white solid, m.p. 98-101 0

C;

320 (CHC1 3 24°C, C FAB MS 558.5 anal: C 3 4

H

4 3

N

3 0 4

C

7

H

8 S0 3

OH

2 0 requires C 65.84%, H 7.14%, N 5.62%, S 4.29%. Found: C 65.48%, H 7.08%, N 5.53%, S 4.31%.

EXAMPLE 8 1- 3 -[acetvl 2- (H-indol-3-vlmethl) -2- L [tricvclo 3.31.1 3 7 dec-2-yloxycarbonvll amino]propvllamino]benzene propanol acetate To a solution of (14) (0.05 g, 0.10 mmol) in dichloromethane (10 mL) at ambient temperature was added triethylamine (1 mL, 7 mmol) followed by acetyl chloride (0.1 mL, 1.4 mmol) and the reactants stirred for 1 hour. The volatiles were removed in vacuo and the residue purified by flash chromatography using hexane:ethyl acetate as eluant. Recovered 0.043 g, of (88a) as an amorphous solid; IR (neat) 2920, 1740 (C 0 ester), 1709 (C 0 urethane), 1632 (C 0 amide) cm 1 WO 92/04045 PCT/US9I/06180 -102- Tricvclo[3.3.1.1 3 ~1e~~~R(*S)aeVd (hydroxvmethyl) -2-phenylethyll aiinol (lH-indol-:3vlmethyl) prop-2-Vlcarbamate (16) To a solution of <15a) (0.03 gj, 0.05 inmol,) in tetrahydrofuran (5 mIL) was added a solution of lithium hydroxide (0.1 g, 2.4 mmol) in water (5 mL) and the reactants stirred for 15 min. The reaction was then acidified with hydrochloric acid (2N aq) and the products extracted with ethyl acetate (50 The extract was dried (magnesium sulphate) and evaporated in vacuo The residue was purified by flash chromatography using hexane:ethyl acetate eluant.

Recovered 0.024 g of (89) as a white solid; m.p.

109-112-C, £CCJD 310 (22WC, CHiC1 3 c IR (neat) 2900, 1694 (C =0 urethane), 1621 (C =0 amide) cnf 1 NMR (CDCl 3 8 8. 1 (1H, s, indole NH) 7. (1H, d, j 8 Hz, indole 7.4-7.0 (8H, m, Ph indole H-5, H-6, 6.9 (1H, s, indole 5.3 (1H, br, urethane NH), 4.8 (1H, brr adamantane H-2), 4.4 (1H, s, OH), 3.9 (1H, d, J 12 Hz, one of CH 2

OH),

3.8-3.7 (2H, m, one of CH 2 0H one of CE 2 N) 3.5 (lE, m, CH), 3.4 (1H, d, J1 14 Hz, one of CH 2 indole), 3.3 (lE, d, J 13 Hz, one of CH 2 N) r 3. 1 (2H, d, J 8 Hz,

CH

2 Ph), 2.8 (1H, d, J 14 Hz, one of CH 2 -indole), (3H, s, CH 3 00), 1.9-1.4 (14H, m, adamantane), 1.1.

(3H, s, CE 3 anal C 34

H

4 .3N 3

O

4 0.5 H20O; requires C 72.06% H 7.82% N 7.41%; found C 7:2.20% H 7.73% N 7.30%; FAB MS (rn/e) 558 H1).

EXAMPLE 9 Tricvclo[3.3. 1.1 3 7 ]dec-2-yl (R)-[1-(1H-indol- 3-vlmethyl) -2-methyl-2-[(2-thenylethyl) aminbl 2-thioxoethyll carbamate To a solution of (29) (0.1 g, 0.2 mmol) in toluene mL) was added Lawesson' s reagent (0.10 g, WO 92/04045 'PCT/US91/06180 -103- 0.25 mmol) and the reaction was heated to reflux for 1 hour. The reaction was allowed to cool to ambient temperature and was purified by flash chromatography (dichloromethane/ether eluant). Recovered 0.065 g of 30) as a white foam, m.p. 81-850C; IR (neat) 2916, 1703 (C=O methane), 1520 cm" 1 NMR (CDC1 3 y8.1 (1H, br, indole NH), 7.8 (1H, br, this amide NH), 7.6 (1H, d, J 8 Hz, indole H-4),7.5-6.9 (9H, m, indole H-6, H-7, H-2, phenyl), 5.3 (1H, br, urethane NH), 4.7 (1H, brs, adamantane 3.8 (2H, m,

CH

2 3.6 (1H, d, J 14 Hz, one of CH 2 -indole), 3.4 (1H, d, J 14 Hz, one of CH 2 -indole), 2.6 (2H, m,

CH

2 2.0-1.6 (14H, m, adamantane), 1.5 (3H, s, CH3); Rf (30% ethyl acetate/hexane) 0.3.

EXAMPLE Methyl (2-hvdrox'y-l-phenvlethyl)amino -4-oxo-2butenoate (18) To a solution of monomethyl fumarate (3.0 g, 23 mmol). in ethyl acetate (40 mL) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol), followed by N,N'-dicyclohexylcarbodiimide (4.5 g, 22 mmol) and the reaction stirred at ambient temperature for 1 hour. The solid was filtered off and discarded. To the filtrate was added phenylglycinol (3.0 g, 22 mmol) and stirring continued for 20 minutes. The volatiles were removed in vacuo (400C) and the residue purified by flash chromatography on normal phase silica gel using hexane:ethyl acetate as eluant. Recovered 2.5 g of (18) as a white solid, m.p. 75-77 0 C; IR (neat) 3250 1729 (C 0 ester), 1666 (C 0 amide), 1640 (C C)cm- NMR (CDC1 3 5 7.3-7.4 m, Ph), 7.0 (1H, d, J 15 Hz, trans alkene), 6.8 (1H, d, J 15 Hz, trans alkene), 6.6 (1H, br d, NH), 5.2 WO 92/04045 PCT/US9I/06180 -104- M, CH), 3. 9 (2H, t, J 3 Hz, CH 2 3.86 (3H, s,

CH

3 2. 3 (1H, t, J 5 Hz, OH); (D -53- (CHC1 3 24 -C, .a anal C 1 3

H

1 5

NO

4 reqpjires C 62. 64% H 6. 07% N 5.62%; found C 62.72%1 H 5.92% N 5.48%.

Tricvclo[3.3.1.1 3 7 1dec-2-vl 3-r (lH-indol-3-Vl)methyll- 3-methvl-4, 9-aioxo-7--phenyl-5, 13-dioxa-2, 8-diazetetradec-lO-enoate (19) '1 To a solution of N,N'-carbonyldiimidazole (0.15 g, 0.90 minol) in dichioromethane (40 mL) was added (23b) 25 g, 0. 63 nunol). After 20 minutes stirring at ambient temperature (18) (0.2 g, 0.8 mmol) was added and the reaction was heated to reflux for 10 hours.

On cooling to ambient temperature the volatiles were removed in vacuo (40 0 C) and the residue was purified by flash chromatography (hexane/ethyl acetate eluant).

Recovered 0.28 g of (19) as a white solid, m.p.

96-991C. IR (neat) 2910, 1730 (C=O ester), 1695 (C=O urethane), 1670 (C=O amide C=C) cmf 1 NI4R (CDCl 3 y 8.3 (1H, br, indole, NH), 7.5 (1H, d, J 8 Hz, indole 7.4 (1H, d, J 8 Hz, indole 7.3-6.9 (LOH, m, indole H-6, H-7, H-2 phenyl amide NH one of alkene CH), 5.3 (1H, br, one of CH2-O), 5.1 (lE, s, urethane NH), 5.0 (1H, br, CH), 4.8 (lE, brs, adamantane 4.1 (1H, dd, J 11 Hz, 4 Hz, one of

CH

2 3.8 (3H, s, CH 3 3.5 (1H, d, J 14 Hz, one of

CH

2 -indole) 3.3 (lE, d, J 14 Hz, one of CH 2 -indole)', 2.1-1.4 (18H, m, adainantane CE 3 EcX3D 250 (CHCI 3 1 2-11C, C 0.2) :FAB MS 6281 H) :Anal;

C

3 6

H

4 -N3O 7 requires C 68.88%; H, 6.58%; N, 6.69%; found C, 68.56%; H, 6.83%; N, 6.57%.

WO 92/04045 PCT/USN9I/06180 -105- EXAMPLE 11 Tricvclo r3. 3.1. 1 3 7 dec-2-yl 3- r (lH-indol-3-yJ) methyll 3-methyl-4, 9-dioxo-7-phenvldioxa-2, 8-diazatetradec- Prepared by a route similar to that used to make compound (19) Recovered 0.30 g of (20) as a white solid, m.p. 104-10OoC; IR (neat) 2920, 1728 (C=0 ester), 1720 urethane), 1700 1670 amide) cnC- 1 NMR (CDCl 3 8 8 .3 (1H, br, indole NH) 7. (1H, d, J 8 Hz, indole 7.4 (1H, d, J 8 Hz, indole 7.3-7.1 (7H, m, indole H-6, H-7 phenyl), 7.1-6.7 (4H, m, indole H-2 amide NH alkenes) 5. 3 (2H, br, urethane NH one of CH 2 4.8 (1H, br, adamantane 4.7 (1H, m, CH), 4.1 (1H, dd, J 11 Hz, 4 Hz, one of CH 2 3.8 (3H, s, ester, OH 3 3. 4 (1H, d, J 14 Hz, one of CH 2 -indole) 3.2 (1H, d, J 14 Hz, one of CH 2 -indole), 2.1-1.5 (17H, m, adamantane OH 3 Ea1D- 3 r 60 (C;-Cl 3 22'C, C1l) FAB MS 628 (mn 4 H) :Anal; C 3 6

H

4 1

N

3 0 7 require:; C, 68.88%; H, 6.58%; N, 6.69%; found; C, 68.86%; H, 6.57%; N, 6.77%.

EXA.M1LE 12 Methyl r(2-hydroxy-1-phenvlethl) aiinoj-4oxobutanoate (21) Prepared by a route similar to that used to make compound (18) (see Example 10) Recovere±d 3.6 g, of (21) ni.p. 59-61"C; IR (neat) 3250 (OH) 1737 0 ester), 1651 (C =0 amnide) cnf 1 NMRP (CDCl 3 7.2-7.4 mn, Ph), 6.4 (1H, br d, NH), 5.1 (1H, m OH) 3.7 (3H, s, OH 3 2.8-2.5 (6H, in, 3 x OH 2 1.7 (1H, br, OH) [a)ID -53' (CHC1 3 22 0 C, c anal

C'

3 Hj 1 7 N0 4 requiires C 62.14% H 6.82% N 5.57%; found C 62.21% H 7.13% N 5.73%.

WO 92/04045 PCT/US91/06180 -106- Tricyclo 1. 1 3 7 1dec-2-,,l 3- r (lH-indol-3-vl) methyll]- 3-methyl-4, 9-dioxo-7-phenvl-5, 13-dioxo-2, 8-diazatetradecanoate (22 To a solution of 1,3-dicyclohexylcarbodii.mide (0.3 g, 1.5 minol) and 4-d~imethylaminopyridine (0.05 g, 0.40 inmol) in di'chloromethane rnL) was added (23) (0.50 g, 1.3 minol. After stirring for 20 minutes at ambient temperature (21) (0.30 g, 12 mmol) was added and the reaction was heated to ref lux for 2 hours.

The volatiles were removed in vacuo (40*0 and the residue purified by flash chromatography (hexane/ethyl acetate eluant) Recovered 0.41 g as a white solid, m.p. 69-71 0 C. IR (neat 2920, 1739 (C=O ester), k 1700 (0=0 urethane), 1660 (C=0 amide) NMR 8 (CDCl 8.3 (1H, br, indole NH), 7.5 (1H, d, J 3 Hz, indole 7. ,4-6.9 (1'JH, m, indole H-5, H-6, H-7, H-2 amide NH ~4 phenyl), 5.3 (1H, m, CH), 5.2 (1H, brs, urethane NH), 4.8 (2H, br, adamantane H-2 one of

CH

2 4.1 (1H, m, one Of CH 2 3.7 (3H, s, ester

CE

3 3.4 (2H, M, CH 2 -indole), 2.7-2.5 (4H, m, 2xCH 2 2.1-1.5 (17H, m, adamantane CE 3 EcXD-18 0

(CHVL

3 1 22 I, 0=1) FAB MS 63 0. 0 H) Anal:

C

3 6N 4 3

N

3 0 7 *0.5H 2 0 requires C, 67.69; H, 6.94; N, 6.58; found C, 67.36; H, 6.99; N, 6.51.

NOTE: some small peaks at 84.4-4.2 iL. the NMR spectrum may indicate the presence of a small amount of another isomer.

EXAMPLE 13 Tricyclor3.3.1.1 3 7 1dec-2-vl tR)-[2-hydroxV-1-(1Hindol-3-ylmethvl) -l-methvlethvlI carbamate (24) To a solution of (23) (R=Me) (1.0 g, 2.4 mmol) in dry TEF (20 mL) at 0 0 C under a nitrogen atmosphere was added a solution of lithium aluminum hydride in ether (3 mL of a 1M solution, 3 mmol) and the reaction was WO 92/04045 PCr/US91/06180 -107stirred f";r 20 minutes. Ethyl acetate (20 MnL) was added t-'usly and the resulting solution was washed with aci,.d (2N HCl, 2x100 mL), dried over magnesium suli te, and evaporated to dryness. Recovered 0.85 g of (24) as a white solid, m.p. 72-74 0 C; (neat 2918, 1693 (C=O urethane) cmf 1 NNR (CDCl 3 8 8.1 (lii, br, indole NH), 7.6 (1H, d, !1 8 Hz, indole 7.35 (1H, d, 1 8 Hz, indole 7.2-7.0 (31H, m, indole H-6, H-7, 4.85 (11H, br s, urethane NH), 4.8 (lH, br, adamantane 4.0 (1H, br, OH), 3.8 (2H, m,

CH

2 3.25 (1H, d, J 14 Hz, one of CH 2 -indole), (lH, d, J 14 Hz, one of CH 2 -indole), 2.1-1.5 (14H, m, adamantane), 1.2 (3H, s, CH 3 tca)D 420 (CHC1 3 22 0

C,

C=1) F.AB MS 383 Anal:

C

2 3

H

3 0

N

2 0 3 0.'5H 2 0 requires C, H, 7.98%; N, 7.15%; found: C, 7.35%; H, 7.83%; N, 6.94%.

3-(1H-indole-3-vl)-2-methyl-2-ff (tricyclor3.3.1. 3 ,71dec-2-vloxy) carbonyll aminolT~or~vl -benzeneacetate To a solution of N,N'-carbonyldiimidazole (0.40 g, mmol) in dichioromethane (20 mL) was added phenylacetic acid (0.30 g, 2.2 mmol). After minutes stirring at ambient temperature alcohol (24) (0.3 g, 0.8 inmol) was added and stirring was conti;nued for 40 hours. The volatiles were removed in vacua and the residuie was purified by flash chromatography (hexane/5% ethyl acetate eluant).

Recovered 0.30 g of (25) as a white foam, m.p. 57-60 0 C; IR (neat) 2917, 1722 (C=O ester), 1700 (C=0 urethane) cm- 1 MNR (CDC1 3 5 8.05 (1H, br, indole NH), 7.5 (1H, d, 1 8 Hz, indole 7.4-7.2 (6H, m, .indole H-5 phenyl), 7.16 (1H, t, J 7 Hz, indole 7.07 (1H, t, 7 Hz, indole 6.9 (1H, d, I.

2 Hz, indole 4.8 (1H, br, adamantane 4.6 WO 92/04045 -108- (1H, br, urethane NH), 4.3 (1H, d

CH

2 4.2 (1H, d, J 11H, one of

CH

2 -Ph, 3.2 (1H, d, J 14 Hz, one c (1H, d, J 14 Hz, one df CH -indole PCT/US91/06180 11 Hz, one of

CH

2 3.7 (2H, s, of CH 2 -indole), 2.1-1.4 (14H, m, adamantane), 1.2 (3H, s, CH 3 [Cc]D+13 (CHC1 3 22°C, FAB MS 501 (m H) Anal: C 3 1

H

3 6

N

2 0 4 requires C, 74.37%; H, 7.25%; N, 5.60%; found: C, 74.20%; H, 7.32%; N, 5.52%.

Tricvclo .1 3 dec-2-y. [l-formvl-2- (H-indol- 3-vlmethyl) -1-methylethyll carbamate (26) To a solution of (24) (0.03 g, 0.08 mmol) in dichloromethane (40 mL) at ambient temperature under argon was added N-methylmorpholine-N-oxide (0.1 g, 0.9 mmol), molecular sieves (4A activated powder, 0.5 and tetra-n-propylammonium perruthenate (0.01 g, 0.03 mmol). After stirring for 30 minutes the volatiles were removed in vacuo (40 0 The residue was taken up in ethyl acetate and purified by flash chromatography (hexane/5% ethyl acetate eluant).

Recovered 0.2 g of (24) as a white solid, m.p.

178-1'790C; IR (neat) 2900, 1732 (C=O aldehyde), 1692 (C=O urethane) cm- 1 NMR (CDC1 3 5 9.6 (1H, s, CHO), 8.1 (1H, br s, indole NH), 7.6-6.9 (5H, m, indole), 5.2 (1H, br, urethane NH), 4.8 (1H, s, adamantane 3.3 (2H, br, CH 2 -indole), 2.1-1.3 (17H, m, adamantane CH 3 [C]D 22D (CHC13, 22 0 C, FAB MS 381 Anal: C 2 3

H

2 8

N

2 0 3 requires C, 72.61%; H, 7.42%; N, 7.36%; found: C, 72.31%; H, 7.46%; N, 7.31%.

WO 92/04045 WO 9204045PCT/US9]/06180 -109- EXAMPLE 14 Tricyclo[3.3.1 3 7 1dec-2-vl 1-rl-(lH-indol-3-vlmethyl) -l-methvl-5-phen-71-2-pentenvlJ carbamate (27) A mixture of triphenyiphosphine (0.35 g, 1.3 mmol) and 1-bromo-3-phenylpropane (0.27 g, 1.3 mmol) was heated to 110 0 C, at which point the molten reactants solidified. On cooling to ambient temperature and trituration with hexane a white solid was recovered (0.4 g, 65%) This was added to a suspension of sodium hydride (50 mg of 50% in oil dispersion, 1 mmxol) in toluene (40 mL) and the reaction was refluxed for 20 minutes. Aldehyde (0.2 g, 0.5 mmol) was added and heating continued 1 hour. The volatiles were removed in vacuo and the residue purified by flash chromatography (hexane/10% ethyl acetate eluant) Recovered 0.20 g of (27) as a white solid, m.p. 49-52 0 C; IR (neat) 2904, 1696 (C=O urethane), 1683 cm-1; NMR (CDCl 3 6 8.3 (1H, s, indole NH), 7.6 (1H, d, 1 8 Hz, indole 7.3-7.0 (8H, m, indole H-5, H-6, H-7 phenyl), 6.9 (1H, s, indole 5.6 91H, d, J 12hz, CH by a-centre), 5.4 (1H, dt, J 5, 12 Hz, CH-CH 2 4.8 (2H, m, urethane NH adamantane 3.3 (1H, d, J 14 Hz), one of

CH

2 -indole) 3. 1 (1H, d, J 14 Hz, one of CH 2 -indole) 2.6-2.4 (4H, m, 2xCH2), 2.1-1.4 (14H, m, adainantane), 1.4 (3H, s, CH 3 EXAMPLE Tricyclot3 1371 dec-2-vl r2-hvdroxv-1- (lH-indol- 3-vimethyl) -l-methvl-5-phenvlpentyll carbamate (28) To a stirred mixture of magnesium metal (0.5 g, 21 mmol) and dry ether (20 niL) at 0OC under a nitrogen atmosphere was added l-bromo-3-phenylpropane (0.20 niL, 0.26 g, 1.3 mmol) and one crystal of iodine. After minutes the reaction mixture became colorless, so WO 92/04045 PCT/US91/06180 -110the solution was removed by syringe and added to a solution of (26) (0.30 g, 0.8 mmol) in dry ether at 0°C under a nitrogen atmosphere. After 20 minutes the reaction was allowed to warm to ambient temperature and was quenched in dilute hydrochloric acid (2N, mL). The products were extracted with ethyl acetate (50 mL), dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash chromatography (hexane:ethyl acetate eluant); recovered 0.31 g of (28) as an oil which appears to be a 1:1 mixture of the possible diastereomers.

Further chromatography gave a single diastereoisomer: IR (neat) 2908, 1690 (C=O urethane): NMR (CDC1 3 8 8.1 (1H, br, indole NH), 7.6 (1H, d, J 8 Hz, indole 7.4-6.9 (9H, n, indole H-5, H-6, H-7, H-2 phenyl), 4.8 (1H, br, adamantane 4.7 (1H, br s, urethane NH), 3.6 (1H, m, CH-OH), 3.5 (1H, d, J 14 Hz, one of CH 2 -indole), 3.1 (1H, d, J 14 Hz, one of

CH

2 -indole), 2.7 (2H, m, CH 2 2.1-1.3 (19H, m, adamantane 2xCH, OH), 1.1 (3H, s, CH 3 EXAMPLE 16 Tricvclo[3.3. 1.13, 7 1dec-2-vlR-(R*, dihydro-4-(phenvlmethyl)-2-thiazolyll-2-(IH-indol- 3-yl)-1-methvlethvl]carbamate (17) To a solution of (13) (0.1 g, 0.2 mmol) in toluene mL) was added Lawesson's reagent (0.10 g, 0.25 mmol) and the reaction was heated to reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was purified by flash chromatography (dichloromethane/ether eluant).

Obtained 0.07 g of the product; IR (neat) 2910, 1697 (C=O urethane), 1620 cm- 1 NMR (CDC1 3 5 8.1 (1H, br, indole NH), 7.7 (1H, d, J 8 Hz, indole H-4), 7.4-6.9 (9H, m, indole H-5, H-6, H-7, H-2 phenyl), WO 92/04045 PCT/US91/06180 -111- 5.8 (lH, br, urethane NH), 4.9 (1H, br, adamantane 4.6 (1l, m, CH), 3.7 (1i, m, one of CH 2 2.9 (1H, m, one of CH 2 2.8 (1H, br, one of CH 2 -Ph), 2.2 (1H, br, one of CH-Ph), 2.1-1.4 (14H, m, adamantane), 1.3 (3H, s, CH 3 FAB MS 529 (m_ 398 (mn-(indole-CH 2 130 (indole-CH 2 100%): R (30% ethyl acetate/hexane), 0.85.

EXAMPLE 17 Phenylmethvl (R)--methvl--ff (tricvclot33.1.1 3 ]dec- 2-yloxy)carbonl]aminol-1H-indole-3-butanoate Stec 1 A solution of N-methyl morpholine (253 mg, 2.50 mr 1) and 2-Adoc-cxMe-R-TrpOH (23b) (990 mg, 2.50 mmol) in anhydrous THF (20 mL) was cooled to 00C and treated with a solution of i-butylchlorof. rmate (360 mg, 2.5 mmol) in anhydrous THF (10 mL) dropwise over 10 mm. This was stirred at 00C for a further minutes and filtered. A solution of diazomethane (6 mmol) in Et 2 0 was added to the filtrate and left at o00C for 4 hours, then allowed to warm slowly to room temperature over 12 hours. Excess diazomethane was quenched with acetic acid and the solvents removed in vacuo. The residue was chromatographed using EtOAc in n-hexane to give the diazoketone (300 mg, IR (film) 3400-3200, 2913, 2854, 2106, 1693, and 1353 cm-1; NMR (CDC1 3 5 1.49 (3H, 1.50-1.60 (2H, 1.70-2.05 (12H, 3.30-3.40 (2H, br 4.86 (1H, br 5.20-5.40 (1H, br 5.56 (1H, 6.95 (1H, d, J 2 Hz), 7.08 (1H, t, J 7 Hz), 7.16 (1H, t, J 7 Hz), 7.33 91H, d, J 8 Hz), 7.55 (1H, d, J 8 Hz), 8.50 (1H, s).

WO 92/04045 PCT/US91/06180 -112- Step 2 A solution of the diazoketone (Scheme 5, No. 31) (1.04 g, 2.50 mmol) in benzyl alcohol (10 mL) was treated with a solution of silver benzoate (4 mL, 17 mmol) in triethylamine (5 mL) portionwise, and left to stir for 1 hour. EtOAc (30 mL) was then added and this solution 'treated with activated charcoal and filtered through a filter and the solvent was removed in vacuo and the residue chromatographed using EtOAc in n-Hexane as eluant to give the benzyl ester (44.0 mg, IR (film) 3500-3200, 2907, 2855, 1720 and 1698 cm-l; NMR (CDC13) 8 1.37 (3H, 1.50-1.55 (2H, 1.65-1.85 (8H, m) 1.90-2.05 (4h, 2.67 (1H, d, J 14.5 Hz, 2.97 (1H, d, J 14.5 Hz), 3.22 91H, d, J 14 Hz), 3.29 (1H, d, J 14 Hz), 4.68 (1H, 4.82 (1H, 5.09 (2H, 6.95 (1H, d, J 2 Hz), 7.06 (1H, dt, J 7.5 and 1 Hz), 7.15 (1H, dt, J 7.5 and 1 Hz), 7.25-7.35 (6H, 7.57 (1H, d, J 8 Hz), 8.28 (1H, s).

WO 92/04045 PCT/US91/06180 -113- EXAMPLE 18 Tricvclof3.3.1.1 7 dec-2-vl (hydroxvmethyl) -2-phenvylethyll aminol (1H-indol-3ylmethvll-1-methyl-3-oxoropy11 carbamic acid tip,

N"

Steo 1 A solution of benzyl ester (Example 17, Scheme No. 32) (440 mg, 0.88 mmol) in absolute EtOH (100 mL) was treated with Pd/C (50 mg, Ca 10% w/w) and put under an atmosphere of hydrogen at 50 psi and 30 0

C

with agitation for 16 hours. The reaction mixture was filtered through a filter aid and the filtrate evaporated to dryness in vacuo. The residue was chromatographed over reverse phase silica using HO0 in MeOH as eluant to give the acid (180 mg m.p. 91-99 0 C (MeOH/H 2 20.00 MeOH); IR (film) 3500-3300, 2912, 2856, 1704 cm-1; NMR (CDC1 3 6 1.41 (3H, 1.53 (1Hi, 1.57 (1H, 1.70-1.85 (9H, 1.95-2.10 (4H, 2.69 (1H, d, J 14.5 Hz), 3.05 (1H, d, 1 14.5 Hz), 3.21 (1H, d, J 14.5 Hz), 3.32 (1H, d, J 14.5 Hz), 4.86 (1H, 5.10-5.30 (1H, br 7.04 (11, d, J 2hz), 7.07-7.20 (2H, 7.35 (1H, d, J 8 Hz), 7.60 (1H, d, J 8 Hz), 8.16 (1H, s).

r L LI WO 92/04045 PCT/US91/06180 -114- Step 2 A solution of the carboxylic acid (Step 1, Scheme 5, No. 33) (160 mg, 0.39 mmol) and pentafluorophenol (72*mg, 0.39 mmol) in EtOAc (20 mL) was cooled to 0 C and treated with a solution of N,N'-dicyclohexylcarbodiimide (80 mg, 0.39 mmol) in EtOAc (5 mL) and left stirring at 0 0 C for 18 hours.

After this time it was filtered and S-phenyl alaninol added (121 mg, 0.8 mmol), and the mixture left at room temperature for 24 hours. The solvent was then removed in vacuo and the residue chromatographed using EtOAc in n-Hexane as eluant to give the product as a white solid (140 mg, IR (film) 3500-3200, 2909, 2855, 1694, 1651, and 1570 NMR (CDC1 3 6 1.27 (3H, 1.51 (1H, 1.55 (1H, 1.70-2.05 (12H, 2.46 (1H, d, J 13.5 Hz), 2.75-2.81 (2H, m), 2.87 (1H, d, J 13.5 Hz), 2.90-3.05 (1H, br), 3.08 (1H, d, J 14 Hz), 3.28 (1H, d, J 14 Hz), 3.50 (1H, dd, J 11 and 5 Hz), 3.61 (1H, dd, J 11 and 3.5 Hz), 4.10-4.20 (1H, 4.81 (1H, 5.14 (1H, 6.26 (1H, d, J 8 Hz), 6.99 (1H, d, J 2 Hz), 7.08 (IH, t, J 7 Hz), 7.10-7.30 (6H, 7.33 (1H, d, J 8 Hz), 7.58 (1H, d, J 8 Hz), 8.32 (1H, s).

c WO 92/04045 PCT/US9I/06180 -115- EXAMPLE 19 Carbamic acid, (1H-indol-3-vlmethvl) -l1-methvl-2- (l-oxo-4-pheny-lbutyl) aminolethyl3-, tricyclor3.3.1.1 3 7 dec-2-vl ester .0N NH

NI

This was prepared in the same manner as described in Example 21. Scheme 5 No. 37d, m.p. 70-750C (foam); [a)D.

2 MeOH); IR (film) 3400-3100, 2908, 2853, 694, 1645, and 1526 cm- 1 NMR (CDC1 3 0' 1.24 (3H, s), 1.50-2.10 (16H, in), 2.20 (2H, t, J 7 Hz), 2.64 (2H, t, J 7 Hz), 2.98 (1H, d, J 14.5 Hz), 3.25 (1H, d, J 14.5 Hz), 3.55 (111, dd, J 14 and 6 Hz), 3.70 dd, 1 14 and 6 Hz), 4.81 (1H, 4.94 (1H, 6.50-6.60 (1H, br s) 7. 00 (1H, d, J 2 Hz) 7. 05-7.30 (7H, in), 7. 35 (1H, d, J 8 Hz) 7.57 (1H, d, J 8 Hz) 8. 17 (1H, s) Anal. C 3 3

H

4 1

N

3 0 3 C, H, N.

WO 92/04045 PCT/US91/06180 -116- EXAMPLE Carbamic acid, [2-(benzovylamino)-1-(1H-indol-3ylmethvl)-1-methylethyll-, tricycloF3.3.1.1 3 7 ]dec-2-vl ester,

D

NM

0 NH NH Ph

NH

This was prepared in the same manner as described in Example 21. Scheme 5 No. 37a, m.p. 220.0-220.1 0

C

(MeOH); aC), 24 0 C (C=0.25, MeOH); IR (film) 3500-3200-2907, 2855, 1695, 1646, and 1533 cm-1; NMR (CDC1 3 8 1.30 (3H, 1.50-1.60 (2H, 1.70-2.10 (12H, 3.07 (1H, d, J 14.5 Hz), 3.31 (1H, d, J 14.5 Hz), 3.76 (1H, dd, J 14 and 6 Hz), 3.89 (1H, dd, J 14 and 6 Hz), 4.84 (1H, 5.03 (1H, 7.01 (1H, d, 2 Hz), 7.05-7.20 (2H, 7.35-7.50 (4H, 7.60 (1H, d, J 8H, 7.77 (2H, d, j 7 Hz), 7.60-7.90 (1H, br), 8.39 FAB MS mI/e 486.3 355.3 (63), 290.3 177.2 154.1 (100); Anal. C 30

H

35

N

3 0 3 C, H, N.

L WO 92/04045 J9cT/t -117 EXAMPLE 21 Carbamic acid, f 2- (lH-indol-3-ylmethvl) -l-methyl-2- 1 (I-oxo-3-phenvlioropvl) aminol ethyl-, tricyclor3.3.1.1 3 7 1dec-2-vl ester, JS91/06180

D

Me 0 Step 1 Carbamic acid, r2-amino-i- C1H-indol-3-ylmethyl) -1methvl-2-oxoethyl)-, tricvclor3.3.1.1 3 7 Idec-2-vl ester, AdOC-ct-Me)DTr-p-NH 2 (See Scheme 5, No. 2-Adoc-aX-Me-R-Tro NH) 2-Adoc-OL-Me-R-TrpOH (23b) (9.5 g, 24 minol) as a solution in EtOAc (150 mnI) was treated with pentafluorophenol (4.4 g, 24 inmol) and cooled to 0 0

C.

A solution of N,N'-dicyclohexylcarbodiimide (5.15 g, mxnol) in EtOAc (20 mLs) was added dropwise and the resultant mixture allowed to stir 6 hours, then left a further 12 hours at 4'C. This was then filtered and the filtrate evaporated to dryness in vacuo. The WO 92/04045 PCT/US91/06180 -118residue was redissolved in THF (100 mL) and ammonia gas bubbled through at 0°C for 1 hour. The solvent was removed in vacuo and the residue chromatographed over reverse phase silica using 30% H 2 0 in MeOH as eluant to give the amide (35, Scheme 5) (9.2 g, 97%) as white crystals, m.p. 136-149 0 C (MeOH); [a]D 42.1 MeOH); IR (film) 3351, 2906, 2855, 1675, and 1588 (CDCl 3 6 1.50-1.60 (2H, 1.58 (3H, 1.70-2.05 (12H, 3.33 (1H, d, J 14.5 Hz), 3.51 (1H, d, J 14.5 Hz), 4.86 (1H, 5.24 (1H, s), 5.40-5.55 (1H, br), 6.20-6.35 (1h, br), 7.04 (1H, d, J 2 Hz), 7.08-7.21 (2H, 7.36 (1H, d, J 8 Hz), 7.63 (1H, d, J 8 Hz), 8.24 (1H, MS (FAB) m/e 396 (100); Anal. C 2 3 H29N 3 0 3 C, H, N.

Step 2 (See Scheme 5, No. 36) Trimethylsilylchloride (4.34 g, 40 mmol) was added dropwise to a solution of LiBH 4 (11 mL of a 2M solution, 22 mmol) in THF under an atmosphere of nitrogen. A solution of 2-AdocaMe-R-TrpNH 2 (Scheme No35) from the previous step (3.95 g, 10.0 mmol) in anhydrous THF (20 mL) was added dropwise over 20 mm and the reaction mixture stirred 10 minutes at room temperature, then at gentle reflux for 3 hours. This was then cooled to 0°C and MeOH (1C.5 mL) added with caution. All solvents were then removed in vacuo and the residue chromatographed over reverse phase silica using 30% H 2 0 in MeOH as eluant to give 1.25 g (32%) of starting amide and 1.29 g of the product amine, m.p. 138-144°C (MeOH); [a]D 51.60 (C=1, MeOH); IR (film) 2912, 2854 and 1690 cm- 1 NMR (CDC1 3 8 1.32 (3H, 1.40-1.55 (2H, 1.65-2.05 (12H, m), 3.04 (1H, d, !J 14 Hz), 3.20-3.30 (2H, 3.40-3.50 (1H, 4.78 (1H, 5.10-5.30 (1H, br 7.00-7.20 (3H, 7.34 (1H, d, J 8 Hz), 7.52 (1H, d, J 8 Hz), WO 92/04045 PCT/US91/06180 -119- 8.56 (1H, 8.67 (2H, br FAB MS m/e 382.3 (100).

Step 3 (See Scheme 5, No. 37c) A solution of 3-phenylpropionic acid (75 mg, mmol) in EtOAc (5 mL) was treated with pentafluorophenol (92 mg, 0.5 mmol) and cooled to 0°C.

A solution of N,N'-dicyclohexylcarbodiimide (103 mg, mmol) in EtOAc (2 mL) was added and the mixture left 12 hours at 4 0 C. This mixture was then filtered and solid amine (from Step 2, Scheme 5 N 0 36) (198 mg, 0.5 mmol) added, and left at room temperature for 24 hoirs. The reaction mixture was washed with 1M citric acid solution (2 x 10 mL), NaHCO 3 (2 x 10 mL of a 1M solution), and H 2 0 (2 x 10 mL) and the organic phase dried over MgSO 4 The solvent was then removed in vacuo and the residue chromatographed over silica gel using 2% MeOH in CH 2 Cl 2 eluant to give the product (230 mg, 90%) as white crystals, m.p. 171-175 0

C

(MeOH); [c]°D-1 2 3 0 (C=0.56, MeOH); IR (KBr) 3400-3100, 2906, 2854, 1694, 1649, an 1528 cm- 1

NMR

(CDC1 3 6 1.13 (3H, 1.50-2.10 (14H, 2.50 (2H, t, J 7 Hz), 2.90 (1H, d, J 14 and 6 Hz), 3.65 (1H, dd, J 14 and 6 Hz), 4.81 (1H, 4.88 (1H, 6.40-6.60 (1H, br), 6.96 (1H, d, J 3 Hz), 7.05-7.30 (7H, m), 7.35 (1H, d, J 8 Hz), 7.53 (1H, d, J 8 Hz), 8.15 (1H, FAB MS m/e 514.4 383.3 205.2 (32), 170.2 135.2 (100); Anal. C 3 2

H

3 9N 3 0 3 C, H, N.

PCT/US91/06180 WO 92/04045

A-

2L WO 92/04045 PCT/US9/06180 -120- EXANPLE 22 Carbamic acid, F1-(1H-indc;l-3-Vlmethyl)-l-rnethv1-2- (2-phenylacetyl) aminol ethyll-, tricyclo3 .3.1.1 3 7 1dec-2-vl ester, R)- Me Ph NN1 0 This was prepared in the same manner as described in Example 21 (see Scheme 5, No. 37b), m.p.

176.5-180C (MeOH); EaD-1.6 0 (C=O 56, MeOH); IR (film) 3400-3100, 2911, 2854, 1694, 1656, and 1520 cm U NNR (CDC.

3 6 1.16 (3H, 1.50-2.10 (14H, m 2.90 (iH, d, J 14 Hz), 3.16 (iH, d, J 14 Hz), 3.50 (iH, d, J 14 and 6 Hz), 3.57 (2H, 3.65 (1H, d, J 14 and 6 Hz), 4.73 (1H, 4.80 (1H, 6.30-6.40 (iH, brs), 6.94 (IN, di, J 2 Hz), 7.07 (IH, t, J 8 Hz), 7.16 (1H, t, J 8 Hz), 7.25-7.40 (6H, 7.48 (IN, d, J 8 Hz), 8.11 (iN, FAB MS m/e 500.5 (100), 369.3 Anal. C 3 1

H

3 7

N

3 0 3 C, H, N.

EXAMPLE 23 Carbanic acid, t2-t 3-fl- (hydroxvmeth)-2-phenylethvllamino]-3-oxopropyllaminol-l-(1H-indo- 3-vlmethvl)-1-methyl-2-oxoethyll-, ricce 3.3.1.1 3 '71 dec-2-vl ester, S*)I The acid as prepared in Example 30, Step 2 (1.17 g, 2.80 moQi) and pentafuorophenol (461 mg, nmol) as a solution in EtOAc (50 nI) was treated with dicyclohexyl carbodiimide (542 mg, 2.60 mmol) and left at OOC for 18 hours. This was filtered and the filtrate treated with s-phenylaianinol (454 mg, WO 92/04045 WO 9204045PCr/US91/06180 -12 1- 3.00 nimol) and the reaction mixture left stirring 18 hours at room temperature. This was then concentrated in vacuo and the residue chromatographed over reverse phase silica using 75% MeOH in H 2 0 as eluant to give the product as a white, noncrystalline solid (1.17 g, m.p. 94-981C; [cX)D20 14.70 MeOH); IR (film) 3306, 2904, 2854, 1693, and 1651 cm- 1 NMR (DMSO-d 6 8 1.29 (3H, 1.60-2.00 (14H, in), 2.05-2.25 (2H, mn), 2.62 (1H, dd, J 14 and 8 Hz), 2.83 (1H, dd, J 14 and 6 Hz), 3.10-3.40 in), 3.85-3.95 (1H, in), 4.70-4.80 (2H, in), 6.70 (1H, br 6.90-7.35 (9H, mn), 7.44 (1H, d, !1 8 Hz), 7.70 (1H, d, J. 8 Hz), 7.75 (1H, br 10.85 (1H, FAB MS m/e 601 100) Anal. C 3 5

H

4 4

N

4 0 5 *0.25H 2 0; C, H, N.

EXAMP2LE 24 Carbamic acid, r-(lH-indol-3-vliethl)2-rr3-[rlrhydroxv-methvl) -2-phenylethyll aminolI-3-oxopropyll amino -1-methyl-2-oxoethvll tricyclor3.3.1.1 3 7 1dec- 2-Vlester, 1- 0 0 0 This was pr-epared in th.,e same manner as described in Example 23 (see Scheme 6, No. 44), m.p. 95-97C (MeOH/H 2 MLD 2 0-31.31 MeQE); IR (film) 3314, 2910, 2856, 1696, and 1651 cm-1; N1MR (CDC1 3 8 1.53 1.70-2.05 (12H, in), 2.10-2.30 (2H, 2.79 (2H, d, L7 7 Hz) 3.25 (lH, d, J 14.5 Hz) 3.35 (1H, d, J 14.5 Hz), 3.30-3.55 (3H, mn), 3.65-3.70 (1H, in), WO 92/04045 PCT/US91/06180 -122- 4.10-4.20 (1H, 4.79 (1H, 5.26 (1H, 6.20- 6.35 (1H, br 6.69 (1H, t, J Hz), 6.97 (1H, d, J 2 Hz), 7.06-7.29 (7H, 7.34 (1H, d, J 8 Hz), 7.57 (1H, d, J 8 Hz), 8.49 (1H, FAB MS m/e 601 (100); Anal. C 3 5

H

4 4

N

4 0 5 50.25H 2 0; C, H, N. MS FAB m/e 614 (m+1) and 217 (100); Anal. C 3 5

H

4 3

N

5 05 0.5H 2 0; C, H, N.

EXAMPLE D-Phenvlalanamide, -methvl-N-[ (tricvclo [3.3.1.13'7]dec-2-vloxv)carbonvl -D-trvptophyl--alanvlrh 0 0 Y W This was prepared using a method similar to Example 26. The acid from Example 30, Step 2 (117 :ng, 0.25 mmol) and pentafluorophenol (46 mg, 0.25 mmol) as a solution in EtOAc (10 mL) was treated with dicyclohexylcarbodiimide (52 mg, 25 mmol) and left stirring at room temperature for 2 hours before being filtered. S-Phenylalaninamide (50 mg, 0.3 mmol) was then added and the mixture left stirring at room temperature for 72 hours. The reaction mixture was then washed with 1M HC1 (10 mL), H 2 0 (10 mL) 1M NaOH (10 mL), and H 2 0 (10 mL). The organic phase was dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed over reverse phase silica gel using MeOH in H 2 0 as eluant to give the product as a white noncrystalline solid (130 mg, m.p.

WO 92/04045 PCT/US91/06180 -123- 113-1181C; [Dc20 27.50 MeOH); IR (film) 3311, 3055, 2908, 1700, and 1659 cm- 1 NMR (CDC1 3 6 1.49 (2H, 1.52 (3H, 1.60-2.05 (12H, 2.19 (2H, t, J 6 Hz), 3.01 (1H, dd, J 7.5 and 14 Hz), 3.08 (1H, dd, J 7.5 and 14 Hz), 3.27 (1H, d, J 14.5 Hz), 3.42 (1H, d, J 14.5 Hz), 3.35-3.50 (2H, 4.59 (1H, dd, J 15 and 7 Hz), 4.80 (1H, 5.29 (1H, 5.47 (1H, 6.20 (1H, 6.50 (1H, d, J 7 Hz), 6.76 (1H, t, J 6 Hz), 6.96 (1H, d, J 2 Hz), 7.05-7.35 (7H, m), 7.34 (1H, d, J 8 Hz), 7.57 (1H, d, J 8 Hz), 8.36 (1H, s).

EXAMPLE 26 L-Phenvlalaninamide, c-methyl-N- [(tricvclo[3 13 dec-2-vloxy)carbonvl -D-trrotonhyl-B-alanvl- \Ph m.p. 112-1180C (MeOH/H20); (a3D20 16.30 MeOH);

.I

IR (film) 3309, 2907, 2855, 1690, 1652 cm-; NMR (CDC1 3 6 1.50-2.05 (17H, 2.10-2.20 (2H, 2.98 (1H, dd, J 14 and 8 Hz), 3.09 (1H, dd, J 14 and 7 Hz), 3.24 (1H, d, J 14.5 Hz), 3.35 (1H, d, J 14.5 Hz), 3.25-3.55 (2H, 4.58 (1H, dd, J 15 and 7.5 Hz), 4.78 (1H, 5.28 (1H, 5.48 (1H, 6.27 (1H, br 6.54 (1H, br 6.75 (1H, 6.99 (1H, d, J 2 Hz), 7.05-7.30 (7H, 7.34 (1H, d, J 8 Hz), 7.58 WO 92/04045 WO 9204045PCT/US91/06180 -124- (1H, d, J 8 Hz) 8.41. (1H, s) FAB MS m/e 614.3 (100)~ Ana. C 5

H

4

N

5 0 5 0.75H 2 0 C, H, N.

EXAMP2LE 27 L-Phenylalaninamile, 0X-methyl-N-E (tricyclo dec-2-vloxv) carbonyll-Ltytpy--lnl D D

M.

m.p. 114-119*C (MeOH/H 2 EcXD 2 MeCH); IR (film) 3323, 2909, 2855, 1700-1640 cnf 1 NbM. (CDC1 3 6 1.50 (2H, 1.54 (3H, 1165-2.00 (12H, in), 2.10-2.20 (2H, br 2.95 (1H, dd, J 14 and 8 Hz), 3.10 (1H, dd, J 14 and 6 Hz), 3.23 (1H, d, J 14 Hz), 3.32 (1H, d, J 14H), 3.20-3.30 (1H, in), 3.40-3.50 (1H, in), 4.55 (0.5H, 0, 1 8 Hz), 4.60 (0.5H, d, J 8 Hz), 4.78 (1H, 5.35 (1H, 5.68 (1H, 6.41 (1H, 6.65-6.85 (1H, mn), 6.82 (1H, t, J 6 Hz), 6.97 (1H, d, J 2 Hz), 7.05-7.30 (7H, in), 7.33 (1H, d, J 8 Hz), 7.57 (1H, d, J,8 Hz), 8.55 (1H, FAB MS in/e 614.3 236.1 (100); Anal. C 3 5

H

4 3

N

5

O

5 '0.5H 2 O; C, H, N.

WO 92/04045 PC/US9I/06180 -125- EXAMPLE 28 D-Phenylalaninamide (x-methyl-N-[rtricyclo r 1. 1.

dec-2-vloxy)carboriv I-L-tZyptophyl-I-a.anylm.p. 113-118'C (MeOH/H 20); I(XID20-30c MeOH); IR (film) 3313, 2909, 2856, 1694-1652 br. cm-i; NMR (cDc1) 5 1.45 (3H, 1.50 (2H, 1.65-2.00 (12H, 2.14 (2H, 2.90 (1H, dd, J 14 and 8 Hz), 3.06 (1H, d, J 14 and 5.5 Hz), 3.2-3.4 (4H, 4.56 (O.SH, d, J 7.5 Hz), 4.60 (0.5H, d, 1 7.5 Hz), 4.80 (IH, s), 5.54 (IHl, 6.14 (1H, 6.70 (1H, 6.67 (1H, 7.00-7.30 (10H, 7.51 (1H, d, J 8 Hz), 8.87 (1H, FAB MS 636.4 (100) 614.4 (61) Anal.

43N5050.5H20; C, H, N.

WO 92/04045 PCT/US91/06180 -126- EXAMPLE 29 12-0xa-2,5,9-triazatridecanoic acid, 3-(1H-indol-3vlmethyl)-3-methyl-4,8,11-trioxo-l10-(phenylmethyl)-, tricycloT3.3.1.1 3 7 dc-2-vl ester, (See Scheme 6, No. 49) "Di In a manner similar to Example 30, the following was prepared, m.p. 86-900C (foam); [o],20 17.40 MeOH); IR (film) 1738, 1698, and 1656 cm-; NMR (CDC1 3 5 1.55 (3H, 1.50-1.60 (2H, br s), 1.65-2.05 (12H, 2.10-2.35 (2H, 2.99 (1H, dd, J 14 and 8 Hz), 3.11 (1H, dd, J 14 and 5 Hz), 3.20-3.30 (1H, 3.31 (2H, 3.55-3.65 (1H, 3.68 (3H, 4.73 (1H, dd, J 13 and 8 Hz), 4.80 (1H, 5.33 (1H, 6.40-6.60 (1H, br 6.90 (1H, br 6.98 (1H, d, J 2 Hz), 7.05-7.35 (8H, 7.59 (1H, d, J 8 Hz), 8.45 (1H, MS FAB m/e 629.2 (100); Anal.

C

36

H

44

N

4 0 6 0.25H 2 0; C, H, N.

WO 92/04045 PCT/US91/06180 -127- EX IPLE L-Phenylalanine,N-[N-a -methyl-N-[ (tricyclo f3.3.1. 13'7] dec-2-yloxy)carbonyll-d-trvptophyll-8-alanyl phenylmethyl ester Step 1 (See Scheme 6, No. 39) A solution of 2-Adamantyloxycarbonyl-a-methyl-Rtryptophan (8.0 g, 20 mmol) in EtOAc (100 mL) was treated with pentafluorophenol (3.68 g, 20.0 mmol) and cooled to 0°C. Dicyclohexylcarbodiimide (4.33 g, 21.0 mmol) was then added and the mixture left to stir for 18 hours at 0°C. After this time the mixture was filtered and 1-alanine methyl ester (2.47 g, 240 mmol) added and the mixture left stirring a further 18 hours at room temperature, filtered, and the filtrate washed with 1M HC1 (3 x 30 mL), H20 (2 x 30 mL), saturated NaHC03 solution (3 x 30 mL) H 2 0 (2 x 30 mL). The organic phase was dried over MgSO 4 and concentrated in vacuo and the product crystallized from ether to give the ester (7.8 g, IR (film) 3700-3200, 3000-2800), 2723, 1695, and 1659 cm_ 1 Step 2 (See Scheme 6, No. 41) B-Alanine,N-I a-methyl-N- (tricyclo 3.3.1.1 3 7 1 dec- 2-yloxy)carbonyll-D-trvptophyl] The ester from Step 1 (5.20 g, 10.8 mmol) as a solution in 1.4 dioxane (300 mL) was treated with a solution of LiOH'H 2 0 (454 mg, 10.8 mmol) in S(100 mL) dropwise at room temperature and left stirring 18 hours. lM HC1 (10.8 mL) was. dded and the mixture distilled to dryness in vacuo ar.. the residue chromatographed over reverse phase silica gel using MeOH in H 2 0; as eluant to give the product (3.23 g, 51%) along with starting ester (1 m.p.

98-103 0 C (MeOH/H 2 2 0 29" MeOH); IR WO 92/04045 PCT/US91/06180 -128- (film) 3351, 2911, 2855, 1706, and 1658 cm- 1

NMR

(CDC1 3 6 1.50-2.00 (17H, 2.39 (2H, br 3.26 (1H, d, J 15 Hz), 3.40-3.50 (3H, 4.80 (1H, s), 5.42 (1H, br 6.75 (1H, t, J 6 Hz), 6.99 (1H, d, J 2 Hz), 7.05-7.20 (2H, 7.33 (1H, d, J 8 Hz), 7.57 (1H, d, J 8 Hz), 8.37 (1H, FAB MS m/e 468 (m+1) and 217 (100); Anal. C 2 6

H

3 3

N

3 05-0.25H 2 0; C, H, N.

Step 3 A solution of the acid from Step 2 (467 mg, 1.00 mmol) and pentafluorophenol (184 mg, 1.00 mmol) in EtOAc (50 mL) was treated with dicyclohexylcarbodiimide (206 mg, 1.00 mmol) at 0°C and left 18 hours. This was then filtered and S-phenyl alanine benzyl ester (306 mg, 1.20 mmol) added and left stirring 18 hours at room temperature. This was then washed with IM HCI (2 x 20 mL), H 2 0 (20 mL), saturated NaHCO 3 solution (2 x 20 mL), and H 2 0 (20 mL) The organic phase was dried over MgSO 4 and concentrated in vacuo and the residue chromatographed over reverse phase silica gel using 75% to 85% MeOH in H 2 0 as eluants to give the product (500 mg, m.p.

75-82 0 C (MeOH/H 2 2 0 28.10 (c=0.45, MeOH); IR (film) 3324, 2908, 2855, 1737, 1698, and 1657 cm-i; NMR (CDC1 3 5 1.50 (3H, 1.50-1.55 (2H, m), 1.70-2.00 (12H, 2.10-2.30 (2H, 3.06 (1H, dd, J 14 and 7 Hz), 3.14 (1H, dd, J 14 and 6 Hz), 3.29 (1H, d, J 15 Hz), 3.25-3.60 (3H, 4.75-4.85 (2H, m), 5.08 (1H, d, J 12 Hz), 5.15 (1H, d, J 12 Hz), 5.29 (1H, br 6.20-6.30 (1H, br 6.81 (1H, br m), 6.95 (1H, d, J 2 Hz), 7.00-7.35 (13H, 7.57 (1H, d, J 8 Hz), 8.20 (1H, Anal. C 4 2

H

4 8

N

4 0 6 C, H, N.

WO 92/04045 PCI/US91/06180 -129- EXAMPLE 31 In a manner similar to Example 30 the following was prepared, m.p. 77-82 0 C (foam); [a]D20-19.2- MeOH); IR (film) 3305, 2906-2857, 1735, 1696, and 1658 cm-1; NMR (CDC1 3 8 1.51 (3H, 1.50-1.60 (2H, 1.70-2.10 (12H, 2.10-2.30 (2H, 3.01 (1H, dd, J 14 and 8 Hz), 3.12 (1H, dd, J 14 and 5 Hz), 3.20-3.30 (1H, 3.31 (1H, 3.55-3.65 (1H, m), 4.75-4.85 (2H, 5.07 (1H, d, J 12 Hz), 5.15 (1H, d, J 12 Hz), 5.28 (1H, br 6.30-6.50 (1H, br s), 6.80-6.90 (1H, br), 6.97 (1H, d, J 2 Hz), 7.05-7.35; MS FAB m/e 705.2 (71) and 327.2 (100); Anal.

C

4 2

H

4 8

N

4 0 6 C, H, N.

EXAMPLE 32 D-Phenylalanine, N-FN-[a-methvl-N-r(tricyclo- (3.3.1.1-3 dec-2-vyloxy)carbonylI-D-tryptophylvl-1alanyjlo /z 0 0 This was prepared in a manner similar to that described in Example 33, m.p. 119-129 0 C (MeOH/H 2 0); [a]o20 5.80 MeOH);IR (film) 2907, 2855, 1700, 1651 cm- 1 NMR (CDC1 3 CD30D) 8 1.53 (5H, s), 1.70-2.05 (12H, 2.10-2.30 (2H, br 2.95-3.05 (1H, 3.15-3.60 (5H, 4.65 7.00-7.40 -i i i WO 92/04045 PCT/US91/06180 -130- (9H, 7.57 (1H, d, J 8 Hz); FAIB MS m/e 615.2 (58), 216.9 (100); Anal. C 3 5

H

4 2

N

4 06-0.5H 2 0; C, H, N.

EXAMPLE 33 S-Phenylalanine, N-[N-f -methyl-N-[(tricyclo- 3.3.31.1 3 7 dec-2-vloxy) carbonyl -R-tryptophyll- alanyl] A solution of the benzyl ester (450 mg, 0.64 mmol) in absolute EtOH (100 inL) was treated with 10% Pd/C mg, 10% w/w) and put under an atmosphere of hydrogen at 50 psi for 2 hours with agitation. The mixture was then filtered through a filter aid and concentrated in vacuo and the residue chromatographed over reverse phase silica gel using 70% MeOH in H 2 0 as eluant to yield the product as a white, noncrystalline solid (300 mg, m.p. 114-119°C; [C]D 2 0 37.8 MeOH); IR (film) 3331, 2911, 2856, 1700, and 1656 cm-1; NMR (CDC13) 6 1.41 (3H, 1.45-1.55 (2H, 1.70-2.00 (12H, 2.10-2.20 (2H, 3.01 (1H, dd, J, 14 and 8 Hz), 3.15-3.50 (5H, 4.00-5.00 (1H, v.br), 4.66 (1H, dd, J 13 and 7 Hz), 4.82 (1H, s), 5.46 (1H, br 6.50-6.70 (1H, br 6.87 (2H, br 7.00-7.30 (8H, 7.52 (1H, d, J 8 Hz), 8.44 (1H, Anal. C 3 5

H

4 2

N

4 0 6 C, H, N.

i I

I

WO 92/04045 PCr/US9]/06180 -131- EXAMPLE 34 L-Phenvlalanine, N-[N-Ccx-methvl--N-[ (tricyc lo- [3.3.1.1 3 dec-2-vloxv) carbonyl I-L-tryptophl-1 alanyl] Ml 9 This was prepared in a manner similar to that described in Example 33, 115-120 0 C (MeOH/H 2 0); [cz)D 0 -O7.21 MeQE); IR (film) 3391, 2906, 2854, 1700, and 1646(s) cm-1; NM. (CDC1 3

CD

3 OD) 6 1.51 (3H, 1.54 (1H, 1.57 (1H, 1.70-2.05 (12H, mn), 2.15-2.30 (2H, mn), 2.99 (1H, dd, J 14 and 8 Hz), 3.15-3.55 (5H, in), 4.66 (1H, dd, J 8 and 5 Hz), 4.79 (lH, s, 7.00-7.40 (9H, in), 7.56 (1H, d, J 8 Hz); FAB MS m/e 615 (100) Anal. C 3 5

N

4 2

N

4 0 6 C, HI, N.

1.~ WO 92/04045 PCU/US91/06180 -132- EXAMMLE Benzenepropanoic acid, aX-f 3-f[3-f (1H-indol-3-vl) -2methvl-l-oxo-2-f r (tricvclo 3 .1 1 3 7 dec-2V-Qxy carbonvillaiinolpropvl) arinol-l-oxopropyl] amino-, 1-

V

116-1240C (MeOH/H 2 cXID 2 0-35' MeOH); IR (film) 3500-3200, 2912, 2856, 1700, and 1654 cin-; NMR (CDC1 3 8 1.42 (3H, 1.47 1.51 (1H, s), 1.65-2.20 (14H, mn), 2.90-3.00 (1H, in), 3.10-3.EC mn), 3.50-4.50 (br, CO 2 H and H 2 0) 4. 61 (1H, s) 4. 82 (1Hi, 5.45 (1H, 6.50-6.80 (1H, br 6.85-7.30 (11H, in), 7.52 (1Hi, d, J 8 Hz), 8.58 (1H, FAB MS in/e 615.2 (100; Anal. C 3 5

H

4 2

N

4

O

6 *O.4H 2 O; C, H, N.

WO 92/04045 PCT/US9 /06180 -133- EXAMPLE 36 Glycine, N- 2-methyl-N- (tricvclo[3.3.1.1 3 idec-2vloxy) carbonyl-D-tryptophyll phenylmethyl ester ii. II 04.NN-0 Ph

NH

A solution of 2-Adocc-Me-R-TrpOH (Scheme 7, N 0 23b) (3.0 g, 7.6 mmol) in EtOAc (40 mL) was treated with pentafluorophenol (1.39 g, 7.6 mnmrvl), and cooled to 0 0 C. A solution of N,N'-dicyclohexylcarbodiimide (1.56 g, 7.6 mmol) in EtOAc (10 mL) was then added dropwise and stirred 12 hours at 4 0 C and filtered.

Glycine benzyl ester hydrochloride (1.8 g, 9.0 mmol) was added followed by the dropwise addition of triethylamine (0.9 g, 9.0 mmol) in EtOAc (10 mL).

This was allowed to stir 18 hours at room temperature.

The reaction mixture was then washed with lM citric acid solution (2 x 50 mL), iM NaHC03 solution (2 x 50 mL) and H 2 0 (2 x 50 mL). The organic phase was dried over MgSO 4 and evaps.rated to dryness in vacuo. The residue was chromatographed over reverse phase silica using 25% H 2 0 in MeOH as eluant to give the product as a white foam (2.83 g, 68%) along with 0.9 g starting active ester, m.p. 76-82 0 C (foam); [C1],20 360 MeOH); IR (film) 3500-3200, 2908, 2855, 1745, 1702, and 1665 cm- 1 NMR (CDC1 3 6 1.45-1.60 (4H, 1.69-2.00 (13H, 3.30 (1H, d, J 14.5 Hz), 3.50 (1H, d, J 14.5 Hz), 3.95-4.10 (2H,

I

WO 92/04045 PCT/US91/06180 -134- (1H, s) 7. 01 (1H, d, J 2 Hz) 7. 08 t, J 7 Hz), 7. 15 (1Hi, t, J 7 Hz) 7.3,0-7. 40 (6H, mn), 7.57 (1H, d, 1 8 Hz), 8.26 (1H, FAB MS 544.4 414.3 (11), 348.2 135.2 (100); Anal.; C 3 2

H

3 7

N

3 0 5 C, H, N.

A

WO 92/04045 P~T/US9 1/06180 -135- EXAPLE 37 Carbamic acid, [2-f (hydroxymethyl) -2phenylethyllamino,1-2-oxoethyll aminol (H-inciol-3vlmethyl)-l-methyl-2-oxoethyll-, tricvclor3.3.1.1 3 7 1dec-2-yl ester, !dOC-(cX-Me)DTrp-Glv- NH -1-(hydroxvrnethyl) -2-phenylethyl) '1 ci Stev 1. Glvcine, N- 3- (li-indol-3-Vl) 2-methvl-1--oxo- 2- r (tricvclo r 3. 3.1. 13,7 dec-2-vloxy)crovI amino I- Provvl-, AdQC-(OM-Me) DTro)-GlV A solution of the benzyl ester (Example 36, Scheme 7, No. 57) (2.5 g, 4.6 minol), in absolute EtOH (2.00 mLd) was treated with 10% 71/C (250 mg, 10% w/w) and put under an atmosphere of ydrogen at 50 psi and 0 C for 5 hours with agitation. ,.jhe reaction mixture wa±s filtered through a filter aid and the filtrate WO 92/04045 PCT/US91/06180 -136concentrated in vacuo. The .esidue was then chromatographed over silica gel using 0.5% AcOH, MeOH in CH 2 C1 2 as eluant to give the product (1.87-3 g, 90%) as a white solid; m.p. 112-117 0

C

(MeOH/H 2 [a]]D 2 0 +400 MeOH); IR (film) 3500-3200, 2910, 2856, 1702, 1660, and 735 cm-l; NMR (CDC13) 6 1.26 (1H, 1.51 (1H, 1.58 (3H, s), 1.70-2.00 (12H, 3.00-4.00 (1H, br), 3.28 (1H, d, J 14.5 Hz), 3.45 (1H, d, J 14.5 Hz), 3.94 (2H, d, J 5 Hz), 4.85 (1H, 5.35-5.50 (1H, br 6.85 (1H, br 7.04 (1H, d, J 2 Hz), 7.05-7.18 (2H, 7.32 (1H, d, J 8 Hz), 7.56 (1H, d, J 8 Hz), 8.39 (1H, s); Anal. C 25 H31N30 5 C, H, N.

SteD 2 A solution of the acid (Scheme 7, No. 59, Step 1) (226 mg, 0.5 mmol) and pentafluorophenol (92 mg, mmol) in EtOAc (20 mL) was cooled to 0°C and treated with a solution of N,N'-dicyclohexylcarbodiimide (108 mg, 0.525 mmol), in EtOAc (5 mL).

This was left 12 hour at 0°C, filtered and the filtrate treated with S-phenylalaninol (91 mg, 0.6 mmol). This reaction mixture was stirred at room temperature for 18 hours, evaporated to dryness in vacuo and the residue chromatographed using n-hexane in EtOAc as eluant to give the product (202 mg, IR (film) 3500-3200, 2911, 2855, 1695, and 1658 cm-l; NMR (CD30D) 8 1.44 (3H, 1.52-1.62 (2H, 1.70-2.10 (14H, 2.78 (1H, dd, J 13.5 and 8 Hz), 2.93 (1H, dd, J 13.5 and 6 Hz), 3.24 (IH, d, J 14.5 Hz), 3.41 (1H, d, J 14.5 Hz), 3.53 (2H, d, J Hz), 3.57 (1H, d, J 17 Hz), 3.71 (1H, d, J 17 Hz), 4.05-4.15 (1H, 4.88 (1H, 6.98 (1H, dt, J and 1 Hz), 7.00-7.25 (7H, 7.32 (1H, d, J 8 Hz), 7.50 (1H, d, J 8 Hz).

WO 92/04045 PCr/US91/06180 -137- EXAMPLE 39 Carbamic acid, r2-[r4-rf l-(hvdroxvmethvl)-2- Dhenylethylamino]-4-oxobutyllamino]-l-(1H-indol-3- Vlmethyl)- l-methyl-2 -oxoethVl] tricyclo r3.3.1.13,7 dec-2-yl ester, 0, N H 1

N"

1*I

II

Sten 1. Butanoic acid, 4-[r3-(1H-indol-3-l)-2methvl-l-oxo-2-f (tricyclo33.3.1 3 7 dec-2-yloxv)carbonyl laminolpropvll aminol-,

D

fLNH A solution of the methyl ester (Example 38, Scheme 8, No. 60) (2.6 g, 5.2 mmol) in 1,4-dioxan (500 mL) was treated dropwise with a solution of LiOH (104 mL of a 0.05M solution, 5.20 mnol) over 24 hours with vigorous stirring. This mixture was stirred at room temperature for 24 hours and quenched with 1M HC1 (5.2 mL). The solvent was removed in vacuo and the residue chromatographed using 0.5% AcOH, 5% MeOH in 1 WO 92/04045 PCT/US91/06180 -138-

CH

2 C12 to give 80 mg of starting ester along with 1.32 g of product, 55% yield, 77% conversion, m.p.

92-96 0 C (CH 2 Cl 2 [iL] 2 0 29.30 MeOH); IR (film) 3600-3200, 2909, 2856-, 1702, and 1651 cm- 1 NMR (CDC1 3 8 1.50-1.55 (2H, mn), 1.61 (3H, 1.62-2.00 (14H, 2.10-2.25 (2H, 3.20-3.40 (2H, 3.24 (1H, d, J 14.5 Hz), 3.45 (1H, d, J 14.5 Hz), 4.84 (1H, s), 5.47 (1H, 6.58-6.65 (1H, br 7.03 (1H, d, J 2 Hz), 7.09 (IH, t, J 7 Hz), 7.17 (1H, t, J 7 Hz), 7.35 (1H, d, J 8 Hz), 7.57 (1H, d, J 8 Hz), 8.59 (1H, s) Anal. C 2 7

H

3 5

N

3 0 5 '0.2H20; C, H, N.

Step 2 A solution of the acid (Step 1, Scheme 8, No. 61) (240 mg, 0.5 mmol), and pentafluorophenol (92 mg, 0.8 mmol) in EtOAc (20 mL) was cooled to 0°C and treated with a solution of N,N'-dicyclohexylcarbodiimide (108 mg, 0.55 mmol) in EtOAc (5 mL).

This mixture was left at 0°C for 12 hours, filtered, and the filtrate treated with S-phenylalaninol. This reaction mixture was left stirring at room temperature for 24 hours, the 'lvent removed in vacuo, and the residue chromatogrE )hed using 10% MeOH in CH 2

CL

2 as eluant to give th product as a white solid (153 mg, IR (film) J500-3200, 207, 2850, 1692, and 1642 cm-; NM (CD 3 0D) 5 1.43 (3H, 1.50-1.70 (4H, 1.75-1.95 (8H, 2.00-2.15 '6H, 2.7s (1H, dd, J 14 and 8 Hz), 2.91 (1H, dd, J 14 and 6 Hz), 2.95-3.35 (3H, 3.45-3.50 (3H, 4.07-4.17 (1H, .n 4.81 (1H FOD), 6.93-7.09 (3H, 7.10-7.30 7.31 (1H, d, J 8 Hz), 7.53 (1H, d, J 8 Hz).

WO 92/04045 PCT/US91/06180 -139- EXAMPLE Tricyclo 3.3. 1. 13, 7] dec-2-vl- 3- (1H-indol-3-lmethyl)-2,5-dioxo-l-(2-phenvlethvl)-3-prrolidinvll carbamate (68) Step 1. Methyl-(±)-B-amino-S-[(phenylmethoxy)carbonvl]-lH-indole-3-butanoate (64) 1-Methyl-(±)-B-cyano-1-[1,1-dimethylethoxy)carbonyl]-1H-indole-3-butanoate (63) (0.241 g, 0.50 mmol) was dissolved in ethanol (5 mL). The solution cooled to -5 0 C in an acetone-ice bath and ethanolic HC1 was added dropwise. H20 (0.1 mL) was added and the reaction was warmed to room temperature.

The solution was left to stir for 24 hours, and the solvent evaporated off in vacuo. The oil was dissolved in ethyl acetate (50 mL) and washed with Na 2

CO

3 (50 mL) solution. The organic layer was dried (MgSO 4 filtered, and evaporated to dryness. The product was isolated by flash chromatography (ethyl acetate:hexane, 1:1) to yield the wanted product.

(0.120 g, 67%) as a yellow oil, 1max (cm thin film) 3350 3425 (NH br); 1741 (CO ester), H (300 M Hz, CDC1 3 5 2.12 (2H, brs, NH 2 3.17 (1H, d, J 18 Hz,

CH

2

CO

2

CH

3 3.28 (1H, d, J 18 Hz, CH 2

CO

2

CH

3 3.37 (1H, d, J 15 Hz, indole-CH 2 3.43 (3H, s, OCH) 3.53 (1H, d, J 15 Hz, indole-CH 2 4.82 (1H, d, J 12 Hz, CH 2 Ph); 4.92 (1H, d, J 12 Hz, CH 2 Ph); 6.73 (1H, d, J 2 Hz, 6.95-7.21 (8H, m, 5-H 6-H 7-H Har,); 7.47 (1H, s, 8.42 (1H, s, NH).

WO 92/04045 PCT/US91/06180 -140- Step 2. Methyl-(±)-8-[(phenylmethoxv)carbonyll-8- [(tricyclo-3.3.1 3 1' 7 Idec-2-loxy)carbonVll amino -1H-indole-3-butanoate Methyl-(±)-1-amino-S-[(phenylmethoxy)carbonyl]- 1H-indole-3-butanoate (64) (120 mg, 0.33 mmol) was dissolved in dry TEF (10 mL) under argon.

0.40 mmol) was injected. The solution was cooled to OC in an ice- alt bath and 2-adamantyl chloride (77 mg, 0.36 mmol) dissolved in THE (5 mL) was injected. The solution was stirred for 12 hours at room temperature before triethylamine hydrochloride was filtered off. Dichloromethane mL) was added and the solution was washed with water (2 x 25 mL). The organic payer was dried (MgSO 4 filtered, and evaporated to dryness. The product was isolated by flash chromatography (ether: hexane, to furnish the title compound (105 mg, m.p. 61.5-62.5C. (cm thin film) 3412 1738 H (300M Hz, CDC1 3 1.49-2.09 (14H, m, adamantyl-H); 3.12 (1H, d, J 15 Hz, CHH 2

CO

2

CH

3 3.30 (1H, d, J 15 Hz, CH 2

CO

2

CH

3 3.38 3H, OCH 3 3.72 (1H, d, J 15 Hz, indole-CH 2 3.80 (1H, d, J Hz, indole-CH 2 4.83 (1H, brs, CH); 4.98 (1H, d, J 112 Hz, PhCH 2 5.11 (1H, d, J 12 Hz, PhCH 2 6.88 (1H, s, NH); 6.79 (1H, s, 7.03 (1H, t, J 7 Hz, 7.14 (1H, t, J 7 Hz, 7.17-7.34 (6H, m, 7-H, Harom), 7.48 (1H, d, J-8 Hz, 8.30 (1H, s, NH). m/z (FABl) 545 501; 130. Found: C, 70.6%; H, N, C 32

H

36

N

2 0 6 requires C, 70.6%; H, N, L WO 92/04045 PCT/US91/06180 -141- Step 3. Methyl-(+()-I-carboxy-.-[ (tricvclo- 3 dec-2-yloxy) carbonvl] amino] -lH-indole-3butanoate (66) In a 250-mL glass vial, (phenylmethoxy)carbonyl]-B-( (tricyclo 3.3.1.13 7 dec- 2-yloxy)carbonyl[amino]-1H-indole-3-butanoate (105 mg, 0.19 mmol). Palladium on charcoal Ca mg) and ethanol (75 mL) was added. The vessel was sealed in a Parr Hydrogenation Apparatus and charged with H 2 gas (45 psi). Shaking was initiated after pressurization and continued for 12 hours. Upon completion, palladium on charcoal was filtered of and the filtrate evaporated to dryness. The product was isolated by flash chromatography (methanol: water, 2:1) to yield a white powder (77 mg, m.p. 108-900C. max (cm thin film) 3413 (NH); 1733 5 H (300M Hz, CDCI 3 1.47-2.07 (14H, m, adamantyl-H); 3.14 (1H, d, J 16 Hz, CH 2

COCH

3 3.26 (1H, d, J 16 Hz, CH2C0 2

CH

3 3.64 (3H, s, OCH 3 3.76 (1H, d, J 15 Hz, indole-CH 2 3.84 (1H, d, J 15 Hz, indole-CH 2 4.83 (1H, brs, CH); 5.75 (1H, brs, OH); 5.96 (1H, s, NH); 6.98-7.04 (2H, m, 2-H 7.10 (1H, t, J 7 Hz, 7.28 (1H, d, J 8 Hz, 7.61 (1H, d, J 8 Hz, 8.34 (1H, s, NH). 6 c (75.5M Hz, CDC1 3 27.0, 27.2 31.3, 31.7, 32.1, 36.4, 37.4, 39.7, 51.8, 62.4, 78,0, 108.9, 111.1, 118.7, 119.4, 121.7, 124.1, 128.2, 135.7, 154.8, 171.3, 176.2. m/z (FAB) 455 411, 217, 135, 130. Found: C, 65.7%; H, N, C 2 5

H

3 0

N

2 0 6 requires C, 66.1%; H, 6.65%; N, 6.2%.

1- z i WO 92/04045 PCT/US9I/06180 -142- Step 4. Methyl- -3-Ft(2-phenylethyl) aminol carbonyl- (tricyclo[r3. 3. 1.1 3 dec--2-vloxy) carbonyl Iamino IlH-indole-3-butanoate (67) Methyl- -13- [(tricyclo [3.3.1.1i 3 dec-2-yloxy) carbonyl[amino]-lH-indole-3-butanoate (66) (200 mg, 0.44 minol) was dissolved followed by dicyclohexylcarbodiamide (100 mg, 0.48 mmol) .The solution was left stirring for 2 hours before phenylethylamine (60 mg, 0.50 mmol) was injected to the solution. The mixture was left stirring overnight. The solution was evaporated down to dryness, ethyl acetate added, and dicyclohexylurea filtered off. The filtrate was evaporated down to dryness and the product was isolated by flash chromatography (hexane:ethyl acetate, 3:1) to give a white solid (180 mg, m.p. 78.0-79.5 0 C. uma, (cmthin film), 3333 (NH) 1730 (CO) 1659 (CO amide), H (300M Hz, CDCl 3 81.51-2.04 (14H, m, adaniantyl-H); 2. 61 (2H, m, CH 2 NH); 2. 94 (1H, d, J 16 Hz, CH 2

CO

2

CH

3 3.21 (1H, d, J 16 Hz, CH2C0 2

CH

3 3. 37 (lIH, d, J 7 Hz, C H 2 Ph) 3.41 (IlH, d, J 7 Hz, CH 2 Ph) 3. 46 (1H, d, J Hz, indole-CH 2 3.57 (1H, d, J 15 Hz, indole-CH 2 3.62 (3H, s, OCH 3 4.78 (1H, brs, CH); 5.88 (lH, brs, NH urethane); 6.58 (1H, brs, NH amide); 6.92 (1H, d, J 2 Hz, 7.03-7.26 (7H, m, 5-H 6-H Haro.m); 7-3 (1H, d, J 8 Hz, 7.56 (1H, d, J 8 Hz, mz/ (FAB) 558 362, 331, 231, 135, 130, 105.

(Found: C, 69.0; H, 6.8; N, 7.2. C 33

H

3 9N 3

O

5 75H 2

O

requires C, 69.4; H, 7.1; N, 7.4).

1 WO 92/04045 PCT/US91/06180 -143- Step 5. Tricyclo[3.3..1.1 3 7 ]dec-2-vl-(±)-[3-(IH-indol- 3-vl-methyl)-2,5-dioxo-l-(2-phenylethyl)- 3-pyrrolidinvll-carbamate'(68) The ester (67) above (110 mg, 0.20 mmol) was dissolved in 20 mL THF and cooled to 0°C. Lithium hydroxide (21 mL, 0.01 M) was added dropwise to the solution over a 3-hour period. The solution was kept stirring for a further 1 hour and then allowed to warm to room temperature. Hydrochloric acid (2.1 mL, 0.1 M) was added and the solution extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried with AgSO 4 filtered, and evaporated to dryness, to afford (105 g, 98%) of crude product.

The product was isolated by flash chromatography (methanol:water, 4:1) as a white powder (84 mg, 1)max (cm- 1 thin film). 3347 2912 (CH); 1781 1701 H (300M Hz, CDC13) 5 1.55-1.97 (14H, m, adamantyl-H); 2.38 (2H, m, NHCH 2 3.00 (1H, d, J 18 Hz, CH 2 CON); 3.05 (1H, d, J 15 Hz, indole-CH 2 3.47 (2H, t, J 8 Hz, CH 2 Ph); 4.80 (1H, s, CH); 5.49 (1H, s, NH); 7.04-7.35 (8H, m, 5-H 6-H 7H Harom; 7.56 (1H, d, J 8 Hz, 8.68 (1H, s, NH). C (75.5M Hz, CDC13), 26.9, 27.1, 31.7, 32.0, 36.3, 37.3, 39.8, 40.2, 59.95, 76.4, 107.3, 111.4, 118.6, 120.2, 122.7, 123.7, 126.4, 127.4, 128.7, 136.0, 138.0, 154.9, 174.1, 176.1. m/z 528 527, 526, 374, 331, 130. Found: C, 72.6%; H, N, C 3 2

H

3 5

N

3 0 4 0.25H 2 0 requires C, 72.5%; H, N, EXAMPLE 41

(R

2 Me, see Scheme A suspension of powdered sodium hydroxide (2 g, mmol) and ethyl 2-cyanopropionate (20 g, 157 mmol) in 150 mL toluene was heated under nitrogen atmosphere WO 92/04045 PCT/US91/06180 -144to 1000C and gramine (30.1 g, 172 mmol) added in portions. After 30 minutes the temperature was raised to 1300C (oil bath) and the mixture gently refluxed for 16 hours. Then 100 mL water and 200 mL ethyl acetate were added, the mixture neutralized with acetic acid, the organic layer separated, washed with water (100 mL), dried (sodium sulfate) and evaporated.

The residue was purified by chromatography over silica gel using toluene/ethyl acetate v/v, Rf 0.4).

2a was isolated as a light brown viscous oil (34.5 g, MS (70eV): m/z 256 (Mi, 130 (100%).

EXAMPLE 42

(R

2 Me, see Scheme Compound 2a (5 g, 19.5 mmol) in 250 mL dioxane, saturated with ammonia, was hydrogenated (100 bar, 0 C) with Raney nickel alloy (0.95 g) in an autoclave for 1 hour. After filtration and evaporation the residue was purified by chromatography over silica gel using dichloromethane/methanol (95:5, v/v, Rf 0.1).

3a was isolated as a colorless viscous oil (4.76 g, 94%) MS (70eV) m/z 260 (M 17), 130 (100), 117 (48).

EXAMPLE 43

(R

1 2-adamantyl, R 2 Me, see Scheme To a stirred solution of 2 -adamantylchloroformate (4.45 g, 20.7 mmol) in dry THF (50 mL) under N 2 atmosphere was added a solution of 3a (4.76 g, 18.3 mmol) in dry THF (100 mL) followed by a solution of triethylamine (3.7 g, 36.6 mmol) in dry THF (50 mL) dropwise. After 15 minutes the reaction mixture was filtered, the solvent removed and the residue column chromatographed on silica gel using CH 2 Cl 2 /MeOH (98:2) WO 92/04045 PCT/US91/06180 -145as eluents to yield 4a as a colorless amorphous solid (7.8 g, MS (70eV): m/z 438 20), 130 (100) EXAMPLE 44

(R

1 2-adamantyl, R 2 Me, see Scheme To a solution of 4a (3.9 g, 8.9 mmol) in dioxane/H 2 0 2:1 (60 mL) was added an excess of LiOH (0.325 g, 13.5 mmol) and stirred at room temperature for 72 hours. After removing the solvent in vacuo the residue was suspended in water (50 mL), neutralized with acetic acid, extracted with CH 2 Cl 2 and the organic layer separated and dried (sodium sulfate).

After filtration and evaporation the residue was chromatographed using CH 2 Cl 2 /MeOH 95:5 Rf 0.3) as eluents to yield the acid 5a as a colorless, amorphous solid (2.5 g. MS (70eV): m/z 410 (M 130(100).

EXAMPLE

(R

1 2-adamantyl, R 2 Me, R 3

-CH

2 OH, c 1, R H, see Scheme Carbamic acid, [3-[[1-(hvdroxymethyl)-2phenvlethyl amino (1H- indol-3-vlmethyl) -2-methvl- 3-oxopropyl]-, tricyclo[3.3.1.13,7] dec-2-yl ester [S- To a solution of 5a (1 g, 2.44 mmol) in dry ethyl acetate (40 mL) was added pentafluorophenol (0.45 g, 2.44 mmol) and stirred for 10 minutes. The reaction mixture was cooled to 0oC and a solution of dicyclohexylcarbodiimide (0.505 g, 2.44 mmol) in ethyl acetate (10 mL) was added dropwise. This solution was stirred for one hour at OOC then at room temperature for four hours before leaving it at 4oC overnight.

The mixture was filtered and the precipitate washed with cold ethyl acetate (10 mL) and a solution of WO 92/04045 PC/US91/06180 -146- (-)-phenylalaninol (0.405 g, 2.68 mmol) in ethyl acetate (25 mL) was added dropwise to the combined filtrates. The mixture was left to stir for 4 days at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL), dried (sodium sulfate) and evaporated. The residue was chromatographed on silica gel using

CH

2 Cl 2 /MeOH (98:2) as eluants to yield 6a as a colorless amorphous solid (0.780 g, 59%, mixture of two diastereomers), m.p. 85-950C. CI-MS (70eV, NH3): m/z 544 100), 392 (76) In an analogous manner Examples 46-57 are prepared: configuration at the chiral C-atom of the substituted 2-phenylethylamide residue, R 2 center is always RS) EXAMPLE 46

R

1 (1S)-2-borny, R 2 Me, R3 R 4 H, c 1) Carbamic acid, [2-(lH-indol-3-vlmethyl)-2-methvl-3oxo-3-rF(2-phenylethyl)aminolpropvl-, 1,7,7trimethylbicvclor2.2.11 hept-2-v1 ester (Bicyclo system is 1S-endo, chain center is RS) m.p. 60-70 0 C, MS (70eV): m/z 515 130 (100) EXAMPLE 47 (RI 1-adamantyl, R 2 Me, R 3

R

4 B, C 1) Carbamic acid, -2-(1H-indol-3-vlmethyl)-2-methyl-3oxo-3-r(2-phenylethyl)aminolpropyl-, tricvclo- [3.3..1 3 7 ]dec-1-l ester, m.p. 75-850C, MS (70eV): m/z 513tM+,100), 305(91)

L--OICI-_

I L -i.

WO 92/04045 PCT/US9I /06180 -147- EXAMPLE 48 (1Rl 2-adamantyl, R 2 Me, -3 R 4 c= Carbamic acid, (1H-indol-3-Vlmethyl) -2-methVl-,3oxo-3-t phenylethvl)aminolpropyll-t tricyclo[3.3.1.1 3 7 1dec-2-yl ester, m.p. 75-850!C, MS (70eV): m/z 513 25) .305 (88), 134 (100) EXAMPLE 49 (Rl UlS) -2-bornyl, R 2 Me, R 3

CH

2 OH, R 4

H,

c 1, C* S) Carbamic acid, (hydroxvmethyl) -2pheny lethvll1amino 1-2--(lH-indol-3-y imethyl) -2-metlh oxo ropyll-1,7,7-trimethVlbicyclo r2.2.11he~t2v ester (Bicyclo system is 1S-endo, hvdroxymeti~v1. cen2t-r is S, other center is RS) rn.p. '75-850C, MS (70eV) :m/z 545 130 (77) 44 (100) EXAMPLE *(RI 2-adamantyl, R 2 Me, j, 3

H,

R

4

-NHCOCH

2

CH

2 00 2 Bz, -c 1, C* =R) 14-Oxa-2, 6, 9-triazapentadecanoic acid, 4- (lH-indol-3- 10, 13-trioxo-8, tricvclo[3.3.1.1 3 7 1-dec-2-yl ester, m.p. 80-9000. Cl-MS (CH4). m/z 611 (21) 459 (21) 135 (100) WO 92/04045 PCC/US9I/06180 -14 8- EXAMPLE 51

-CR

1 2-adamantyl, Me, R 3 wH, R= NHCOCH CHC0 2 Me,- ,Cc R 14-Oxa-2, 6, 9-triazapentadec-li-eloic acid, [4-(1Hindol-3-vl-methyl) -4-methyl-S. 10, 13-trioxo-8-phenvl-.

tricvclot3.3.1.j 3 dec-2-vl ester, m.p. 105-1200C, CI-MS (CH 4 mlz 641 (MH~l 151 135 (100) EXAM4PLE 52 (RI 2-adamantvl.,- R 2 =me, R 3 H, 1, NHCO, -t-BUL c ItC =R) 11-Oxa-2, 6.9-triazatridecanoic acid, 4- C 1H-indol-3tricyclot3.3.-1.1 3 7 1 dec-2-vl ester, m.p. 100-IIOOC, CI-MS (CH 4 m/z 629 (Mli 4 8)r 135 (100) 2-adamantyl, R2 Me, R 3 Hi, utanic aid,4-Ur2-rr2-(lH-indol-3-vlmethyl)-2methl-loxo--tt(tricvcloC3.3.1.137dc2 %,Ixv~arbnylamino) -,ropv1) aminol-1- -oeveihlamino1-4-oxo-, RC*R)1 110-125 C -MS (CH 4 m/z 628 (M 121), 164 (100) wVo 92/04045 PCr/US91/06180 -149- EXAM~PLE 54

C(R

1 2-adamantyl, R, =-MeR H, R4 NHCOCH CH- CO,2H, c 1, C* R) 2-Butenoic acide 4-f 2-f f2-(1H-indol-3-vlmethyl) -2methyl-1-oxo-3-f f (tricyclor3.3.1..1 3 7 ]dec-2vloxv) carbonvillamino) -pro~y')aminol -1-thenvlethvl1 -4oxo- center RS; -other center R, double bond EY m.p. 210-2200C, CI-MS (CHO)' m/z 626 474 (100)t, 164 (88) EXAMPLE (RI 2-adamantyl. R 2 Me, R 4 c 0) Carbamic acid, V 2- (1H-indol-3-vlmethvl) -2-methyl-3oxo-3-f (phenyl methyvl)-aminolpropyll-, tricvclor3.3.1.1 3 7 1dec-2-vl ester, m.p. 80-900C, MS (70eV): 499 291 (47), 130 (100) EXAMPLE 56

(R

1 (IS)-2-bornvl, R 2 Me, R 3

=CH

2

OCOCH

2 CHCo 2 R4 H, c =1I C' S) Butanedioic acid, mono 2-fr2-(1H-indol-3-vlmethvl)-2methvl-1-oxo-3- f 7-trimethylbicvclo[2.2.11he~t-2vloxy) carbonyll -am.iolpro-oy11amino1 -3-PhenvlDro~vl ester (Bicvclo system is iS-endo, phenylmethvl center is S, other center is RS) m.p. 115-130, CI-MS (CHO) m/z 646 (MWl", 34), 528 (78)t, 101 (100) WO 92/04045 PCT/US91/06180 -150- EXA2MPLE 57

(R

1 2-adamantyl, R 2 Me, R 3

CH

2 0COCH2CH 2

CHCO

2 R H, c 1, C S) Butanedioic acid, (2-([2-(1H-indol-3-vlmethyl)-2methvl-1-oxo-3-[ r (tricyclo[3.3.1.1 3 7 1dec-2vloxy)carbonyllaminolproevl)-aminol-3 phenylropyl ester(Trp cehter RS; other center S) m.p. 85-950C, CI-MS (C 4

H

10 m/z 643 16), 642 235 (100) The conversion of compound 5a (R 1 2-adamantyl,

R

2 Me) to the compounds 6f, 6g, 6h, 6i, 6k, and the conversion of compounds 6a and 6e to the compounds 6m and 6n has been done in analogy to already described procedures. Compounds of general formula Ia, where

R

2 R3 and R 4 are H are also prepared according to synthetic scheme EXAMPLE 58 (c 1, see Scheme A solution of N-(P-phenylethyl)cyanoacetamide (8a, 18.8 g, 0.1 mol), indole-3-carboxaldehyde (14.5 g, 0.1 mol) and piperidine (5 drops) in ethanol (100 mL) was refluxed for 16 hours. After cooling to room temperature the precipitate was filtered off, washed with ethanol (2 x 20 mtL) and dried to give 9a as yellow crystals (29 g, MS (70eV): m/z 315 195 (100).

EXAMPLE 59 (c 1, see Scheme Compound 9a (3.15 g, 10 mmol) in 50 mL dioxane, saturated with ammonia, was hydrogenated (100 bar, BOOC) with Raney nickel alloy (0.5 g) in an autoclave for 17 hours. After filtration and evaporation the

I

i 3 -t WO 92/04045 PCT/US91/06180 -151residue was chromatographed on silica gel using

CH

2 C12/MeOH 9:1 as eluents. 10a was obtained as colorless crystals from ethyl acetate (1.16 g, 36%).

MS (70eV): m/z 321 (M 46), 170 130 (100).

EXAMPLE

(R

1 2-adamantvl, c 1, see Scheme Carbamic acid, f2-(1H-indol-3-vlmethyl)-3-oxo-3-[(2phenylethyl) aminolpropyl tricvclor3.3.1.1 3 '7 dec-2vl ester, The conversion of 10a to 11a was done according to the conversion of 3a to 4a. After chromatographic separation using CH 2 C12/MeOH 98:2 as eluents lla was isolated as a colorless amorphous solid m.p.

115-1400C. MS (70eV): m/z 499 (M 291 (100).

EY MPLES 61 AND 62 (c 1, see Scheme A suspension of powdered sodium hydroxide (0.5 g, 12.5 mmol) and N-(P-phenylethyl)cyanoacetamide (8a, 8 g, 42.5 mmol) in 50 mL toluene was heated under nitrogen atmosphere to 100oc and gramine (7.4 g, 42.5 mmol) added in portions. After 30 minutes the temperature was raised to 1300C (oil bath) and the mixture gencly refluxed for 2 hours. Then 50 mL water and 200 mL ethyl acetate were added, the mixture neutralized with acetic acid, the organic layer separated, washed with water (100 mL), dried (sodium sulfate) and evaporated. The residue was separated by chromatography on silica gel using CH 2 C12/EtOAc 9:1 as eluents.

1. fraction: compound 13a as colorless crystals g, 47%) MS (70eV) m/z 446 (M 130 (100).

2. fraction: compound 12a, colorless crystals from WO 92/04045 PCT/US91/06180 -152-

I+

ethanol (3.05 g, MS (70eV): m/z 317 18), 130 (100) EXAMPLE 63 (Rk 2-adamantyl, c 1) Carbamic acid, 12,r2-bis(1H-indol-3-vlmethyl)-3-oxo-3- (2-phenlethyl) aminol propvl1-, tricvclor3.3.1.1 3 7 dec-2-vl e. -er The conversion of 13a (c 1) to 17a 2adamantyl, c 1) was completed in analogy to the conversion of 2a to 4a. After purification by chromatography on silica gel using CH 2 Cl 2 /MeOH 98:2 17a was isolated as a colorless amorphous solid (yield from 13a), m.p. 105-1100C. CI-MS (NH 3 m/z 629 (MHl, 100%) EXAMPLE 64 (R1 1-adamantvl, R 2 Me, see Scheme 16) To a stirred solution of 3a (3 g, 11.5 mmol) in anhydrous THF (100 nL) at room temperature was added adamantane-1-carbonyl chloride (2.28 g, 11.5 mmol), followed by a solution of triethylamine (3.2 mL, 23 mmol) in THF (20 mL) dropwise. The reaction was complete after 30 minutes as assayed by thin layer chromatography. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purifie( by chromatography over silica gel using

CH

2 Cl 2 /MeH 98:2 as eluents. 18a was isolated as a colorless amorphous solid (3.25 g, MS m/z 422 35), 293 130 (100) EXAMPLE (R 1-adamantyl, R 2 Me, see Scheme 16) To a solution of 18a (3.25 g, 7.7 mmol) in 1.4dioxane/H 2 0 90 mL) was added an excess of LioH i WO 92/04045 PCT/US91/06180 -153- (0.37 g, 15.4 nunol) and the solution stirred at room temperature for 48 hours. After removing the solvent in vacuo the residue was dissolved in water (150 mL), acidified with citric acid (10% in water) and extracted with dichloromethane (2 x 100 mL) The organic layer was dried (Na 2

SO

4 and evaporated. 19a was isolated as a colorless, amorphous solid (3 g, =100%) .TLC (silica gel): Pf 0. 2 (CH 2 Cl 2 '/MeOI4 95:5).

EXAMPLE 66 (R1 =-1-adamantyl, R 2

R

3 =-CH OH, c- 4

H,

see Scheme 16) 1H-Indole-3-propanamine, N-f1- (hydroxymethyl) -2vhenylethyll-- methl-o-rr (tricyclor3.3.1.1 3 7 1dec-2ylcarbonvl)aminolmethyll- (indole center is R.S, other center is S) The conversion of 19a to 20a was done in analogy to the conversion of Sa to 6a. After purification by chromatography on silica gel using CHC1 2 /MeOH 98:2 was isolated as a colorless amiorphous solid m.p. 85-950C. MS (70eV) m/z 527 335 (100).

There is obtained in an analogous manner: EXAMP'LE 67

(R.

1 1-adamantyl, R. e H, c P.

4

-H)

IH-Indole-3-propanamide. cc-methyl-N- (2-phenylethyl) r f (tricvclot3.3.1.1 3 ,'Thdec-2-vlcarbonVl) aminolmethyll, A colorless amorphous solid, m.p. 80-900C. MS m/z 497 305 184 135 (64), 130 (100).

L

WO 92/04045 PCT/US91/06180 -154- EXAMPLE 68 (See Scheme 17) In an autoclave l-(3'-indolyl)-butan-3-one (12.32 g, 65.9 mtol), potassium cyanide (4.7 g, 72.3 mmol), ammonium carbonate (6.9 g, 71.8 mmol) and ammonium hydroxide 13 mL) in water (25 mL) and methanol (75 mL) were heated to 600C for 16 hours with stirring. The solution was diluted with water (100 mL), the methanol evaporated and the residual mixture acidified (2n HC1). The precipitated hydantoin 21 was filtered off, washed with water and dried. Yield: 15.2 g colorless crystals. MS m/z 257 (M 22), 144 130 (100) EXAMPLE 69 -(See Scheme 17) In an autoclave 21 (10 g, 38.9 mtol) in 5% aqueous sodium hydroxide (125 mL) was heated to 1500C for 16 hours. After cooling to room temperature, the solution was neutralized with hydrochloric acid (37%) and if necessary filtered immediately to remove traces of hydantoin 21. The solution was stirred at room temperature for 2 hours and the precipitated amino acid 22 filtered off, washed with water (20 mL) and dried. 22 was isolated as pale beige crystals (8.52 g, MS (70eV): m/z 232 (M 26), 144 qi (100), 130 (92).

EXAMPLE (See Scheme 17) A solution of 22 (5 g, 21.5 mmol) in dry methanol (375 mL) was warmed to 400C and saturated with hydrogen chloride (1 hour). After stirring at 40-450C for 5 hours and at room temperature for another hours the solvent was evaporated. Water (100 mL)

-J

i- C WO 92/04045 PCr/US9/06180 -155was added, the mixture neutralized with aqueous sodium carbonate and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with diluted sodium bicarbonate solution (50 mL) then with water (50 mL) and dried (Na 2

SO

4 After removing the solvent the residue was chromatographed on silica gel using CH 2 C12/MeOH 98:2 as eluents. 23 was isolated as beige crystals (4.0 g, MS (7 eV): m/z 246 (M 25), 144 130 (100).

EXAMPLE 71

(R

1 2-adamantvl, see Scheme 17) The reaction of aminoester 23 with 2-adamantylchloroformate was done according to the conversion of 3a to 4a. 24a was isolated in 86% yield as a colorless amorphous powder. MS (70eV): m/z 424 42), 281 144 (100), 135 (78).

EXAMPLE 72

(R

1 2-adamantyl, see Scheme 17) The hydrolysis of 24a with lithium hydroxide was done according to the hydrolysis of 4a to 5a. 25a was isolated without chromatography as a pale beige amorphous powder in quantitative yield, pure enough to be used in the next step (see Example 73) without further purification. MS (70eV): m/z 410 (Mi, 130 (100).

EXAMPLE 73

(R

1 2-adamantyl, R 3

R

4 H, c 1, see Scheme 17) Carbamic acid, r3-(lH-indol-3-vl -l-methyl-.-L (2phenvlethvl) aminol carbor:vl]propyl1 tricvcl r3.3.1.1 3 7dec-2-vl ester, The conversion of 25a with 2-phenylethylamine to 26a was done according to the conversion of 5a to 6a.

~1- WO 92/04045 PCT/US9I/06180 -156- After chromatographic separation on silica gel using

CH

2 C1 2 /MeOH 98:2 26a (Rf 0.2) was isolated in 69% yield as a colorless amorphous powder, m.p.

75-850C. MS (70eV): m/z 513 370 130 (100).

In analogous manner are prepared: configuration at the chiral C-atom of the substituted 2-phenylethylamide residue, other center is always RS) EXAMPLE 74

(R

1 2-adamantyl, R 3 CH20H, R 4 H, c 1, C S)_ Carbamic acid, rI- r 1- (hvdroxvmethyl) -2-phenvlethyll amino I carbonyl (1H-indol-3 -vl) -1 -methyipropl I l-, tricyclor3.3.1.1 3 7 1dec-2-vl ester (hvdroxvmethvl center is S, other center is RS) m.p. 80-900C, Cl-MS (C 4

H

10 m/z 544 2) 392 (100) EXAMPLE

(R

1 (S)-2-bornyl, R 3 R4 H, c 1 Carbamic acid, 13-(1H-indol-3-Vl)-1-methyl-1-r (2phenylethyl) -aminol carbonylipropyl]-, 1,7, 7-trimethylbicvcloE2.2.llhept-2-yl ester, r1R-f1a,28(S), 4(IIm.p. 70-8000, Cl-MS (OH 4 m/z 516 362 (100) EXAMPLE 76

(R

1 2-adamantyl, R 3 H, R 4 NHCOCH CHCO 2 Me, c 1, C* R) 13-Oxa-2,5,-8-triazatetradec-O-enoic acid, 3-[2-(lHindol-3-vl) ethyl)-3-methyl-4,5,12-trioxo-7-phenyl-, tricyclo-[3.3.1.1 3 7 1dec-2-l ester (TRP center is R/S mixture, other center is R, double bond E) m.p. 117-1230C, CI-MS(C4H1O): m/z 640(M-,19), 487(100) 1 WO 92/04045 PCr/US91/06180 EXAPL 77 (Rl 2-adamantvl, R 3

R

4 NHiCOCH2CHi2002Bz, c =1 13-oxa-2,5, 8-triazatetradecanoic acid, 3-r2-(lH-indolethyl] -3-methyl-4, 9, 12-trioxo-7, 14-diphenyl-, tricvclo-[3.3.j..1 3 7 jdec-2-V1 ester (TRP center is R/S mixtu~re, other center is R) m.p. 85.-950C, Cl-MS (C 4

H,

0 m/z 627 475 (100), 251 (44) EXAMPLE 78 (RI (1S)--2-bornyl, R 3

=CH

2 0H, R 4 c C" S) Carbamic acid, f 2-[rf1- (hydroxvmethyl) -2- D~henvlethvl] aminol -carbonvil]-3- (lH-indol-3-vl) -1methvlpro-oy11-, 1,7, 7-trimethylbicyclo-r2 .2 .1]he~t-2vl ester (Bicvclo system is IS-endo, hydroxvmethvl center is S, other center is RS) m.p. 75-850C, Cl-MS (CH 4 :m/z 546 (MU 4 82) 153 (100) EXAMPLE 79 2-adamantyl, R 3 H, R 4

NHCOCH

2

CH

2 2Co 2 H, c 1, Butanoic acid, 4-f f2-f f4-(lH-indol-3-yl) -2-methyl-loxo-2-[ (tricyclo [3.3.1.1 3 7 Idec-2-vloxy)carbonyllaminolbutyl] amino] -1-vhenylethv1] amino] -4-oxo- (indole center is RS, other center is R) m.p. 115-1250C, Cl-MS (C 4

H

1 0 :m/z 629 (MHi4, 1) 191 (28) 135 (100) i i_.l- WO 92/04045 PCT/US91/06180 -158- EXAMPLE

(R

1 2-adamantvl, R 3 H, R -NHCOCH CHCO2H, c 1, C* R) 2-Butenoic acid, 4-[2-[[22-2-(1H-indol-3-vl)ethyl]-2methyl-1-oxo-3-[ (tricyclo[3.3.1.1 3 '7]dec-2-vloxy)carbonvl]amino]propvllamino]-1-phenylethyl]-4-oxo- (indole center is RS, other center is R, double bond

E)

m.p. 190-2000C, CI-MS (NH 3 m/z 626 24), 201 151 (100) The conversion of 26d to 26h and the conversion of 26e to 26g were done in analogy to already described procedures.

EXAMPLE 81 (See Scheme 18) The method is as described for 2a (compare lit.

J. Orq. Chem. 18:1440, 1447, 1953). Alkylation of diethyl methylmalonate with gramine provided compound 28 after chromatographic separation on silica gel using CH 2 C12/MeOH 98:2 as eluents as a light red brown syrup (yield MS (70eV): m/z 303 (M 11), 130 (100).

EXAMPLE 82 (See Scheme 18) To a solution of the diester 28 (31 g, 0.102 mol) in dry ethanol (80 mL) was added a solution of potassium hydroxide (6.5 g, 0.116 mol) in ethanol mL) dropwise at room temperature (1 hour) and stirred for another 16 hours. The reaction mixture is filtered and the filtrate evaporated. The residue is suspended in water (700 mL), neutralized with hydrochloric acid and extracted with ether (3 x 1 WO 92/04045 PCT/US91/06180 -159- 250 mL). The ether solution was dried (Na 2

SO

4 evaporated and the residue purified by chromatography on silica gel using CH2C1 2 /MeOH 95:5 as eluents.

The monoacid 29 (Rf 0.1) was isolated as a light redbrown syrup (18 g, MS (70eV): m/z 275 (M 130 (100).

EXAMPLE 83 (See Scheme 18) To a solution of compound 29 (37 g, 0.134 mol) in dry tetrahydrofuran (500 mL) at 0oC under nitrogen was added dropwise a 2 M solution of borane-methyl sulfide complex in tetrahydrofuran (100 mL, 0.2 mol) (45 min.) and stirred for 3 hours at 00C. Then water (100 mL) was added dropwise, the mixture diluted with more water (400 mL) and ethyl acetate (800 mL). The organic layer was separated, washed with water (3 x 150 mL), dried (Na 2

SO

4 and evaporated. The residue was suspended in CH 2 Cl 2 (100 mL), the precipitated 29 filtered off and washed with CH 2 C12 (30 mL) 29 was isolated as colorless, sometimes slightly red crystals (26.74 g, pure enough to be used in the next step. TLC (silica gel): Rf 0.15 (toluene/tetrahydrofuran 1:1).

EXAMPLE 84 (See Scheme 18) To a solution of 30 (26.6 g, 0.114 mol) in dry methanol (1.5 1) were added 4 mL sulfuric acid 97%) and the solution stirred at room temperature for 2 days. The solution was neutralized with sodium bicarbonate solution, partially evaporated to remove the methanol, diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The organic layer was washed with water (250 mL), dried I. WO 92/04045 PCT/US91/06180 -160- (Na 2 S0 4 and evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate as eluentr. 31 was isolated as a colorless, viscous syrup (25.7 g, MS m/z 247 (M 130 (100).

EXAMPLE (See Scheme 18) To a solution of 31 (5.0 g, 20.2 mmol) and pyridine (3.2 g, 40.4 mmol) in dry dichloromethane (100 mL) at 000 was added p-toluene sulphonyl chloride g, 26.3 mmol) in small portions. The solution was allowed to stand for 4 days in the refrigerator at 0-50C. The solution was washed with sodium bicarbonate solution (2 x 50 mL), dried (Na 2

SO

4 and evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate 95:5 as eluents.

Compound 32 (Rf 0.3) was isolated as a viscous oil, which was recrystallized from diisopropyl ether to yield colorless crystals (6.94 g, MS m/z 401 (M 130 (100).

EXAMPLE 86 (See Scheme 18) Compound 32 (3.5 g, 8.13 mmol) and potassium cyanide (0.850 g, 13.1 mmol) in dry dimethylformamide (60 mL) were stirred at 1100C for 16 hours. The solution was evaporated in vacuo and the residue dissolved in ethyl acetate (200 mL) and water (200 mL) The organic layer was separated, dried (Na 2

SO

4 and evaporated. The residue was purified by chromatography on silica gel using toluene/ethyl acetate 9:1 as eluents. Compound 33 was isolated (Rf 0.4 in toluene/ethyl acetate 4:1) as a WO 92/4045 WO 92/44 PCT/US91/06180 -161colorless syrup (1 g, MS (70eV): m/z 256 (M 8) 130 (100) EXAMPLE 87

(R

1 2-adamantyl, R3 R 4 H, c 1, see scheme 18) Carbamic acid, (1H-indol-3-ylmethyl)-3-methvl-4oxo-4-[(2-phenylethyl)aminolbutvll-, tricycior3.3.1.1J,7]de\.-2-vl ester, (il- The conversion of compound 33 to compounds 37 has been done in analogy to the conversion of compounds 2 to compounds 6 (see synthetic scheme 15a). 37a has been isolated after chromatographic separation on silica gel using CH 2 Cl 2 /MeOH 98:2 as eluents as a colorless amorphous solid in 52% yield, m.p. 800C. MS (70eV): m/z 527 (M 130 (100) EXAMPLE 88

(R

1 2-adamantyl, R 3 -CH0H, R 4 H, c 1, see Scheme 18) Carbamic acid, r4-[ 1-(hydroxvmethyl)-2-Phenylethyllaminol-3-(1H-indol-3-Vlmethyl)-3-methvl-4-oxobutll-, tricvclo-3.3.1.a 3 7 ]dec-2-yl ester In an analogous manner to the synthesis of 37a, compound 37b has been isolated after chromatographic separation on silica gel using CH 2 C1 2 /MeOH 98:2 (v/v) as eluents as a colorless amorphous solid in 52% yield, m.p. 70-8000. MS (70eV): m/z 527 130 (100). 37b is a mixture of two diastereomers (S-configuration at the chiral center derived from (S)-(-)-phenylalaninol) EXAMPLE 89 Ethvlidene-isopropylamine (69) Isopropylamine (85 mI, 1.0 mol) was added gradually over a period of 1 hour to acetaldehyde p~ J I WO 92/04045 PCT/US91/06180 -162- (56 mL, 1.0 miol) cooled in an ice bath. After the addition was complete, the mixture was stirred for an additional 20 minutes. Potassium hydroxide flakes were added until the solution separated into two layers. The organic phase was separated and stored over crushed potassium hydroxide at 0 C. The dried material was distilled under vacuum at room temperature to yield the title compound (51.4 g, b.p. 25-30"C/10 mm; 8 H (300 M Hz; CDC1 3 1.09 (6H, d, J 6.3 Hz, 2CH 3 1.88 (3H, d, J 4.8 Hz,

CH

3

CH).

3-(Isooropyl-aminoethylidene)-indole A solution of indole (25.0 g, 0.213 mol) in glacial acetic acid (150 mL) was cooled in an ice bath and ethylidene-isopropylamine (69) (17.3 g, 0.203 mol) in toluene (50 mL) added dropwise, with stirring over a period of 1 hour. The resulting mixture was kept at 0 C for 5 days. After this period the mixture was poured onto an ice-ether mixture. The ether layer was separated and extracted with 1N potassium hydrogen sulphate (2 x 100 mL). The combined aqueous phase was washed with ether (2 x 50 mL), then made basic with 1ON sodium hydroxide (keeping the temperature below 0 The alkaline solution was extracted with ether (4 x 250 mL). The organic phase was dried (MgSO 4 and evaporated to dryness to give the title compound (2) (24.6 g, m.p. 107-1120C (lit., 1 108-114-C); 1max (film) 3 479 cm (indole NH); 8 H (300 M Hz, CDC1 3 1.01 (3H, d, J 6 Hz, CH) 1.09 (3H, d, J 6 Hz, CH 3 1.52 (1.52 (3H, d, J 6.6 Hz, CH 3 2.88 (1H, septet, J 6 Hz, CH(CH 3 4.27 (1H, q, J 6.6 Hz, indCH)CH 3 7.08-.25 (4H, 7.35 (1H, s, J 8 Hz, NH), 7.71 (1H, d, J 8 Hz, indole 8.21 (1H, brs, indole NH).

WO 92/04045 PCT/US91/06180 -163- Dibenzvlacetamidomalonate (71) Diethylacetamidomalbonate (9.1 g, 42 mmol) [Aldrich] in benzyl alcohol (26 mL, 0.25 mmol) was heated in an oil bath at 200 0 C. A slow stream of nitrogen was bubbled through the solution and the ethanol distilled out. After 4 hours the reacti n mixture was cooled to room temperature and the excess benzyl alcohol removed in vacuo with the oil bath temperature being slowly raised to 185-190 0 C, at which point distillation became very slow. The solution was cooled to room temperature and the resulting precipitate recrystallized from isopropanol to yield the title compound (71) (12.2 g, m.p. 11l-1120C 110-113 0 Uma. (film) 1752, 1734 (ester C 1651 (amide C 740 and 694 cm 1 (mono substituted pH); 5 H (300 M H. ZDC1 3 2.05 (3H, s,

CH

3 CO), 5.17 (2H, s, CH 2 Ph), (2H, s, CH2Ph), 5.29 (1H, d, J 7 Hz, CHCO 2

CH

2 Ph) 2 6.53 (1H, brd, J 6 Hz, NH), 7.27 (10H, m, 2Ph), 5 c (75.5 M Hz, CDC1 3 22.5, 56.5, 68, 128.5, 134.5, 166, 170.

Dibenzyl (3-indolvlethylidene)acetamidomalonate (72) The amine (70) (5.41 g, 26.7 mmol), diester (71) (9.12 g, 26.7 mmol) and sodium methoxide (38 mg, 0.70 mmol) were heated in toluene (30 mL) at 85-95°C (bath temperature) while a slow stream of nitrogen was bubbled through the solution. The reaction mixture was kept at this temperature for 5 hours, then cooled Sto -40°C (freezer). The crude product was filtered and recrystallized from isopropanol to yield the title compound (72) (8.22 g, m.p. 162-163°C (PrioH) (lit., 1 161-163C); Umax 1737 (ester C 1672 (amide C 743 and 697 cm~ 1 (monosubstituted Ph); H (300 M Hz, CDC1 3 1.57 (3H, d, J 7 Hz, CH 3 1.97 (3H, s, C- 3 CO), 4.32 (1H, q, J 7 Hz, CH CH 3 4.72 L it L_~L.il-:i i; i. WO 92/04045 PCT/US91/06180 -164- (1H, d, J 12 Hz, one of CH 2 Ph), 4.89 (1H, d, J 12 Hz, one of CH20H), 5.08 (1H, d, J 12 Hz, one of CH2Ph), 5.20 (1H, d, J 12 Hz, one of Ch 2 Ph), 6.56 (1H, s, NH), 6.86 (1H, d, J 2 Hz, indole 7.02-7.33 (13H, m, indole 2Ph), 7.54 (1H, J 8 Hz, indole 8.15 (1H, br s, indole NH), S C (75.5 M Hz, CDC1 3 18, 23, 37, 68, 70, 111.5, 115, 119.5, 122, 122.5, 127, 128, 134.5, 136, 167, 168, 169.5.

(3-Indolvlethylidene)acetamidomalonic acid (73) The diester (72) (930 mg, 1.92 mmol), palladium hydroxide on carbon (Pearlman's catalyst) (125 mg) and ethanol (110 mL) were placed in a Parr hydrogenation vessel and subjected to a hydrogen pressure of 45 psi at 25 0 C for 3 hours (until the uptake of hydrogen ceased). The reaction mixture was filtered through Celite to remove the catalyst, then evaporated to dryness to give the title compound (73) (576 mg, 99%) which was used without further purification. 8 H (300 M Hz; D 2 1.55 (3H, d, J 7 Hz, CH 3 1.99 (3H, s, CH3CO), 4.09 (1H, brd, J 7 Hz, CH, (CH 3 7.12-7.24 (3H, 7.49 (1H, d, J 8 Hz, indole 7.71 (1H, d, J 8 Hz, indole 4-H).

2-Acetamido-3-(3-indolvl)butanoic acid (74) The malonic acid (73) (5.48 g, 18.0 mmol) was refluxed in pyridine/water (20 mL) until no diacid remained (SOi 2 :EtOH-EtOAc 1% AcOH; rf 0.26). The reactionmixture was cooled, diluted with water (50 mL), and acidified with 10% sulphuric acid mL). The resulting solution was left at 0 C overnight to crystallize. The brown solid was filtered off and dried to yield 2-acetamido- 3-(3-indolyl)butanoic acid isomer A (74A) (1.30 g, 5 H (300 M Hz; d 6 -DMSO), 1.32 (3H, J 9 Hz, CH 3 WO 92/04045 PCT/US91/06180 -165- 1.84 (3H, s, CHH 3 CO), 3.46-3.55 (1H, m, indCH(CH 3 4.58-4.67 (1H, m, CH(COOH)NHAc), 6.93-7.19 (3H, m), 7.34 (1H, d, J 8 Hz, amide NH), 7.54 (1H, J 8 Hz, indole 8.04 (1H, d, J 9 Hz, indole-4H), 10.81 (1H brs, indole NH), ca 12.4 (vbrs, C02H). The filtrate was extracted with ethyl acetate (4 x 100 mL). The ethyl acetate extracts were combined and washed with water (2 x 50 mL) then extracted with 10% sodium hydrogen carbonate (2 x 100 mL). The sodium hydrogen carbonate extract was acidified with 4N sulphuric acid then extracted with ethyl acetate (2 x 75 mL). The ethyl acetate solution was washed with water (2 x 25 mL) then evaporated to dryness to give a beige foam, 2-acetamido-3-(3-indolyl)butanoic acid isomer B (74B) (2.17 g, 8 H (300 M Hz, d 6 -DMSO), 1.32 (3H, d, J 7 Hz, CH 3 1.84 (3H, s, CH 3 CO), 3.50 (1H, M, ind

CH(CH

3 4.66 (1H, m, CH(COOH)NHAc), 6.93-719 (3H, 7.34 (1H, d, J 8 Hz, amide NH), 7.63 (1H, d, J 8 Hz, indole 7.84 (1H, d, J 9 Hz, indole 4-H), 10.83 (1H, s, indole NH), ca 12.5 (vbrs, C02H).

Deacetvlation of acids (74A) and (74B) The acids (74A) and (74B) were deacetylated separately by the same procedure. Nitrogen was bubbled through a mixture of acid (74B) (3.96 g, 15.2 mmol) in 4N sulphuric acid (25 mL) for minutes, then the mixture was refluxed until all the solid dissolved. The solution was cooled to room temperature and neutralized to pH 8 with 0.4N barium hydroxide. The barium salts were precipitated with solid carbon dioxide, the mixture heated to boiling point and filtered hot. The solvent was removed in vacuo and the crude product purified by reverse phase column chromatography [methanol-water as eluant] WO 92/04045 PCT/US91/06180 -166to give 2-amino-3-(3-indolyl)butanoic acid (2.34 g, 71%) in a ratio of 1:3 (75A:75B), m.p. 198-212 0 C (lit.

1 218-225°C dec); isomer A 6 H (300 M Hz, D 2 1.33 (3H, d, J 7 Hz, CH 3 3.66-3.75 (2H, m, indCH(CH 3 CH(Co 2

H)NH

2 7.20-7.34 (2H, m), 7.57 (1H, d, J 8 Hz, indole 7.87 (1H, d, J 8 Hz, indole isomer B, 8 H (300 M Hz, D 2 1.37 (3H, d, J 7 Hz, CH 3 3.30-3.42 (2H, in, ind CH(CH 2

-CH(CO

2

H)NH

2 7.09-7.24 (3H, 7.48 (1H, d, J 8 Hz, indole 7.73 91H, d, J 8 Hz, indole 4-H).

2-Adamantvlchloroformate A solution of 2-adamantanol (10.1 g, 66.5 mmol) in dichloromethane (200 mL) was cooled in an ice bath.

Bis(trichloromethyl)carbonate (triphosgene) (7.55 g, 25.4 mmol) was added followed by dropwise addition of pyridine (6.2 mL, 77 mmol) at such a rate that the temperature remained below 20 0 C. After a further minutes the mixture was warmed to room temperature and stirred for a further 2.5 hours. The dichloromethane was removed in vacuo without heating and the residue slurried with ethyl acetate (50 mL).

The pyridinium hydrochloride was filtered off and the filtrate evaporated to dryness without heating to yield 2-adamantylchloroformate (76) (13.7 g, 8 H (300 M Hz, CDC1 3 1.48-2.32 (14H, m, adamantyl), 5.01 (1H, t, J 3 Hz, adamantyl (lit., 2 H (CC1 4 1.3-2.4 (14H, 4.95 (1H, s).

2-(2-Adamantyloxvcarbonvl)amino-3-(3-indolyl)butanoic acid (77) Percent amino acid (75) (449 mg, 2.29 mmol) in 1N sodium hydroxide (2.29 mL) was added to sodium hydrogen carbonate (211 mg, 2.5 mmol). This mixture was cooled to 0 C (ice bath), dioxan. (2.29 mL) was WO 92/04045 PCT/US91/06180 -167added, followed by dropwise addition with stirring of a solution of the chloroformate (76) (742 mg, 34.46 mmol) in dioxan (2.29 mL). When all the amino acid had gone (TLC Si0 2 methanol in dichloromethane), the dioxan was removed in vacuo and the residue partitioned between 10% citric acid and ethyl acetate. The aqueous phase was extracted further with ethyl acetate. The organic extracts were combined, dried (MgSO 4 and evaporated to dryness.

The crude acid was purified by column chromatography on normal silica [hexane:ethyl acetate (3:20 acetic acid as eluant] to give 2-(2-adamantvloxvcarbonvl)amino-3-(3-indolvl) butanoic acid (77) (570 mg, 6 H (300 M Hz, d 6 -DMSO), 1.34 (3H, d, J 8Jz. CH 3 1.68-2.00 (14H, m, adamantyl), 3.40-3.53 (1H, m, indCH(CH 3 4.36 (1H, brt, CH(CO 2 4.59 (1H, s, adamantyl 6.73 (1H, d, J 9 Hz, urethane NH), 6.96 (1H, t, J 7 Hz, indole 7.06m (1H, t, J 7 Hz, indole 7.17 (1H, brs, indole 7.33 (1H, d, J 8 Hz, indole 7.60 (1H, d, J 8 Hz, indole 10.83 (1H, s, indole NH)m, ca 12.6 (vbrs,

CO

2

H).

2-Adamantyloxvcarbonyl-D,L-8-methvl-D,L-tryvtophan-Lphenvlalaninol (78) The carboxylic acid (77) (288 mg, 0.726 mmol), N,N'-dicyclohexyl-carbodiimide (DCCI) (173 mg, 0.838 mmol) and l-hydroxybenzotriazole (HOBT) 9121 mg, 0.895 mmol) in ethyl acetate (5 mL) were stirred for 1 hour at 0°C. Dimethylaminopyridine (DMAP) (23 mg, 0.19 mmol) and phenylalaninol (163 mg, 1.08 mmol) were added, and the mixture stirred for a further 2 hours at 0 C then for 48 hours at room temperature. The mixture was filtered and the filtrate washed with citric acid (2 x 10 mL), saturated sodium hydrogen WO 92/04045 PCT/US91/06180 carbonate (10 mL), 5% citric acid again (10 mL), and brine (10 IL), dried (MgSO 4 and evaporated to dryness. The crude product was purified by column chromatography on normal silica [ethyl acetate:hexane as eluant) to yield 2-adamantvloxvcarbonv1-D,L P-methyl-D, L-trvptoohan-L-phenvlalaninoI (78) (45 mg, m.p. 99-101 0 C (Found: C, 71.7; H, 7.65; N, 7.4.

C

32

H

3 9N 3

O

4 -0.5H 2 O recuires C, 71.35; H, 7.5; N, 'Umaxr (film) 3360 1 695 (urethane C 1658 (amide C 746 and 702 cm- 1 (monosubstituted Ph); (300 M Hz, CDC1 3 1.42 (3H, d, 7 Hz, CH 3 1.45-2.10 (14H, m, adamantyl), 2.20 (1H, brs, OH), 2.43-2.69 (2H, m, CH 2 Ph), 2.84 (lH, brs, ind CH.(CH 3 3.39 (2H, br, m, CH 2 OH), 3.86 (1H, brs, CH(CH2Ph)CH 2 0H) 4. 4 9 (1H, m, CLH (NMR) (CONH-), 4.79 (1H, s, adamantyl 5.49 (1H, brs, urethane NH), 6.87 (1H, brs, amide NH), 6.95-7.38 (9H, m, indole Ph), 7.69 (1H, d, 1 7 Hz, indole 8.26 (1H, s, indole NH); m/z (FAB) 530 257, 232, 217, 181, 144, 126 109.

EXANPLE (H-indol-3-ylmethyl)-3-methyl-N-r(tricvclo 3. 3. 1.1 3 7 1 dec-2-vloxy) carbonvlI -8-alanvl I-L-2phenylqlycine, AdOC-((D)-3-(1H-indol-3-ylmethyl)bAla- -2-phenvl) GlV Step 1. Synthesis of 2AdoccMeRTrp CHN 2 (diazoketone).

A solution of N-methylmorpholine (253 mg, 2.50 mmol) and 2ADOCaMe-R-TrpOH (990 mg, 2.50 mmol) in anhydrous THF (20 mL) at OC was treated dropwise with a solution of iso-butyl chloroformate (340 mg, 2.50 mmol) in anhydrous THF (10 mL) and left stirring for 20 minutes). The reaction mixture was then filtered and a solution of diazomethane (6 mmol) in ~~ul WO 92/04045 PCT/US91/06180 -169ether was added to the filtrate. This was then allowed to warm to room temperature and left 12 hours.

Excess diazomethane was quenched with AcOH (1 mL) and the mixture evaporated to dryness in vacuo. The residue was then separated by silica gel chromatography using n-hexane:EtOAC (4:1 then 3:1) as eluants to give the diazoketone (Scheme 19, No. 2) as yellow crystals. M.p. 182.2-182.7°C (MeOH); +640 (c 0.5, MeOH); IR (film) 3400-3200, 2913, 2854, 2106, 1693 and 1352 cm-1; N1M (CDC1 3 )8 1.49 (3H, 1.50-1.60 (2H, 1.70-2.05 (12H, 3.30- 3.40 (2H, br 4.86 (1H, 5.20-5.40 (1H, br s), 5.56 (1H, 6.95 (1H, d, _J 2 Hz), 7.08 (1H, t, J 7 Hz), 7.16 (1H, t, J 7 Hz), 7.33 (1H, d, J 8 Hz), 7.55 (1H, d, J 8 Hz), 8.50 (1H, MS 71e (FAB) 421.3 393.2 351.2 307.2 (22) and 259.1 (100); Analysis for C 2 4

H

2 8

N

4 0 3 Calc.: C, 68.55; H, 6.71; N, 13.32% Found: C, 68.51; H, 6.73; N, 13.26% Phenylmethyl (R)-8-methyl--r (tricvclo [3.3.1.1 3 '1 dec- 2-vloxy)carbonyl aminol-lH-indole-3-butanoic acid Step 2. Synthesis of the above compound (Scheme 19, No. 3) A solution of the diazoketone (as prepared in Step 1) (4-20 g, 10.0 mmol) in benzyl alcohol (30 mL) was treated with a solution of silver benzoate (6 mL of a solution containing 1 g silver benzoate in 10 mL Et 3 N) at room temperature. This was stirred for 4 hours, treated with activated charcoal and filtered through gypsum. The benzyl alcohol was removed in vacuo and the residue separated by silica gel chromatography using CH 2 C1 2 as eluant to give the -L~CII-i~-LI WO 92/04045 PC/US91/06180 -170benzyl ester (Scheme I, No. 2) as a glass (3.3 g, m.p. 47-52°C; [a])20 +17.6° (c 1, MeOH); IR (film) 3500-3200, 2908, 2855, 1750-1680 cm-1; NMR (CDC1 3 1.39 (3H, 1.51 (1H, 1.54 (1H, s), 1.70-2.05 (12H, 2.68 (1H, o, J 14.3 Hz), 2.97 (1H, d, J 14.3 Hz), 5.10 (3H, 6.99 (1H, d, J 2.3 Hz), 7.08 (1H, t, J 7 Hz), 7.16 (1H, b, J 7 Hz), 7.30-7.35 (6H, 7.58 (1H, d, J 7.8 Hz), 8.05 (1H, MS M/e (FAB) 501.3 370.3 326.3 306.2 (32) and 135.2 (100); Analysis for C3 1

H

3 6

N

2 0 4 Calc.: C, 74.37; H, 7.25; N, 5.60% Found: C, 74.44; H, 7.20; N, 5.75% -8-methvl-B-f r (tricyclo r3.3.1.1 3 7 dec-2vloxy)carbonvllaminol-lH-indole-3-butanoic acid, AdOC- (a-Me)DTrp Step 3. Synthesis of the above compound (Scheme 19 No. 4) A solution of the benzyl ester (as prepared in Step 2) 1.0 g, 2 mmol) in absolute ethanol (100 mL) was treated with 10% palladium on carbon (100 mg, w/w) and the resulting suspension subjected to an atmosphere of hydrogen at 50 psi for 4 hours with agitation at temperature of 30 0 C. This reaction mixture was then filtered through gypsum and the solvent removed in vacuo. The residue was column chromatographed over reverse phase silica using MeOH:H 2 0 as eluant and the solid product recrystallized from chloroform to give the acid as a white solid (700 mg, m.p. 198-201 0 C (CHC1 3 0 +200 (c 1, MeOH); IR (film) 3500-3300, 2912, 2856, 1704 and 734 cm" 1 NMR (CDC1 3 1.41 (3H, s), 1.53 (1H, 1.57 (1H, 1.70-1.85 (9H, m), e i WO 92/04045 PCT/US91/06180 -171- 1.95-2.10 (4H, 2.69 (1H, d, J 14.3 Hz), 3.05 (1H, d, J 14.3 Hz), 3.21 (1H, d, J 14.3 Hz), 3.32 (1H, d, J 14.4 Hz), 4.86 (1H, 5,10-5.30 (1H, br 7.04 (1H, d, J 2.2 Hz), 7.07-7.20 (2H, 7.;35 (1H, d, J 8 Hz), 7.60 (1H, d, J 7.7 Hz), 8.16 (1H, MS M/e (FAB) 411.5 and 217.2 (100); Analysis for C 2 4 H3 0

N

4 0 4 Calc.: 70.22; H, 7.37; N, 6.82% Found: 70.03; H, 7.38; N, 6.78% Methyl N-[D-3-(1H-indol-3-vlmethyl)-3-methyl-N- (tricvclo 3.3.1.1 3 7 1 dec-2-yloxy) carbonvl -8-alanv.l L-2-phenvlqlvcine Step 4. Synthesis of the above compound (Scheme 19 No. A stirred solution of the acid (as prepared in Step 3) (500 mg, 1.20 mmol) and pentafluorophenol (224 mg, 1.20 mmol) in EtOAC (50 mL) at 0 C was treated with N, N'-dicyclohexylcarbodiimide (263 mg, 1.30 mmol). This mixture was stirred 18 hours at 0°C, tered and S-phenyl glycine methyl/ester (303 mg, 1.50 mmol) added to the filtrate. This reaction mixture was left at room temperature for 48 hours, washed with 1M citric acid solution (2 x 20 mL), saturated NaHCO 3 solution (2 x 20 mL) and (2 x 20 The dried (MgSO 4 organic phase was evaporated to dryness in vacuo and the residue separated by reverse phase silica gel chromatography using MeCH:H 2 0 as eluant to give the ester (Scheme 1 No. 5) as a noncrystalline solid (600 mg, M.o. 72-82 0 C; [a]2 2 +55.36 (c 1, MeOH); IR (film) 3500-3200, 2916, 2856, 1743, 1694, 1657 and 1504 cm- 1 NM (CDC13) 8 1.35 (3H, 1.40-1.55 (2H, 1.70-2.05 (12H, 2.54 (1H, d, J 13.3 Hz), 3.04- WO 92/04045 PCT/US91/06180 -172- 3.15 (2H, 3.31 (1H, d, J 14.2 Hz), 3.71 (3H, s), 4.71 (1H, 5.09 (1H, 5.48 (1H, d, J 6.6 Hz), 6.85 (1H, d, J 6.1 Hz), 7.04 (1I, d, J 2 Hz), 7.08 (IH, g, J 7 Hz), 7.17 (1H, g, J 7 Hz), 7.30-7.40 (6H, 7.59 (1H, d, J 7.6 Hz), 8.14 (1H, MS M/e (FAB), 558.3 383 198.1 170.1 (27) and 135.1 (100); Analysis for C 3 3

H

3 9

N

3 0 5 Calc.: C, 71.07, H, 7.05; N, 7.53% Found: C, 71.31; H, 7.30; N, 7.28% Glvcine, N-FD-3-(1H-indol-3-vlmethvl)-3-methyl-Nr(tricclor3.3.1.1 3 71dec-2-vloxv)carbonvll--alanvll- L-2-nhenvl-AdOC-((D)-3-(1H-indol-3-vlmethvl)bAla-((L)- 2-henvl)Glv Me ~NHY Ph 0 CD 2 h

/N

Step 5. Synthesis of Example 90, Scheme 19, No. 6 A stirred solution cf the ester (as prepared in Step 4) (399 mg, 0.70 mmol) in THF (20 mL) was treated with a solution of C10H (30 mg, mmol) in H 2 0 (5 mL) at room temperature. After 2 hours the mixture was made acidic to pH paper by adding 1M HCl solution.

The solvent was then removed under vacuum and the residue separated by reverse phase silica gel chromatography using MeOH:H 2 0 as eluant to give the product (Example 90) as a noncrystalline solid (200 mg, m.p. 120-125 0 C; [a]20 +49.20 WO 92/04045 17-PCT/US91/06180 0.5, MeOH); IR (film) 3450-3250, 2916, 2856, 1750-1600, 1510 and 1256 cm- 1 NM (CDCl 3 -5 1. 34 (3H, 1.50-1.55 (2H, in), 1.60-200 (12H, mn), 2.58 (1H, d, J 12.7 Hz), 3.00-3.25 (3H, mn), 2.50-4.00 (1H, br), 4.60-4.75 (lH, br 4.90-5.20 (lE, br 5.54 (1H, d, J 6.5 Hz), 7.00-7.60 (10H, mn), 7.58 (1I, d,J 7.9 Hz), 8.14 (1H, s); Analysis for C 3 2

H

3 7

N

3

O

5 3- H 2 0: Caic.: C, 70.00; H, 6.90; N, 7.65% Found: C, 69.97; H, 6.85; N, 7.64% EXAPLE 91 fR- 5)1-ci- f3- (lH-indol-3-vl) -2-inethy'l-l-oxo-2f f (tricyclo r3-3. 1.1 3 7 1dec-2-vlox) carbonyll amino] -Dropyll aiinolbenzeneacetic acid, F -AdOC- (a- Me'DTrp-L-phenlalycine (See Scheme Step 1. Synthesis of oxazolone (1H-indol-3ylmethyl) -4-inethyl-2- (tricyclo 3. 1. 13,71 dec-2-yloxy) 5(4H)-oxazolone) (No. 2, Scheme A solution of AdOCaMe-R-TrpOH (1.0 g, 2.5 mmxol) and N,N'dicyclohexylcarbodiimide (0.52 g, 2.5 mmiol) in anhydrous DMF (5 inL) was stirred for 1 hour at room temperature. This mixture was then filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on silica gel using hexane:EtOAC as eluant to give the oxazoline Scheme as white crystalline needles (850 mg, M.p. 150.5-150. 9 0 C (hexana) 2 0 0, (g 1, MeOH) IR (film) 2910, 2857, 1823, 1681 and 1399 cm- 1 NMR (CDCl 3 8 1.10-1.20 (1H, in), 1. 30 in), 2.04 (1H, 3.20 (1H, d, J 14.5 Hz), 3.25 (lH, Jj 14.5 Hz), 4.72 (lH, t, j 3.5 Hz), 6.99 (1H, d, J 2.4 Hz), 7.07 (lH, dt, J 7.1 Hz), 7.14 (lzi, dt,. J and 1 Hz), 7.29 (1H, d, J~ 7.3 Hz), 7.64 (1H, d, J WO 92/04045 PCT/US9I/06180 -174- 7.6 Hz), 8.02 (1H, MS M/et (CI) 379.2 178.3 163.3 135.2 (74) and 130.2 (100); Analysis for C 2 3

H

2 6

N

2 0 3 Calc.: C, 72.99; H, 6.92; N. 7.40% Found: C, 72.88; H, 6,96; N, 7.37% Step 2 A suspension of S-phenylglycine (42 mng, 0.28 minol), NaHCO 3 (23 mg, 0.28 minol) and the oxazolone (Scheme 20, No. 2) (100 mg, 0.26 mmiol) in

DM?:H

2 0 (10 inL) -as stirred a't room temperature for 18 hours. The solvent was then r emoved in vacuo and the residue suspended between ELOAC (20 mL) and 1M citric acid solution (20 inI) The aq-ueous phase was partitioned and extracted with EtOAC (2 x 20 nli) and the corbined organic phases washed with H 2 0 (3 x 10 mLd), dried over MgSO4 and the solvent removed in vacuo. The residue waz then subject to silica gel ch;NInatography using 3% MeOH in CH 2 Cl 2 then 5% MeOH,

H

2 0H in CH 2 C1 2 to give the product (Example 91) as a noncrystalline solid (206 mng, 77%) M.p. 138-143'C; D=+820 1, MeOH); (film) 3500-3200, 2913, 2855, 1696, 1666 and 1499 cm- 1 NM?. (CDCl 3 8 1.40-1.50 (2H, in), 1.56 (3H, 160-1.95 (12Hj mn), 3.24; (1H, d, J 14.6 Hz), 3.40 (1H, d, J 14.6 Hz), 4.73 (2 s), 5.68 (1h, d, J 6.8 Hz), 5.40-5.80 (1H, br) 6.90 (1H, 7.00-7.15 (2H, in), 7.20-7.30 (6H, t.35 (1H, d,, J 6.8 Hz), 7.53 (1H, d, J 7.5 Hz), 8.41 (IH, MS M/ef (FAM) 530.5 217.2 (38); Analysis for C 3

:H

3 5

N

3 0 5 02H 2 0: Calc. C, 69.83; H, 6.69; N, 7.88% Found: C, 69.85; H, 6.66; N, 7.74% WO 92/04045 PCr/US91/06180 -175- EXAMPLE 92 Tricyclo [3.3.1.13' 7]dec-2-yl [2-phenylethyl) amino]-1-(lH-indol-3-vl)-l-methvlethvl carbamate (See Scheme 21) To a solution of lithium borohydride (4 mL, 2M solution, 8 mmol) in dry THF under a nitrogen atmosphere was added a solution of chlorotrimethylsilane (1.75 g, 16.0 mmol) in dry THF mL). A white precipitate (of lithium chloride) was observed. After 2 minutes a solution of (18) (1 g, 2 mmol) in THF (15 mL) was added slowly (over 3-4 minute period) and the reaction mixture was stirred for 20 hours at ambient temperature. The reaction was treatec :autiously with MeOH (5 mL) and the volatiles were removed in vacuo at 40 0 C. The residue was purified by silica gel chromatography using hexane:ethyl acetate (80:20) as eluant to give (19) (0.14 g, 14%) as a colorless oil, and recovered (18) (0.52 g; yield of (19) based on recovered starting material The amine (19) (0.14 g, 0.28 mmol) was taken dissolved up in MeOH (5 mL) and treated with 4-toluenesulfonic acid hydrate (0.054 g, 0.28 mmol). The solution was evaporated to leave a white solid. [a]D +220 (c 0.25, MeOH) IR (film) 2928 and 1708 (c urethane). NMR (DMSO-d 6 8 1.2 3 R, s, CH 3 1.4-2.1 (14H, m, adamantyl), 2.3 (3H, s,

CH

3 Ph), 2.9-3.7 (8H, m, 4 x CH 2 4.7 (1H, br s, adamantyl 6.9-7.6 (15H, m, aromatics), 8.3 (1H, br, one of 8.5 (1H, br, one of 11.0 (1H, s, indole NH); MS M/e (FAB) 486 H) (100), 136 (52); Analysis for C 3 1 E 3 9

N

3 0 2

C

7 H8S0 3 0.75H 2 0: Calc.: C, 67.98; H, 7.28; N, 6.26 Found: C, 67.96; H, 7.31; N, 600. M.p. 90-93 0

C

WO 92/04045 PCT/US91/06180 -176- EthvltR-(R*,S*)1-4-r[2-phenvlethvll-f3-(1H-indol- 3 Vl)-2-methyl-2- F r(tricvclor3.3.1.1 3 7 1dec-2vloxv)carbonyllaminolpropyllaminol-4-oxo-butanoate (19b, Scheme 21).

Prepared by a similar method to compound (19a).

Recovered a white solid 0.102 g 21 +260 (c 0.5, CHCl 3 IR (film) 2905, 2853, 1732, 1711, 1634 cm- 1 NMR (CDC1 3 8 1.2 (6H, 1.3-2.1 (14H, m), 2.6 (4H, br 2.9 (2H, 3.0 (1H, d, J 14 Hz), 3.3-3.8 (4H, 4.0-4.2 (3H, 4.8 (1H, br 5.3 (1H, br), 6.9-7.6 (10H, 8.1 (1H, br MS M/e (FAB) 614 (36) (M 483 (100), 419 (24); Analysis for C 37

H

47

N

3 0 5 Calc.: C, 72.40; H, 7.72; N, 6.85% Found: C, 72.11; H, 7.87; N, 6.16%. M.p. 67-700C Tricyclof3.3.1.1 3 i 7 1dec-2-v 1R-(R*,S*)1-f2-FacetvlF2phenvlethvllamino1l--(1H-indol-3-vlmethyl)-1methylethyllcarbamate (19a in Scheme 21) To a solution of (19) (0.1 g, 0.2 mmol) in dichloromethane (20 mL) at 0 0 C was added acetyl chloride (0.3 mL, 4 mmol), followed by triethylamine (4 drops). Stirring was continued at o00C for minutes, then the reaction mixture was dissolved in ethyl acetate (50 mL), washed (HC1 aq, H 2 0, NaHC03 ag), dried (MgS0 4 and evaporated to dryness. The residue was purified by column chromatography using hexane-ethyl acetate eluent to give an off-white solid (0.092 g, 21 +240 (c 0.25, CHCL 3

IR

(film) 2909, 2855, 1709, 1610 cm- 1 NM (CDC13) 6 1-3 (3Hr 1.4-2.1 (17H, 2.8 (2H, 3.1 (1H, d, J 14 Hz), 3.3-3.7 (4H, 4.0 (1H, d, J 14 Hz), 4.8 (1H, 5.5 (1H, br 6.9-7.7 (10H, 8.1 (1H, br MS M/f (FAB), 528 (45) 397 (100), 333 (27).

WO 92/04045 PCT/US91/C06180 -177- (1Fl- indo1- 3-yl) 2-methyl-2-[[(tricyc lo 3. 3. 1. 1 3 7 dec-2-yloxy) carbonyll amino] propyl] (2-phenylethyl) amino) 4-oxobutanoic acid (19d, Scheme 21).

To a stirred solution of (19b) (0.04 g, 0.06 minol) in THF (5 mL) was added methanol (5 mL) water (5 mL) and lithium hydroxide monohydrate (0.1 g, 2.4 minol), The reaction mixture was stirred for 40 minutes at ambient temperature, then acidified (2NHC1 ag, 50 mL) and the products extracted into ethyl acetate (50 mL).

The organic phase was dried with magnesium sulphate and evaporated ir vacuo (40 0 C) The oily residue was purified by column chromatography using dichloromethane/ methanol as eluent. Recovered 0.031 g of a white solid; IR (film) 340 (br) 2912, 2852, 1714, 1700, 1635 cm-1; NMR (MeOH-d 4 8 1.1-2.2 (17H, m,

CH

3 adamantane) 2. 6-3. 2 (6H, m, 3 x CH 2 3. 4-4. 1 (6H, m, 3 x CH 2 4. 8 (lH, br, adamantane H-2) 7. 0-7. 6 m, aromatics); CaJD +40 (MecE, C 0.2, 22 0

C);

FAB MS 586 (51) m+ 455 (100), 391. (24)% Analysis of C 3 5

H

4 3

N

3 0 5 0.25 H 2 0: Cabc.: C, 71.22, H, 7.43; N, 7.12 Found: C, 71.24; 7.46; N, 6.87%, m.p. 99-96*C EXAMPLE 93 Tricyclo13.3.1.1 3 ,71dec-2-yl ri- (hydroxymethyl) -2 -phenylethyl Iamnino 1-1 -(1H-indol -3ylrnethyl) -2-oxoethyl I carbamate The carboxylic acid 56 (380 mg, 1.0 mimol) and H,H'-dicyclohexylcarbodiimide (230 mg, 1.1. mmol) and pent af luorophenol (200 mg, 1.1 nwiol) were suspended in EtOAC (25 mL) and stirred for 2 hours then treated with (S)-2-amino-3-phenyl-l-propanol (150 mg, mimol) and stirred at 400C for 18 hours. The mixture was filtered and the filtrate was washed with sat aqueous citric acid followed by sat aq Na.HCO3- WO 92/04045 PCT/US91/06180 -178followed by H 2 0. The organic layer was dried (MgSO 4 filtered, concentrated in vacuo and purified by reverse-phase silica gel chromatography (LiChroprep® RP-18) using MeOH:H 2 0 as eluant to give the product 6 (0.36 g, [a]D 2 20.4° (c 0.25,

CH

2 C1 2 NMR (CDC1 3 6 1.8 (14H, 2.60 (2H, 3.30 (4H, 4.05- (1H, 4.42 (1H, q, 4.78 (1H, m), 5.45 (1H, br 6.15 (1H, br 7.30 (8H, 7.37 (1H, d, 7.67 (1H, 8.25 (1H, br s).

Hydroxyamide (See Scheme 22) (517 mg, 1.00 mmol), imidazole (146 mg, 2.15 mmol), and tertiarybutyldimethylsilyl chloride (354 mg, 2.35 mmol) in DMF (6 mL) were stirred at room temperature for 18 hours. The reaction was quenched with H 2 0 (40 mL) The emulsion was extracted with ether (8,0 mL). The ether was washed with brine, dried (MGS0 4 filtered and concentrated in vacuo. The crude material was purified by column chromatography [SiO 2 :hexane-ethyl acetate as eluant] to give the silyl protected amide (474 mg, 75%) as a white foam. H NMR (CDC1 3 8 8.12 (1H, s, indNH) 7.76 (1H, d, J 7 Hz, ind 7.40 (1H, d, J 8 Hz, ind H-7), 7.34-7.06 (8H, m, Ph+ind H-2, H-5, 6.98 (1H, s), 5.91 (6H, br s, 5.44 (0.4H, br s, 4.90 (1H, s, adamantyl 4.53 (1H, m, NHCH(CH 2 ind)CO), 4.14 (1H, m, NHCH(CH 2 0Si)CH 2 Ph), 3,39 (2H, m, CH2ind), 3.22 (2H, br, m, CH 2 Ph), 2.12-1.54 (14H, br, m, adamantyl), 0.88 9H, tBu), 0.02 (6H, s, 2 x CH 3 IR (film) vmax 2927 2856 (adamantyl), 1703 (CO 30 urethane), 1663 cm' (CO amide).

Silyl protected amide (418 mg, 0.664 mmol) and Lawesson's reagent [Aldrich] (268 mg, 0.663 mmol) were refluxed in toluene (10 mL) for 30 minutes. The solution was cooled to room temperature and poured onto a column of silica gel. The column was eluted WO 92/04045 PC/US91/06180 -179with CH 2 C1 2 to remove the toluene and a high rf (0.74) Lawesson's reagent by-product. Elution was then continued with a hexane-ethyl acetate gradient (0-30%) to give thiazolene (73 mg, 21%) as a white foam.

M.p. 56-63 0 C. 1 H NMR (CDC1 3 6 8.16 (1H, s, ind NH), 7.63 (1H, d, J 8 Hz, ind 7.38-6.96 (9H, m, ind H-7, H-6, H-5, H-2 Ph), 5.44 (1H, br, d, J 7 Hz, urethane NH), 4.88 (1H, br s, ind CH 2 CH), 4.82 (1H, s, adamantyl 4.62 (1H, m, NCHCH 2 Ph), 3.44-2.83 m, ind CH 2 PhCH 2 CH of CH 2 2.68 (1H, dd, J 9, 14 Hz, CH of CH 2 2.09-1.43 (14H, m, adamantyl); IR (film) vmax 2909 2854 (adamantyl), 1698 (CO urethane), 1621 cm- 1 (C MS (M/e; Analysis for C 3 1

H

3 5 N3SO 2 Calc.: C, 72.48; H, 6.87; N, 8.18; S, 6.24% Found: C, 72.32; H, 7.09; N, 7.75; S, 6.09% EXAMPLE 94 (1-Phenvlcvcloventvl)methylr1S-r1R* I and r1S- 2-hydroxy-1-(hvdroxvmethvl)-2phenviethyll amino) (1H-indol-3-vlmethvl) -1-methvl-2oxoethyll carbamate (1-Phenvlcycloventvl)methyl carbonochloroidate Step A. To a stirred solution of 1-phenyl cyclopentylmethanol (0.53 g, 3.0 mmol) in methylene chloride (15 mL) was added bis (trichloromethyl) carbonate (0.33 g, 1.1 mmol) followed by pyridine A (0.24 g 3.3 mmol) in methylene chloride at 0 0 C. The reaction mixture was warmed to room temperature and stirred for an hour. The reaction mixture was concentrated and diluted with ethyl acetate (25 mL).

The pyridinium hydrochloride precipitate was filtered off and filtrate was concentrated to give semisolid (0.65 g, 1 H NMR (200 MHz, CDC1 3 6 7.50-7.10 WO 92/04045 PCT/US91/06180 -180- 4.30 (2H, 2.10-1.90 (4H, 1.90-1.75 (4H, m).

a-Methyl-N-[[(l-phenylcyclopentyl)methyllcarbonyll-DLtryptophan methyl ester Step B. To a stirred solution of 1-phenyl 1cyclopentyl methylchloroformate (0.65 g, 2.75 mmol) in dry THF (10 mL) was added a solution of a-methyl-DLtryptophan methyl ester (0.60 g, 2.5 mmol) followed by triethylamine (0.5 g, 5.0 mmol) in dry THF. The reaction mixture was stirred for 30 minutes and then filtered, concentrated and chromatographed to give an oil (0.9 g, 1 H NMR (200 MHz, CDC13) 8 8.0 (1H, br 7.50 (1H, d, J 7 Hz), 7.40-7.0 (8H, 6.6 (1H, br 5.35 (1H, br 4.15 (2H, 3.65 (3H, 3.6-3.0 (2H, 2.10-1.85 (4H, 1.85-1.60 (4H, 1.55 (3H, s).

a-Methyl-N-r (l-phenvlcyclopentvl)methyllcarbonyl]-DLtrvytophan Step C. To a stirred solution of intermediate B (0.87 g, 2 mmol) in aqueous 1,4-Dioxane (6 mL) was added LiOH (0.13 g, 3 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated, diluted with water (50 mL), acidified with dilute HC1, extracted with ethyl acetate and chromatographed to give a white foam (0.8 g, 1H NMR (200 MHz, CDCl 3 8.05 (1H, br 7.55 (1H, d, J 7 Hz), 7.45-7.00 (9H, 5.25 (IH, br 4.20-3.90 (2H, 3.35-3.05 (2H, 2.00-1.85 (4H, 1.85- 1.65 (4H, rr 1.50 (3H, br s).

i 1.-i WO 92/04045 PC/US91/06180 -181- (1-Phenylcyclopentyl)methy1flS-r1R*(R*) and fiS- 2-hvdroxv-l-(hvdroxvmethyl)-2phenviethyl]amino]-l-(lH-indol-3-ylmethyl) methvl-2oxoethyl]carbamate Step D. A solution of intermediate C (0.42 g, mmol) in ethyl acetate (10 mL) was treated with dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) and l-hydroxybenzotriazole hydrate (0.17 g, 1.1 imol).

After stirring for an hour at room temperature, it was filtered. To this filtrate, 2-amino-l-phenyl-1,3propanediol (0.18 g, 1.05 mmol) in 1:1 mixture of methylene chloride and ethyl acetate was added and stirred overnight. The reaction mixture was filtered, concentrated and chromatographed to yield (0.25 g, 44%) of the title compound as a white foam.

m.p. 78-83 0

C.

EXAMPLE (4-NitroPhenvl)methyl r4S-[4(x,5 X(R*)1 and r4Sr4cx,5cx(S*)11-r2-F(2,2-dimethyl-4-henyl-1,3-dioxan-5yl) amino] (1H-indol-3-ylmethyl-l-methyl-2-oxoethyll carbamate oX-Methvl-N- r (4-nitrophenyl) methoxv] carbonylI -DLtryptophan methyl ester Step A. The method was as described in Step B, Example 94, except p-nitro benzyl chioroformate was used. The title compound was obtained as a semisolid g, 1 HNMR (250 MHz, CDCl 3 8 8.20 (2H, d, J Hz), 8.10 (1H, br 7.60-6.80 (7H, 5.64 (1H, br 5.2-5.0 (2H, 3.71 (3H, 3.55 (1H, d, J 14 Hz), 3.35 (1Hi, d, J 14 Hz), 1.72 (3H, s).

L WO 92/04045 PCT/US91/06180 -182aX-Methyl-N- (4 -nitrophenyl) methoxv I carbonv. I -DLtryptophan Step The method was as described in Step C, Example 94, except the product of Step A was used.

The title compound was obtained as a foam (1.8 g, 1 ENMR (250 MHz, CDC1 3 5 8.15-7.95 (3H, i), 7.60-6.9 (7H, 5.53 (1H, br 5.20 (21, 3.60- 3.20 (2H, 1.73 (3H, br s).

(4-Nitrophenyl)methyl r4S- 4aI,5cx(R*) and f4Sr4a, 5(x 11 (2,2-di imethyl-4-phenvl-l,3-dioxan-5yl)amino -l-(1H-indol-3-vlmethyl-l-methvl-2oxoethvlcarbaiate Step C. The method was as described in Step D, Example 94, except the product of Step B and 2,2-dimethyl-4-phenyl-1,3-dioxan instead of the product of Step C and 2-amino-1-phenyl-1,3propanediol, respectively. The title compound was obtained as a foam (2.3 g, i.p. 92-102 0

C.

EXAMPLE 96 r4S-[4a,'5a(R*yI1 and r4S-[4a, 5(x(S* 3]-N-(2,2-dimethvl- 4-phenyl-I,3-dioxan5-yl) a-inethl--t (1-phenvlcyclopentyl)methyl1aminolcarbonvll-lH-indole-3propanamide r4S- 4(X,5Ca(R*)11 and r4S-r4 4, 5c(S*)11- c-amino-N- (2,2 dimethvl-4-henvl-1,3-dioxan-5-vl)- ethvl-1H-indole- 3-propanamide Step A. A solution of the title compound of Example 95 (1.65 g, 2.8 mmol) in absolute ethanol was treated with catalytic amount of 10% palladium on carbon and stirred overnight under a positive pressure of hydrogen. The reaction mixture was then filtered over celite and washed with ethanol. The filtrate was WO 92/04045 PCUIUS9I /06180 -183concentrated and passed through small plug of silica gel to give a white foam (1.1 g, 100%) m.p. 182- 185 0

C.

f4S-[4o.,5cx(R*)11 and t4S.F4c(X,5c(S*)11-N(2,2-dimethvl- 4-p~henyl-l? 3-dioxan-5-yl) -cX-methyl-o(- [frFF(I-phenylcyclop~entvl)methylaminol carbonyll -lE-indole-3propanamide Step B. To a stirred solution of the product of Step A (0.49 g, 1.2 nunol) in dry THF (15 mnI), was added 1-phenyl cyclopentylmethylisocyanate (0.26 g, 1.3 minol) in dry THF (5 mL) at room temperature. The reaction mixture was concentrated, chromatographed and crystallized to give the title compound (0.21 g, m.p. 125-280C.

EXAMPLE 97 rlS-flR*(R*),2R*ll and rlS-rlR*(S*),2R*11-N-[2hvdroxv-l- (hydroxymnethyl) -2--ohenyl ethyl) (lH-indol- 3-Vlmethyl)-2-methvl-N 1 tricyclor3.3.1.1 3 7 1dec-2vlpropanediamide N,N,N-Trimethyl-1H-indole-3-methanaminium iodide Gramine methiodide (JACS 66 200 (1944)) Gramine (43.5 g, 0.29 mxnol) (see Synthetic Scheme 23 for Compounds 1-23) was dissolved in absolute ethanol (200 mnL) and methyl iodide (17 mL, 0.27 mmol) was added dropwise over 0.5 hour. A mild e exothern occurred with the formation of a white precipitate. The reaction mixture was stirred overnight at room temperature and then cooled to 0 0

C

for 2 hours. The white solid was collected by filtration, washed four times with ethanol (50 mL), three times with diethyl ether (50 mL), and dried in vacuo. The product was obtained as a white solid.

WO 92/04045 PCT/US91/06180 -184- 70.4 g IR (KBr) 3306, 1483, 1346, 810, 760 cm Diethyl(1H-indol-3-ylmethyl)methylpropanedioate (3) Sodium hydride (4.0 g, 0.1 nunol) was added in portions over 10 minutes to a mixture of diethylmethyl malonate (17.4 g, 0.1 mmol) in DMF (200 mL) at room temperature. The reaction mixture was stirred and gramine methiodide (33.5 g, 0.11 mmol) was added and the whole mixture warmed to 50°C for 0.5 hour and was then stirred overnight at room temperature. Water (200 mL) was carefully added to quench the reaction. The entire mixture was diluted with diethyl ether (500 mL) and water (300 mL). The layers were separated and the organic layer was washed with water (3 x 200 mL). The combined aqueous layers were extracted with diethyl ether (1 x 500 mL), the ether layer washed with water, the organic extracts combined, dried (MgS0 4 filtered and concentrated.

The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate, 1/1, as eluant. The product containing fractions were combined, concentrated, and filtered through silica gel (70-230) using 8/2 hexane/EtOAC as eluant. The product was obtained as a red viscous oil. 13.1 g IR (film) 3397, 2983, 1731, 1376, 1254, 1108 cm 1 Ethyl hydroaen(lH-indol-3-vlmethyl)-methyloropanedioate (4) To a solution of diester (4.85 g, 0.016 mmol) in 95% ethanol (50 mL) at room temperature was added IN aqueous sodium hydroxide solution (16 mL) and enough water until the solution just became cloudy. Water was added as the reaction proceeded. After 2 hours WO 92/04045 PCT/US91/06180 -185the reaction mixture was concentrated on the rotary evaporator to remove ethanol, diluted with water, washed with ethyl acetate, made acidic with 10% citric acid solution, brine was added, and the entire mixture extracted with ethyl acetate. The ethyl acetate solution was dried (MgS0 4 filtered and concentrated to a brown oil. The brown oil was chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluant and then rechromatographed on silica gel (70-230 mesh) using hexane/ethyl acetate, 1/1, as eluant. The product 4 was obtained as an orange/tan oil. 2.92 g IR (film) 3402, 2982, 1718, 1458, 1098, 742 cm 1 Ethyl(±)-a-methyl-a- (tricyclo 3,3, 1.1 3 dec-2vlamino)carbonyll -H-indole-3-proDanoate A mixture of acid (1.41 g, 0.005 mmol), adamantanamine hydrochloride (0.95 g, 0.005 mmol) 1- (0.68 g, 0.005 mmol), and

CH

2 Cl 2 (50 mL) was cooled to 0°C and triethylamine (0.8 mL, 0.0057 mmol) was added and the mixture stirred 5 minutes. Then dicyclohexylcarbodiimide (1.04 g, 0.005 mmol) was added all at once. The reaction mixture was stirred 3 days at room temperature, concentrated to dryness, the residue taken up in ethyl acetate, washed with 10% citric acid, sodium carbonate and sodium chloride solutions.

The organic layer was dried (MgS0 4 filtered, and concentrated to an orange oil. Addition of 1/1, hexane/ethyl acetate caused the oil to solidify. The solid was collected by filtration. 2.05 g IR (KBr) 3418, 3327, 2907, 1713, 1630, 1540, 1457, 1113 cm 1

M

WO 92/04045 PCT/US91/06180 -186- (±)-a-methyl-a-[ (tricyclo[3.3.1.

3 '7 dec-2vlamino)carbonvl-ilH-indole-3-propanoic acid (6) The ester (1.04 g, 2.5 mmol) was dissolved in ethanol (10 mL) and iN sodium hydroxide solution (3.5 mL) was added and just enough water to make the solution cloudy. The reaction mixture was briefly warmed to 50 0 C to get solution. The reaction mixture was allowed to sit 14 days at room temperature. The reaction mixture was concentrated to remove ethanol, diluted with water, washed the aqueous solution with ethyl acetate, made the aqueous layer acidic with citric acid solution, extracted with ethyl acetate, washed the ethyl acetate solution with brine, dried (MgSO 4 filtered, and concentrated to an off-white foam. The foam was filtered through silica gel (70-230 mesh) using ethyl acetate as eluant. The product was obtained as an otf-whit solid. 0.87 g IR (KBr) 3411, 2908, 1716, 1617, 1540, 740 cm 1 [4S-[4a,5a(R*)11 and [4S[4a,5a(S*)]]N-(2,2-dimethvl-4- Dhenyl-1,3-dioxan-5-yl)-2-(lH-indol-3-ylmethvl)-2methyl-N 1 (tricyclo[3.3.1.13 7]dec-2-yl)propanediamide Dicyclohexylcarbodiimide (0.30 g, 1.46 mmol) was added to a mixture of (4S,5S)-(+)-5-amino-2,2dimethyl-4-phenyl-l,3-dioxane (0.31 g, 1.44 mmol), acid (0.53 g, 1.39 mmol), and 1-hydroxybenzotriazole (0.22 g, 1.63 mmol) in a mixture 10/1, CH 2 C12/DF, mL) at 0 C. The reaction mixture was allowed to sit 1 hour at 0°C and then 3 days at room temperature.

The reaction mixture was concentrated to dryness, the residue taken up in ethyl acetate, the ethyl acetate solution washed with saturated sodium chloride solution, dried (MgSO 4 filtered and concentrated to I Il I IZ~n ~sl WO 92/04045 PCT/US91/06180 -187an orange oil. The oil was purified by filtration through silica gel (70-230 mesh) using hexane/ethyl acetate, 7/3, as eluant. The product was obtained as a white solid. 0.247 g IR (KBr) 3341, 2910, 1665, 1508, 1201, 742 cm- 1 flS-[1R*(R*),2R*11 and hvdroxy-1-(hydroxymethyl)-2-phenyl ethyll-2-(1H-indol- 3-vlmethyl) -2-methyl-N'tricyclo r 3.3.1. 13, 71 dec-2vlpropanediamide (8) A mixture of the acetonide (0.16 g, 0.28 mmol), methanol (10 mL), and 1N HC1 (1 miL) was allowed to sit at room temperature for 4 hours. The reaction mixture was concentrated to dryness without heating. Ethyl acetate was added, the ethyl acetate dried (MgSO 4 filtered, concentrated, and the residue chromatcgraphed on silica gel (70-230 mesh) using ethyl acetate as eluant. The product was obtained as a white foam. 0.0727 g EXAMPLE 98 [1S-[1R* 2R*11 and [1R* hvdroxv-1--(hydroxvmethyl)-2-henylethvll-2-(lH-indol- 3-vlmethv 1) -2-methyl-N' (tricyclo f3.3.1.13' 7 dec-1vlmethyl)-rooanediamide Ethyl a-methyl-- [(tr.-icyclof3.3.1.1 3 7 ldec-1ylmethyl)aminol carbonvll -1H-indole-3-propanoate (9) Compound 9 was prepared from Corpound 4 according to the procedure for Compound 5. Th product was obtained as an off-white solid. 3.49 g IR (KBr) 3402, 3337, 2913, 2904, 1718, 1652, 1116 cm-.

S- WO 92/04045 PCU/US91/06180 -188- (-methvl-rx- (tricclo 3. 3.1.1-3 "7 dec-l-vlmethvl) amino]carbonvll-lH-indole-3-propancic acid Compound 10 was prepared from Compound 9 according to the procedure for Compound 6. The product was obtained as a white solid. 1.95 g IR (KBr) 3440, 2912, 1713, 1652, 1621, 1189, 746 cm- 1 F4S [4a,5a(R*)]1 and [4S- [4a5a(S:*) -N-(2,2-dimethvl 4-'henyl-1, 3-dioxan-5-yl) (1H-indol-3-vlmethl -2methyl-N'- (tricyclor3.3.1.1 Idec-l-vlmethylpropanediamide (11) Compound 11 was prepared from Compound according to the procedure for Compound 7. The product was obtained as a white foam. 0.83 g, IR (KBr) 3418, 2904, 1666, 1558, 1106 cm- 1 r[Ls- 2R*11 and rlS- FR* 2R*11 -N-F2hvdroxv-l-(hvdroxymethyl)-2-phenvlethyll-2- (l-indol- 3-vlmethyl) -2-methyl-N (tricyclo F3 .3.1.13,'l dec-1vlimethyl) propanediamide (12) Compound 12 was prspared from Compound 11 according to the procedure for Compound 8. The product was obtained as a white foam. 0.2633 g IR (KBr) 3341, 1652, 1588, 1544, 1477, 699 cm'-.

I

WO 92/04045 PCT/US91/06180 -189- EXA1PLE 99 f1S-[IR*(R*) and [1S-[lR*(S*),2R*11-[[[rrr2,6bis(1-methvlety3" )phenvl]amino]carbonvl]amino]-N-[2hvdroxy-l-'hydroxvmethyl)-2-phenylethvll-C-methvl-1Hindole-3-propanamide t4S-r4a,5c(R*)]] and f4S-f4c,5a(S*)]-l1,1-dimethylethvlr2-r(2,2-dimethyl-4-phenvl-1,3-dioxan-5-vl)amino]-1-(1H-indol-3-ylmethyl)-l-methvl-2-oxoethll carbamate (14) Compound 14 was prepared according to the procedure of Compound 7. The product was obtained as a white foam. 4.70 g IR (KBr) 3413, 1707, 1663, 1507, 1501, 1458, 1168, 743 cm 1 f4S-f4c,5a(R*)11 and r4S-f4,5(S*)11-a-amino-N-(2,2dimethvl-4-phenvl-l,3-dioxan-5-yl)-a-methyl-1H-indole- 3-proDanamide Anhydrous hydrogen chloride gas was bubbled through a solution of t-butyloxy carbonyl amine 14 (3.4 g, 6.7 mmol) in dichloromethane (80 mL) for 5 minutes. The reaction mixture was allowed to sit at room temperature for 1 hour and was then poured into saturated aqueous sodium bicarbonate solution. Sodium chloride solution was added and the aqueous solution as extracted two times with ethyl acetate. The organic extracts were combined, dried (MgSO 4 filtered and concentrated. The residue was filtered through silica gel (70-230 mesh) using ethyl acetate as eluant to give the product as an off-white solid.

2.18 g IR (KBr) 3356, 3244, 1646, 1514, 744 cm 1 .r WO 92/04045 PCT/US91/06180 -190- 4 S- r 4x, I] or r -r4(,5 S* I- -rrrr2 -i 1 methylethvl)phenyl] amino] carbonvi] amino] (2,2dimethyl-4-Thenyl-1, 3-dio. an-5-y1) -(-methyl-I1H-indole- 3-p~ropanamide (16a) -[4S-r4cx,5ct.CR*)]] or r4-4x5(*1-Xrr26bsl methvlethvl) phenyl] amino] carbonyl] amino] (2,2dimethyl-4-phenvl-1, 3-dioxan-5-vl) -a.-methyl-lH-indole- 3-propanamide (1 6b) A mixture of amine 15 (0.40 g, 1 minol) and 2,6diisopropylphenyl isocyanate (0.23 g, 1.1 nunol) in ethyl acetate (30 mL) was heated briefly to achieve solution. The reaction mixture was allowed to sit 2 days at room temperature. The reaction mixture was concentrated to a viscous oil, which was chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluant. The less polar diastereomer, 16a, was obtained as a white solid. 0.2876 g. The more polar diastereomer, 16b, was obtained as a white solid. 0.2369 g. Total yield IR (Kbr) 3431, 2964, 1675, 1500, 12:39, 741 cm-.

r1S-flR*(R*),2R*ll and [1s-rlR*(S*),2R*]cx-Cfrr[2,Gbis (l-methylethvl) phenyl] amino] carbonyl] amino] r2hvdroxv-1- (hvdroxvmethyl) -2-phenylethyl] -a.-methyl-1Hindole-3-propananide (17a) Compound 17a was prepared from 16a according to the procedure for Compound 8. The product was obtained as a white foam. 0.0893 g IR (KBr) 3400, 3343, 1733, 1663, 1513 742 cm-1.

WO 92/04045 WO 9204045PCT/US91/06180 -191- EXAMPLE 100 rlS-rlR* 2R*1I orz [1S-flR* 2R*1 I 2.6bis (l-methylethyl)phenvll amino Icarbonyll amino] -N-rf2hvdroxv-l- (hvdroxymethyl) -2-phenylethyll1-at-methy1-lHindole-3-propoanamide (17b) Compound 17b was prepared from 16b according to the procedure for Compound 8. The product was obtained as a white foam. 0.096 g IR (KBr) 3420, 3299, 1734, 1716, 1662, 1507, 1058 cm- 1 EXAMPLE 101 N- 1-dimethylethoxy) carbonyll -L-phenylalanyl-axtrv-oto-ohanamide [4S-r4cx,5Q1R*)11 and r4-~,aS)I-2[22 dimethyl-4-thenvl-1, 3-diox.n-5-vl) aminol (l-indolvlmethyl) -l-methyl-2-oxoethyl] carbamate (18) The amine 15 (0.4 g, 1 mmol) and E-da44i7z,)pvphen.-. chioroformate (0.51 g, 2 mxnol) ralA-dcrfuran (50 mL) and ramo) was added. The W room' The WO 92/04045 PC/US91/06180 -192a-methyl-N-L-phenVylalanylV-DL, methvlester, Anhydrous hydrogen chloride gas was bubbled through a solution of -19 (1.50 g, 3.1 mmol) in dichloromethane (50 mL) for 2 minutes at room temperature. The reaction mixture was allowed to sit overnight at room temperature. The solvent was removed in vacuo, Ether was added twice and concentrated. The residue was taken up in methanol I and then concentrated. Ether was added and then removed on the rotary evaporator yielding the product as a tan foam. 1.32 g IR KBr) 3403, 3396, 3343, 3231, 1734, 1684, 1677, 1498, 1216, 743 cm 1 N-rN-F(1,1-dimethylethoxy)carbonvll-L-Dhenvlalanvll-Ca methV1-DL-trvptophyl (21) Compound 21 was prepared from 19 according to the procedure for Compound 6. The product was obtained as a white foam. 2.34 g IR (KBr) 3375, 1716, 1708, 1702, 1498, 1457, 1368, 1164, 743 cm-.

-r(1,1-dimethvlethoxy)carbonvll-L-Dhenylalanvl-'nithyl-N-tricyclo r3.3.1.13,i dec-2-v1-DLrvatoohanamide (22) Compound 22 was prepared from 21 and -adamantamine according to the procedure for zompound 7. The product was obtained as a white clid. 0.585 g IR (KBr) 3411, 3333, 1696, Q72, 1653, 1519, 1165 cm-.

EXAMPLE 102 SN-f(tricyclo r3.3.1.1 3 7 1dec-2-yloxy)carbonvl1-ILnvlalanyl -DL-tryptophan, methylester (23) Compound 20 (1.25 g, 3.0 rrmol) was added to -adamantyl chloroformate (0.70 g, 3.3 mmol) in THF b-i nn~- WO 92/04045 PCT/US91/06180 -193mL), then triethyl amine (0.9 mL, 6.5 mmol) was added and the reaction mixture cooled to 0°C. After hour the reaction mixture was concentrated to dryness, the residue was dissolved in ethyl acetate.

2 5 The ethyl acetate solution was washed with 10% aqueous citric acid and saturated sodium chloride solutions, dried (MgSO 4 filtered and concentrated. The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate as eluant. The product was obtained as a white foam. 1.12 g IR (KBr) 3342, 2912, 1672, 1663, 1507, 1361, 1254, 1101 cm- 1 EXAMPLE 103 Tricvclof3.3.1.1 3 7 dec-2-vl (3,4-dihvdro-2H-lbenzoDvran-3-vl)amino]-l-(1H-indol-3-vlmethyl)-1methvl-2-oxoethvllcarbamate A solution of 2-adamantyl oxycarbonyl amethyl, DL tryptophane (0.79 g 0.002 mmol) in ethyl acetate mL) was treated with dicyclohexylcarbodiimide (0.495 g, 0.002 mmol) and 1-hydroxybenzotriazole hydrate (0.3 g, 0.0023 mmol). After stirring for 2 hours at room temperature the precipitated dicyclohyexyl urea was removed by filtration. To the clear filtrate was added 3 4 -dihydro-2,4-1-benzopyran- 3-amine (0.37 g, 0.002 mmol). The reaction mixture was stirred at room temperature overnight. The ethyl acetate solution was washed with 5% citric acid, NdHCO 3 and brine. The organic phase was dried over MgSO 4 and concentrated in vacuo to yield a white foam.

The product was chromatographed over silica using ethyl acetate, 50% hexane as eluant to give the title compound (0.66 g, 61%).

Analysis for C 3 2

H

37

N

3 0 4 0H 2 0 MW 536.679; Calc.: C, 71.61; H, 7.13; N, 7.82; Found: C, 71.67; H, 6.93; N, 7.75.

WO 92/04045 PCT/US91/06180 -194- EXAMPLE 104 Tricyclo 1. 13'7] dec-2-yl (1H-indol-3vlmethyl)-l-methyl-2-oxo-2-[[(1,2,3,4-tetrahydro-1naphthalenyl)methyl] amino]carbamate In a process analogous to Example 103 by substituting 1,2,3, 4-tetrahydro-l-naphthalenemethenamine (0.32 g, 0.002 mmol) for 3,4-dihydro-2,4- 1-benzopyran-3-amine one obtains the title compound (0.76 g, 69%).

Analysis for C 3 4

H

41

N

3 0 3

H

2 0 MW 548.734: Calc.: C, 74.42; H, 7.71; N, 7.65; Found: C, 74.27; H, 7.57; N, 7.36.

EXAMPLE 105 Tricvclo[3.3.1.1 3 ,71dec-2-yl -(lH-indol-3vlmethyl)-l-methyl-2-oxo-2-[(9H-xanthen-9-vlmethvl)aminolethyllcarbamate A solution of 2-adamantyl oxycarbonyl-a-methyl DL tryptophane (0.79 g, 0.002 mmol) in methylene chloride mL) was treated with hydroxybenzothiazole hydrate (0.3 g, 0.0022 mmol), l-(2-dimethylamino propyl)-3 ethyl carbodiimide-HC1 (0.38 g, 0.002 mmol) and triethyl amine (0.202 g, 0.002 mmol). After stirring at room temperature for 2 hours a solution of 3Hxanthane-9-methenamine (0.495 g, 0.002 mmol) in methylene chloride (10 mL) was added. The reaction mixture was stirred at room temperature overnight.

The clear solution was concentrated in vacuo. The resulting oil was taken up in ethyl acetate. The ethyl acetate solution was washed with 1 NHC1, saturated NdHCO 3 and brine. The organic phase was dried over MgS04 and concentrate in vacuo to give a white foam. the product was chromatographed over silica using 50% ethyl acetate; 50% hexane as eluant to give the title compound (0.72 g, 59%).

WO 92/04045 -195- Analysis for C 37

H-

3

N

3

O

4 Ii 2 O MW 607.761: Caic. C, 73.13; H, 6.79; N, 6.91; Found: C, 73.53; I-1, 6.80; N, 6.61.

PCTr/US91 /06 180

Claims (4)

1. A compound of formula R 2 1+ RI-A-E-(CH 2 m-C-(CH 2 q-(CHR 3 r-(CHR 4 s'-(Y-(CR 2 R 12 u-(CHR) v-Ar I (CR 5 R 6 Ar 2 or a pharmaceutically acceptable salt thereof wherein: R 1 is a cyclo or polycycloalkyl hydrocarbon or mono- or polyheterocyclic moiety wherein the hetero atom(s) can be N, 0, and/or S, of from 3 to 12 carbon atoms with from 0 to 4 substituents each independently selected from a straight or branched alkyl of from 1 to 6 carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF 3 6 or (CH 2 )OR5 wherein R 5 and R 6 are each independently hydrogen or a straight or branched alkyl of from 1 to about 6 carbon atoms or R 1 is i n i O (PhCH 2 2 N a- K 1- c I i 1 i- I 1.97 A j 0~ orK m, n, p, q, r, s, t, u, and v are each independently an is inre ff- of from 0 to G with the proviso that a, r and s are not all 1 when mn, t, u and v are all 0 excent. when X is not CONPJ9 or A-E is not (C-I 2 )n COINE-, -so 2 -jNHCONR-,-CH2n -SCONH-, -O(CHI)n CO-, or -HC=CHCO."NE- wherein n is as above, A is a bond, 0, NTR* 2n CO-Zt -so2-Z -198- -NHCO -Z, 0 -(CH-I 2 )n -OC-Z provided that n is not 0, (CH I) CO-Z, -HC=CHCO- Z, wherein Z is a bond, oxygen, sulphur, or -NR*- wherein R* is as defined above; E is a bond, an amino acid residue, -(CHR 3 )r' -(CER 3) r-(CHR4 1 -CONH-, -NHCO-, -OCO-, -coo-, -CH 1\7(R

3- -C.H 0-, 2 -CH S-, -CH=CH-, S -C-NR3 3_ -so 2 NR -NR 3so 2 -NHCONII- M r cr^l~l ~-rx 199 J S N N-O -C N-N 4 wherein r and s are indenendenty as defined above and R 3 and R. are as defined below; R andR20 are each inde-endently hvdrcgen, a straiaht or branched alk7l of from 1 to G carbcn atoms, 2' (C:-I2 )C4=C:2 (CH 2 n CIr is (Ci 2 )fnsr, 2 -(C 2 )n OAr -(CH 2 )nCO)R*, -(C 2 NR5G wherein n, R* and R are as defined above, and Ar and Ar are as defined below; X and Y are each indenendently: -CONEH-, -CONR -INECO-, -OCO- -coo-, -CH 2 N(R CI 2 0- _CH 2 S_' -200- *OCH 2 *SCH 2 -CH=CH-, S -C-NR~ S -NR 3-C-, 3 so 2 NR -NR s S2-' -NHCONH-, -CH CH 2 COCH 2 -CH 2co-, -NR 3C Q -4 N-0 _4N N -N I ,or N -201 wherein Q is 0, S, or NP.9 42 P. and P. are earh independently the same as Ror -(CH 2 )nI -B-D wherein n' is an integer of from 0 to 3 or P. 3 is -CH 2 CCOCH=CHCO H; B is a bond, -OCO(CH 2 )n-I -0(CH -NHC-,J(CH 2 -CONH(CH 2)n- -NHCOCH=CH-, -CO0(CH 2 )n-I -Co (C 2 -S (CE 2 n- -so 2 (CH 2 )n-I* NHCO-C=C-, I I HEH NECO-C-C-, 78 CONE-C=C-, or I I R7 R8 -202- HH I I CONH-C-C-, 1 1 7 8 RR wherein R and R are each independently selected from hydrogen and R 2 or together form a ring (CE 2 )m wherein m is an integer of from 1 to D is -COOR*, -CH 2 OR*, -CHR 2R*,. -CH 2 SR*, -CHR SR*, -CONR R -CN, 5 6 R -OH, and acid replacements selected from tetrazole; 0 HO R 10 N4 R 1 0 is OH, NH 2 CH 3 or C1 SN2 HS'. O '-P03H2 1,2,4 oxadiazole S* R N-N N R" is CN, C0 2 or CF 3 KN, 2K HN1 N N N H H H H H N-N PhSO 2 NHCO-k, O CF 3 CONHCO4 N O N CF 3 SO 2 NHCO-A 0 O CH 3 H H 2 NS02 r

203- H HH NN HNHR 5 HO N-1N -S (0 -S(0)S (Z) 1= wherein b is an integer of frcm 0 to 2, wherein 5 6 R R 5 and R are as defined above; R is s, or a straight or branched alkyl of from one to six car cn atoms, -(CH )2CC 2 R* (Ca 2 )2OAr 1 5 6 (CH2)Iz-- I(C:-El) nR R where2.n n, R and R are as defined above or and as isfne asov deiedr itaken from R3 and is as definedi below; IR and Pi3 are each indenendently hydrogen or taken together for a double bond, or are )a**D as defined above; and A 1 and Ar 2 are each indevendently a monocyclic unsubstituted or substituted carbocyjclic aromatic moiety, a polycyclic unsubstituted or substituted carbocyclic aromatic moiety, a monocyclic unsubstituted or 203a substituted heterocyclic aromatic moiety, a pol,"cyc2.ic unsubstituted or substituted heterocyclic aromatic moiety, a monocyclic unsubstituted or substituted carboaromatic moiety, a polycycJlic unsubstituted or substituted carboaromatic moiety, a monocyclic unsubstituted or substituted heteroaromatic moiety, or a polycyclic unsubstituted or substituted heteroaromatic moiety; or a compound selected fromi 5,13-dioxa-2, 8-diazatetradec-lO-enoi-c acid, 3- (lH-indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7-phernyl-, tricyclo (3.3.1.1 3 7 dec-2-yl ester, tS-(R-,S*fl-, 5,13-dioxa-2, 8-diar-atetradecan-oi-c acid, 3- (1H-indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7-phEnyl-, tricycloL3.3.1.1 3 ,7 dec-2-yl ester, 6..12-dioxa-2,4, 8-triazatridec-9-enoi-c acid, 3-1(2- (lHi-indo2.-3-yl) ethyl] -3-methyl-7, tricyclot3.3.1.1 3 7 dec-2-yl ester, glycine, N- IN- cr-methyl-N- t(t ricyclol3.3.1.1 3 ,71 dec-2-yJloxy) carbonyl] -D-tryptophy.]-D-phe.-ylalanyl] or 2, 4-heptadienoic acid, 6- (1H-indol-3-yl) 2-methyl-l-oxo-2- £1(tricyclo£3 .3 .1.JA 3 7 ]dec-2-yloxy) carbonyl] amino] propy.) amino] -7-phenyl, CR- CR*, S* E, E)11-; with the proviso that when R 1is cycloalky. or polycycloalkyl; A-E is (CH 2 )n CONH,-SO 2 NI,-SONE, -NH.CONH, (CH 2 )n OCONHI-SCONH, -o(CH 2 )n CNH HC=CHCONH; m 0; then Ar c t 2. A compound accordings to claim~ wherein.- Ar i phenyl. substituted phenyl, fused aryl, heterocycle, fused heterocycle, or 3. perhydroaryl. 3. A compound according to claim I. wherein Ar is 2- or 3-thienyl, 2- or 3-furanyl, or 4-pyridinyl, -203c i El and F are each independently hydrogen, zne, chlorine, bromine, iodine, methyl, methoxy, .0romethyl, nitro, hydroxy, NH21 OCF 3 and ~ined above. A compound according to claim I wherein the .,cloalkyl is selected from the group consisting of I \I" ain W, X, Y and Z are each independently hydrogen, a .ght or branched alkyl of from one to six carbon -3 CF 3 1 NR 5 R 6 (CHq 2 n C 2 R*g CN, F, Cl, SR*, wherein R, and R6are as defined -".aim l and w is an integer of from I to 3. A compound according to claim 1 named: Carbamic~ acid, C (hydroxymethyl) -2- phenylethyl) -amino) (1H-indol-3-ylmethyl) ethyl] Carbamic acid, -0 12-1 (l-(hydroxymethyl)-2-phelylethyll-amil-1- (I-indol-3-ylmethyl) ethyl]-, tricyclo- f3.3.2..1 3 ,7 dec-2-yl ester, TriLcyclo (3.3 3 7 ]jdec-2-yl I(1-f i-hydroxy- methyl) -2-phenylethyl] carbonyl) amino) (1H-indol-3-yl) ethyl) carbamate, Carbamic acid, 2-f[ (2-hydroxy-2-phenylethyl) -amino] 1- (1E-indol-3-ylmethayl) -1-methylethyl) tricyclo- [3.3.1.1 3 7 ]dec-2-yl ester (hydroxy center is RS, other center is WO 92/04045 P~T/US91/O618O -204- Carbamic acid, f2-[[i-(hydroxymethyl)-2- phenyl-ethyl) amino] (H-indol-3-ylmethyl) -1- methylethyl]-, tricyclo(3.3.1.1 3 7 ]dec-2-yl ester, 4-methylbenzenesulfonate (1:1) (salt), Benzenepropanol, 5-f f2- (1H-indol-3-yl) -2- ((C(tricyclo [3.3.1.1 3 7 dec-2- yloxy) carbonyl] amino] -propyl] amino]-, acetate (ester), 4-methylbenzenesulfonate (salt), Carbamic acid, (acetyl(1- (hydroxymethyl) 2-phenylethyl] amino] (H-indol-3-ylmethyl) -1- methyl~ethyl]-, tricyclo[3.3.1.1 3 7 ]dec-2-yl ester, 13-Dioxa-2, 8-diazatetradec-lO-enoic acid, 3- (1H-indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7- phenyl-, tricyclo[3.3.1.1 3 7 ]dec-2-yl ester, 13-Dioxa-2, 8-diazatetradecanoic acid, 3- (1H-indol-3-ylmethyl) -3-methyl-4, 9, 12-trioxo-7- phenyl-, tricyclo[3.3.1.1 3 7 )dec-2-yl ester, Carbamic aci, (lH-indol-3-ylmethyl) -1- methyl-2- (-oxo-4-phenylbutyl) amino] ethyl] tricyclo[3.3.l.1 3 7 ]dec-2-yl ester Carbamic acid, (benzoylamino) (H-indol- 3-ylmethyl) -1-methylethyl]-, tricyclo[3.3.l.1 3 ,71- dec-2-yl ester, Carbainic acid, (lH-indol-3-ylmethyl) -1- methyl-2-[t(l-oxo-3-phenylpropyl) amino) ethyl) tricyclo[3.3.l.1 3 7 )dec-2-yl ester, Carbamic acid, (lH--indol-3-ylmethyl) -2- methyl-2-( (2-phenylacetyl)aminolethyl)-, tricyclo- [3.3.l.1 3 7 ]dec-2-yl ester, WO 92/04045 PCT/US9I /06180 -205- Carbamic acid, (hydroxymethyl) -2- phenylethyl) amino) -3-oxopropy.) amino (lH-indol- 3-ylmethyl) -l-methyl-2-oxoethyl)-I (Rh, Carbamic acid, C1- (lH-indol-3-ylmethyl) -2- (hydroxymethyl) -2-phenylethyl) amino) -3- oxopropyl) amino) -l-methyl-2-oxoethyl) tricyclo- (3.3.1.1 3 7 )dec-2-yl ester, D-Phenylalaninamide, cx-methyl-N-C(tricyclo- i3' 7)dec-2-yloxy) carbonyl) -D-tryptophyl-B- alanyl-, L-PhenylaJlaninamide, (x-methy-N'-( (tricyclo- [3.3.1 .1 3 7 3dec-2-yloxy) carbonyl)-D-tryptophyl-B- alanyl-, L-Phenylalaninamide, ca-methyl-N-t (tricyclo- alaiy 1-, D-Phenylalaninamide, cX-methyl-N- EtricycJlo- 3. 3.1. 13,'7) dec-2-yloxy) carbonyl) -L-tryptophyl-3- alanyl-, 12-Oxa-2, 5, 9-triazatridecanoic acid, 3-(lIH- indol-3-ylmethyl) -3-methyl-4, 8, 11-trioxo-lO- (phenyJlmethy.) tricyclo(3 1 3 7 )dec-2-yl L-Phenylalanine, N-[N-(X-methyl-N-[ (tricyclo- 1 3 7 )dec-2-yloxy) carbonyl)-D-tryptophyl-3- alanyll-, phenylmethyl ester, Propanoic acid, 2-[[3-[[3-(lH-indol-3-yl)-2- methyJ.-1-oxo-2-[[£(tricyclo[3.3.1. 1 3 7 )dec-2- yloxy) carbonyl) aminolpropyl) amino) -1-oxopropyl) amino)-3-phenyl-, phenylmethy. ester, D-Phenylalanine, N-[N-[cx-methvl-N-( (tricyclo- 3.1. 7) dec-2-yloxy) carbonyl)3 -D-tryptophyl)3 -13- alanyl) -206- L-Phenylalanine, N- £a-methy1 -N-C1(tricyclo- £3.3 3,7 dec-2-yloxy) carbonyl] -D-tryptophyl] r-alanyl] L-Phenylalanine, N- [a-methyl-N-[£(tricyclo- (3.3.1.1 3 7 ]dec-2-yloxy)carbonyl]-L-tryptophyl] !3-alanyl] Benzenepropanoic acid, a- [13- 1(1I-indoJ.-3-yl) 2-methyl-1-oxo-2-[[l(tricyclo 13.3.2. 3,7 dec-2-vloxy) carbonyl] amino) propyl] amino] -1-oxopropyl] -amino] I Glycine, N-[2-methyl-N-[(tricyclo-[3.3.1.1 3 7 ]1- dec-2-yloxy) carbonyl] -D-tryptophyl] phenylmethyl ester, Carbamic acid, (lH-indol-3-ylmethyl) -2,5-dioxo-1- (2-phenylethyl) -3-pyrrolidinyl] tricyclo[3.3.1.1 3 7 ]dec-2-y. ester,(±- Carbamic acid, (lH-imidazol-4-ylmethyl) -1-methyl- 2-oxo-2- [(2-phenylethyl) amino] ethyl]-, 1,1-dimethylethyl 4 ~ester,(±- Carbamic acid, [3-(lH-indol-3-yl) -1-methyl-l- [[(2-phenylethyl)aminolcarbonyllpropyl]-, tricyclo[3.3.1.1 3 7 dec-2-yl ester, Carbamic acid, [1-[[(2-hydroxymethyl)-2- phenylethyl] -amino] carbonyl] (1H-indol-3-yl) -1- methyipropyl]-, tricycloll3.3.1.1 37]dec-2-yl ester (hydroxymethy. center is S, other center is RS), 13-Oxa-2,5,13-triazatetradec-10-enoic acid, 3- 12- (lH-indol-3-yl)ethyl]-3-methyl-4,5,12-trioxo-7-phenyl-, 207 tricyclo[3.3.1.l 3 7 dec-2-yl ester [TRP center is R/S mixture, other center is RI, L-Phenylalaninamide, N- f l-dimethyl-ethoxy) carbonyl] -a-rethyl-L-tryptophyl] -L-methionyl-L-a- aspairtyl-, Glycine, N- 12-methyl-N-I (tricyclo- L3.3.l.1 3 7 ]dec- 2-yloxy) carbonyl] -D-tryptophyl] -L-phenyllalanvl-, Carbamic acid, (1-1 (hydroxymethyl) -2- Dhenyleth-yl] amino] carbonyl] (lH-indol-3-yl) -propyl] tricyclo [3 1 3 7 ]dec-2-yl ester (hydroxymethyl center S, other centers RS), 2,4-Heptadienoic acid, 6-I [3-(lH-indol-3-yl) 2-rnethyl-l-oxo-2- II(tricyclo [3.3.1.1 dec-2- yloxy) carbonyl] amino] propyl] am-no] -7 -phenl l-, I Glycine, N- [2-methyl-N- I(tricyclo-[3.3.l.1 I- dec-2-yloxy) carbonyl] -D-tryptorhyl] phenylmer-hyl ester, .3,7 dihydro-4- (phenylmethyl) -2-thiazolyl] (lH-indol-3-yl) l-methylethyllcarbamate. 46. A oharmaceutical composition for suppressing appetite, for reducing gastric acid secretion, for reducing anxiety, for treating gastrointestinal ulcers, for treating psychotic behaviour, for blocking the reaction caused by withdrawal from drug or alcohol use, for potentiating the effects of morphine and other opioids in treating pain, and/or for treating and/or 208 preventing panic, in a mammal, said composition comprising an effective amount of a compound according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier. 7. A method of suppressing appetite in a mammal, comprising administering an effective appetite suppressing amount of a compound according to any one of claims 1 to 8. A method of reducing gastric acid secretion in a mammal, comprising administering an effective gastric acid secretion reducing amount of a compound according to any one of Claims 1 to 9. A method of reducing anxiety in a mammal, comprising administering an effective anxiety reducing amount of a compound according to any one of Claims 1 to A method for treating gastrointestinal ulcers in a mammal comprising administering an effective gastrointestinal ulcer treating amount of a compound according to Claim 1. 11. A method of treating psychosis in a mammal, comprising administering an effective psychosis treating amount of a compound according to any one of Claims 1 to 12. A method of blocking drug or alcohol withdrawal reaction in a mammal comprising administering an effective withdrawal reaction blocking amount of a compound according to any one of claims 1 to i 209 13. A method of treating pain in a mammal, comprising administering an effective amount of a compound according to any one of claims 1 to 14. A method of treating and/or preventing panic in a mammal, comprising administering an effective amount of a compound according to any one of Claims 1 to Method of use of a radioactive iodo compound of formula I to prepare a pharmaceutical or diagnostic composition for the treatment or diagnosis of gastrin-dependent tumors. 16. A compound of formula I as defined in claim 1, substantially as herein described with reference to any one of Examples 1 to 105. DATED this 26th Day of April 1994 WARNER-LAMBERT COMPANY Attorney: IAN T. ERNST Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS r F d INTERNATIONAL SEARCH REPORT International Application, NO. POT/US9 1/06180 1. CLASSIFICATION OF SUBJECT MATTER (it several classification symbols apply, indicate alil) According to International Patent Classification (IPC) or to botII NatioallsifctoanIP A61K 37/02; C07K 5/08, 5/10 U.S.C1.: 530/330, 331; 514/18 11. FIELDS SEARCHED Minimum Documeintation Searched I Classification System Classification Symbols U.S.C1. 530/330, 331; 514/18 Documen"tatiOn Starched other than Minimum Documentation to the Eatent that such Documents I Included In the Fields Searcheda APS, BIOSIS, SEARCH TERM3: CCK ANTAGONISTS 111. DOCUMENTS CONSIDERED TO B3E RELEVANT'I Cateecory Citation of Document, It with indication, where approorinte. ot the ielevant vassunes il Reirnant to Climi 1o, i2 A US,A, 4 7 5 7 ,157HORWELL) 12 JULY 1

1988. see entire document. 12 X EP,A 0,227,173( AB3BOTT LABORA-TORIES) 1-22 Y 11 OCTOBER 1989, see entire document. 3-22 -Special calego' z of cited documents:** later document pubtished alter the intvrnational filing date or priority date and not in conflict wiii the atpplicationi but dotument defining the general, 1tate ot the art which is nrot cited to understand the principle or theory underlying the considered to be of particular lleance Invenion earlier document but published on or alter the Interntonail "XI document of particular rlevance:, the claimed invention fi ling date cannot be considered novel or cannot be considered to document wh~ch may throw doubts an priority claints) ar involve an inventive slap which Is cited to establish the publication data o1 another T' document of particular relevance: the claimed Invention citation or other special reason (as Specified; cannot be considered to involve an inventine step when the document referring to an orat discloaure. use, ehlbitlolt of document is combined with one or more other such docu. other means manta. such combination being obvious to a person skilled document Published prior to the international riling date but In the ArM satar than the Priority data claimed ""document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date Iof Melling of t1.national Search Report November 1991 E 1901 International Searching Authority ISA/US G. Marsha1±q i