PT94623A - PROCESS FOR THE PREPARATION OF COLONIZOCHININ ANTAGONISTS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

-3-

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House 4714.ΡΘ.01

DESCRIPTIVE MEMORY

This is a continuation in part of U.S. Application Serial No. 376,778, filed July 7, 1989, which is a. part of the PC2 patent application PCT / US89 / 01412, filed April 4, 1989, which in turn is a continuation in part of the U.S. patent application Serial No. 177,715, filed April 5, 1988.

The present invention describes processes for the preparation of compounds and compositions that antagonize cholecystokinin (CCK) and gastrin, synthetic intermediate compounds used in these methods and a method for treating gastrointestinal disorders, central nervous system disorders , cancer of the gastrointestinal system (i.e., pancreas, gallbladder, etc.), hypo-insulinemia or to increase the potency of analgesics or to regulate appetite disorders with these compounds.

Background of the Invention

Cholecystokinins (CCK) constitute a family of polypeptide hormones. CCK and a 33 amino acid fragment of CCK (CCK33) were first isolated from the gut of the pig (Mutt and Jorpes, Biochem, J 125, 628, 1981).

Recently the CCKGG fragment has been found in the brain, where it appears to be the precursor of two smaller fragments, a CCKg octapeptide and a CCK4 tetrapeptide (Dockray, Mature 264, 4022, 1979). The CCKg, carboxy terminal octapeptide fragment of CCK, is the smallest CCK fragment that remains fully biologically active (Larsson and Rehfeld, Brain Res. 165, 201-218, 1979). The localization of CCK fragments in the brain cortex suggests that CCK may be an important neuromodulator of memory, learning and control of primary sensory and motor functions. CCK and its fragments are thought to play an important role in regulating appetite and satiety (Della-Fera, Science206, 471, 1979; Gibbs et al., 4

-4 • J 71 210

Case 4714.PC.01

Nature 289, 599, 1981; and Smith, Eating and Its Disorders, eds., Raven Press, New York, 67, 1984).

CCK antagonists (B.J.Gertz in N u r o 1 og and ________ & π d

Neurobiology Vol 47, Cholecystokinin___Antagonists, Wang and

Schonfeld eds. Alan R. Liss, Inc., New York, NY, 327-342, 1988; Silverman et al. , Am. J. Gastroent., 82, (8), 703-8, 1987) are useful in the treatment and prevention of CCK-related perspacings of the gastrointestinal (GI) systems (Lotti et al., J Pharm ExgTherap , 241 (1), 103-9, 1987), central nervous system (CNS) (Panerai et al, Neuropharmacology, 26 (9), 1285-87, 1987) and regulating the appetite of animals, especially man. CCK antagonists are also useful for potentiating and prolonging narcotic-induced analgesia and thus have application in the treatment of pain. (Faris et al., Science 226, 1215, 1984 Rovati et al.

Clinical Res., 34 (2), 406A, 1986; Dourish et al., European J. Pharmacology, 147, 469-72, 1988), Diseases that can be treated with CCK antagonists are disorders of gastric emptying, gastroesophageal reflux disease (Setnikar et al., Arq. Forsch./Drug Research, Pancreatitis, pancreatic and gastric carcinomas (Douglas et al., Gastroenter., 96, 4629, 989; Beaucharnp et al., Am Surg, 20, 2, 313-9, 1). 985), disorders of bowel mobility, biliary dyskinesia, anorexia nervosa, hypoglycemia (Rossetti, Diabetes, 36, 1212-15, 1987; Reagan, European J Pharmacology, 144, 241-3, 1987), diseases of the gallbladder , and the like.

Previously, four different chemical classes of CCK receptor antagonists have been reported. The first class comprises cyclic nucleotide derivatives, such as dibutyrylcyclic GMP (N. Barbos et al., Am., J. Physioi 242, G161, 1982 and references cited therein). The second sequence is represented by C-terminal fragments of CCK (see Jensar et al., Biochem Biophys Acta, 757, 250, 1983, and Spanarkel Biol Chem, 258, 6746, 1983). The third class comprises amino acid derivatives of glutamic acid and tryptophan, such as for example β-propanol (and analogs thereof) and benzotrypto (see Hahne et al., Proc. Natl. .. Sei, ...... USA 78, 6304, 1981 and Jensen et al., Biochem.BJophys.

Example 5

Acta 76, 269, 1983). The fourth and most recent class comprises 3-substituted benzodiazepines, for example L-364 718 (see: Evans et al., Proc Natl Acad Sci USA 83, 4918, 1986).

Except for certain recently described substituted benzodiazepines and proglumide analogs (Makovec et al,

Arzeim.-Forsch./Prug.Res. 36, (I), 98-102, 986), all of these compounds are relatively weak antagonists of CCK, with IC 50 usually showing between 10 -4 and 10 " 6 M. Benzodiazepines antagonists of CCK or its metabolites may have in vivo due to their interaction with the benzodiazepine or other receptors. The C-terminal pentapeptide fragment of CCK is the same C-terminal pentapeptide fragment of another polypeptide-hormone, gastrin. Gastrin, such as CCK, exists in system 01. Gastrin antagonists are useful in the treatment and prevention of gastrin-related disorders of system 01 such as ulcers, ΖοΠinger-ΠΠison syndrome, and central cell hyperplasia. There is no efficient receptor antagonist, the in vivo effects of gastrin. (Moreiy, 6ut, Pept. Ujcer proc., Hiroshima Symp. 2nd, 1, 1983). A recent report (8ock J, ..... Med. Chem., 32, 13-16, 1989) describes potent in vitro antagonists of gastrin, D and cleavage of the ...... Invention According to the present invention, there are cholecystokinin antagonists of the formula:

Kg 0

(D) or a pharmaceutically acceptable salt thereof, wherein G is (1) NH2 or

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Example 4714.P6.01 (2) substituted amino

R1 is (1) hydrogen (2) lower alkyl (3) lower alkyl (3) alkyl substituted with carboxy (4) alkyl ester substituted with carboxyester R1 is (1) 1) hydrogen (2) lower alkyl (3) alkyl made functional (4) cycloalkyl (5) aryl (6) oxyalkyl made functional or (7) heterocyclic or Rjj taken together, with D is (1) Where q is 1 to 3, r is 1 to 3 and V is (1) -0- (ii) "s- (iii) Wherein R 25 is hydrogen, lower alkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or a N ou or R protector protecting group taken together with D is (1) C--C alquil alkylene, (CH2) p-V- (CH2) where p is 1 to 3, t is 1 to 3 and V is defined as above.

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C (S) - or (3) -S (O) 2 B is (1) absent (2) alkylene (3) alkenylene (4) alkenylene (5) is absent or is -CH2- and R2 'is -O-, -S-, -NH- or -N (lower-alkyl) - or 6) -R27 "CH2 where R2y is defined as above.

Ar is (1) aryl or (2) a heterocyclic group.

Compounds wherein D is indolylmethyl, indolylmethyl or oxindolylmethyl are described in the copending base application

PCT Patent Application Serial No. PCT / US89 / 01412, filed April 4, 1989.

The terms " lower alkyl " used herein refer to straight or branched chain alkyl radicals containing from 1 to 8 carbon atoms, including, but not limited to, the methyl, ethyl, n-propyl, iso propyl, n-butyl, iso-butyl, sec-butyl. n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl and the like. The expression " alkyl made functional " used herein includes (1) (2) haloalkyl (3) arylalkyl (4) arylalkyl wherein the alkyl group is substituted with (i) -OR g where R g g is hydrogen or a hydroxy protecting group (1) wherein R - [g is hydrogen or a protecting group of N, (iii) -OR- wherein R3 is lower alkyl

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Wherein R 14 is an aryl group or (v) -SR 13 where R 13 is lower alkyl. (5) heterocyclic-alkyl (6) heterocyclic-alkyl wherein the alkyl group is substituted with (i) wherein R | is hydrogen or a hydroxy protecting group. (ϋ) -NHR 5 where R 5 is hydrogen or a nitrogen protecting group. (iii) -OR1 where R13 is lower alkyl (iv) wherein R4 is an aryl group or (v) wherein R13 is lower alkyl (7) lower alkyl substituted by -S-lower alkyl, -S (O) -a lower alkyl or -S (O) 27 lower alkyl, (8) lower alkyl substituted by -S-aryl, -S (O) -aryl or -S (O) 2 " (ii) wherein R4 is independently selected from lower alkyl, alkenyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl (iii) wherein R12 is (i) hydrogen (ii) ) Wherein R4 is independently chosen as above

(iv) a protecting group of N (v) -C (O) -A-aryl wherein A is alkenylene, substituted alkenylene, -OCH 2 ", SCH 2 -j-NH-, -N (lower alkyl) -, -S- or -O-

The terms " oxyalkyl made functional " used herein include -T-OR11 where T is (1) alkylene or (2) ar11alkylene and R11 is (1) hydrogen (2) lower alkyl

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(4) alkenyl (5) arylalkyl (6) hydroxyl protecting group (?) -C (O) - (L) s - R 4 where R 4 is independently chosen as above * s is 0 or 1 and L is (I) or (iii) NH or (8) -C (O) -A-aryl wherein A is independently defined as above the term " has " used herein refers to a lower alkyl radical in which one or more hydrogen atoms have been replaced by halo groups including, but not limited to, fluoromethyl, trifluoromethyl, chloroethyl, 2,2-difluoroethyl, 2,3-dibromopropyl and the like. The term " a 1 " used herein refers to an alkoxy group attached to a lower alkyl radical. The term " cyanoalkyl " used herein refers to a cyano group (-CN) attached to a lower alkyl radical, the term " hydroxyalkyl " used herein refers to a hydroxyl group (-OH) attached to a lower alkyl radical. The term " cyclohexyl " used herein refers to an alicyclic ring having 3 to 7 carbon atoms including (but not limited to) cyclopropyl, cyclopentyl, cyclohexyl and the like. The term " cycloalkylalkyl " used herein refers to a cycloalkyl group attached to a lower alkyl radical including (but not limited to) cyclopropylmethyl, cyclohexylethyl and the like. The term " carboxy substituted alkyl " used herein refers to a carboxy group (-C H H) attached to a lower alkyl radical.

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The term " carboxy-ester-substituted alkyl " used herein refers to an esterboxy ester group (-CRRR onde where R é is lower alkyl, cycloalkyl, aryl or arylalkyl) attached to a lower alkyl radical. The term " alkenyl " as used herein refers to a straight or branched chain of 2 to 8 carbon atoms containing a carbon-carbon double bond including (but not limited to) vinyl, allyl, butenyl and the like. The term " alkylene group " used herein refers to a straight or branched chain spacer group containing 1 to 8 carbon atoms including (but not limited to) -CH 2 ", -C 1 -CHCH 2) -, -CH (CH 3) CH 2 - 2) 3 " and the like.

The terms " alkenylene group " used herein refer to a straight or branched chain spacer group of 2 to 8 carbon atoms containing a carbon-carbon double bond, including (but not limited to) -CH = C H-, -C (CH 2) = CH- , -CH2 -CH = CH-, -CH (CH3) -CH2 -CH = CH-CH2-, and the like.

The terms " substituted alkenylene " used herein refer to an alkenylene group substituted with one or two substituents independently selected from lower alkyl, haloalkyl, halo and harm. The term " cycloalkylalkylene " used herein refers to a cycloalkyl group attached to an alkylene radical.

Where R- | " substituted amino " R 2 and R 2 are independently selected from (1) hydrogen (2) lower alkyl (3) haloalkyl (4) alkoxyalkyl (5) alkenyl (6) aryl (7) arylalkyl (8) ) cycloalkyl (9) cycloalkylalkyl

J 71 210 Case 4714.PG.01 -11-

(10) cyanoalkyl (11) lower alkyl substituted with -CO₂R ^ where Rg is (i) hydrogen (ii) lower alkyl (111) cycloalkyl (1v) aryl or (v) aralkyl (12) lower alkyl substituted with -C (Vi) aryl and (vii) aryl and (vii) aryl and (vii) aryl and (vii) aryloxy, arylalkylene (13) -W-CO 2 R 3 where R 3 is defined as above and W is (1) cycloalkylalkylene (ii) arylalkylene or (iii) heteroarylalkylene (14) adamantyl (15) indanyl and (16) -CH (aryl) -X where X is arylalkyl; with the proviso that R- and R2 are not both hydrogen. Substituted Amino also includes

where n1a3, r1a3eJe:

Case 4714-ΡΘ. 01 (1) -S (2) -S (O) - (3) -S (O) 2- (4) -O " (5) -CH2- " (6) -NR g) " wherein R 4 is defined as above and R 5 is defined as above, or (7) -N (C (Q) R 4) wherein R 4 is defined as above and R 2 represents one, two or three substituents independently selected from: ) wherein R4 is independently defined as (6) -C (Q) N (Rg) (Rg) where Rg and Rg are independently defined as (7) -OR 15 where R 6 is (I) hydrogen or (II) hydroxyl protecting group (8) hydroxyalkyl (9) alkoxyalkyl (10) -NR 15 R 15 wherein R 6 is (i) hydrogen or

(ii) a protecting group of M (11) cyano and (12) halo. The term " alkylamino " used herein refers to -NHR 40 where R 40 is a lower alkyl group. The term " dialkylamino " used herein refers to "where R4 is selected from the group consisting of halogen, C1 -C4 alkyl, The term " aminocarbonyl " used herein refers to -C (O) NH2 * The term " alkylaminocarbonyl " used herein refers to -C (O) RgQ where Rgg is an alkylamino group.

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The term " dl at 1Â ° C. used herein refers to -C (O) Rg where Rc is a dialkylamino group. The term " at 1 to 10 amino acids " used herein refers to -C (O) NHR52 where R 53 is an alkenyl group.

The terms " halogen " or " halo " used herein refer to F, Cl, Br, I.

The terms " alkoxy " and " thioalkoxy " used herein refer respectively to R j- and R jgSS-, where R j é is a lower alkyl group. The term " alkoxycarbonyl " used herein refers to -C (O) OR4 where R4 is lower alkyl.

The terms " aryl " or " aryl group " used herein refer to a monocyclic, bicyclic or tricyclic, carbocyclic ring system containing one or more aromatic carbocyclic rings including (but not limited to) phenyl, naphthyl, indanyl, fluorenyl, (1,2,3,4- ) -tetrahydronaphthyl, indenyl, isoindenyl, and the like. The aryl groups may be unsubstituted or substituted by one, two or three substituents independently selected from lower alkyl, alkoxy, thioalkoxy, carboxy, alkoxycarbonyl, arylcarbonyloxy, arylalkylcarbonyloxyl, heterocyclicocarbonyloxy, heterocyclic T -cylcarbonyloxy, arylalkoxy, heterocyclic alkoxy, OSOg H, cyano, nitro, haloalkyl, hydroxyl, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino and dialkylamino. The term " arylalkyl " used herein refers to an aryl group attached to a lower alkyl radical. The term " arylalkylene " used herein refers to an aryl group attached to an alkylene radical. The term " arylcarbonyl " used herein refers to R4 C (O) O- where R54 is an aryl group. The term " arylalkylcarbonylloxy " used herein refers to

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Case 4714.PG.01 "14-

Rg is C (O) O- wherein Rg is an arylalkyl group. The term " arylalkoxyl " used herein refers to RggO- where Rg is an arylalkyl group. The term " heteroarlo " used herein refers to a monodicyclic or bicyclic aromatic ring system, each ring having 5 or 6 atoms, one to four of which are independently selected from oxygen, sulfur and nitrogen. Heteroaryl groups also include a heteroaryl ring, as defined above, fused to a benzene ring. The heteroaryl groups may be unsubstituted or substituted by one, two or three substituents independently selected from lower alkyl, halo, hydroxy, cyano, nitro, haloalkyl, alkoxy, thioalkoxy, amino, aminocarbonyl, aminocarbonyl, dialkylaminocarbonyl, alkenylaminocarbonyl, alkylamino, dialkylamino, amino. N-protected, protected hydroxyl, carboxylic acid, carboxamide, arylcarbonyl, arylalkylcarbonylloxy, heterocyclicocarbonyloxy, heterocyclic alkylcarbonyloxy, arylalkoxy, heterocyclicalkoxy, or -OSO3H, carbamyl and aryl. The term " heteroarylalkyl " used herein refers to a heteroaryl radical group attached to a lower alkyl. The term " heteroarylalkylene " used herein refers to a heteroaryl group attached to an alkylene radical. . The terms " heterocyclic ring " or " heterocyclic " used herein refer to any 3 or 4 chain ring containing a heteroatom selected from oxygen, nitrogen or sulfur; or a 5- or 6-membered ring containing one, two or three nitrogen atoms; a nitrogen and a sulfur atom; or a nitrogen and an oxygen atom. The 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen heteroatoms may optionally be quaternized. The term " heterocyclic " includes any bicyclic or tridecyl group wherein the heterocyclic ring is fused

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With one or two benzoyl rings or one or two heterocyclic groups defined independently as above. The heterocyclics include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azinoethyl, isoindazole benzopyranyl, benzoxazinyl, quinoxadinyl, chrominyl, chromanyl, isochromanyl, carbolinyl, and the like. The heterocyclic groups may be unsubstituted or substituted by one, two or three substituents independently selected from lower alkyl, haloalkyl, oxo, hydroxy, protected hydroxy, alkoxy, thioalkoxy, amino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,

alkenylaminocarbonyl, alkylamino, dialkylamino, N-protected amino, cyano, nitro, carboxylic acid, carboxamide, arylcarbonyloxy, arylalkycarbonyloxy, heterocyclylcarbonylloxy, heterocyclylalkylcarbonylloxy, arylalkoxy, heterocyclicalkoxy, -OSQgH, carbamyl, and aryl. The term " heterocyclic alkyl " . used herein refers to a heterocyclic group attached to a lower alkyl. The term " heterocyclicocarbonyloxy " used herein refers to R57C (O) 0- where R57 is a heterocyclic group. The term " heterocyclic alkoxycarbonyl " used herein refers to RggC (O) 0- wherein Rg is a heterocyclic alkyl group. The term " heterocyclic alkylene " used herein refers to a heterocyclic group attached to an alkylene radical. The term " heterocyclic alkoxy " used herein refers to R 6 O- where R 6 7 is a heterocyclic alkyl group.

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Case 4714.PG.01 · -16-

The terms " nitrogen protecting group " or " N protected " used herein refer to those groups intended to protect the N-terminus of an amino acid or peptide, or to protect an amino group against undesirable reactions during the synthesis processes or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds , and includes (but is not limited to) the sulfonyl, acyl, acetyl, pivaloflo, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), benzoyl or a α-aminoacyl residue which may itself have N protected analogously.

The terms " hydroxyl protecting group " used herein refers to a substituent which protects the hydroxyl groups against undesirable reactions during the synthesis processes and includes (but is not limited to) substituted methyl ethers, eg methoxymethyl, benzyloxymethyl , 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted etheter ethers, e.g., 2,2,2-trichloroethyl and t-butyl; e.g., trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, e.g. methyleneacetal, acetonide and benzylideneacetal; cyclic ortho-esters, e.g. methoxymethylene; cyclic carbonates; cyclic boronates and esters, e.g. acetates or benzoates. Examples of compounds of the present invention are N- (3'-quinolinylcarbonyl) -R-Valine-di-n-pentylamide, N- (2-indolinylcarbonyl) -R-Valine-di-n-pentylamide

N- (2'-naphtho1) -R-Valine-di-n-pentylamide N- (3-methoxycarbonyl) R-Norleucine di-n-pentylamide N- (2-phenylcarbonyloxy) -R-Norleucine di-n-pentylamide N- (3'-quinolinylcarbonyl) N- (3'-quinolinylcarbonyl) - (2R, 3S) - (O-benzyl) threonine di-n-pentylamide N- (3'-quinolinylcarbonyl) - ( 2R, 3S) -Treonine di-n-pentylamide M- (3-quinolinylcarbonyl) - (2R, 3S) - (O-acetyl) threonine di-n-

N- (3-quinolylcarbonyl) - (2R, 3S) - (O-methyl) threonine di-η-pentylamide

| (2'-indolylcarbonyl) -R-Histidine-di-n-p-toluenesulfonic acid N- (3-quinolylcarbonyl) -3- (2-thienyl) pentylamide N- (3-quinolylcarbonyl) -R-Histidine-di-n-pentylamide

N - (3'-quinolinylcarbonyl) -N- (benzyloxycarbonyl) -R-Lysine di-n-penicillamide N- (3-quinolinylcarbonyl) -R-phenylalanine di-n-pentamide

(2-chlorobenzyloxycarbonyl) -R-Lysine-di-n-penti-1-one

N- (3-quinolylcarbonyl) -R- (4-hydroxyphenyl) -6-ene-di-n-pentylamide [(3-quinolinylcarbonyl) -N'- (acetyl) -R-Li N- (2,3-dichlorobenzoyl) -R-Tyrosine-di-n-pentylamide N- (2-pyrrolidinyl) -R-tyrosine di-n-pentylamide N- (3-quinolylcarbonyl) -R-Tyrosine di-n-pentylamide Methyl N- (3-quinolylcarbonyl) -R-Tyrosyl-S-phenylglycinate 2-indol-11-carbonyl) -R, S-Homoserine di-n-pentylamide and N- (3-quinolylcarbonyl) -R, S-Homoserine di-n-pentylamide and N- (2-indolylcarbonyl) -R-methionine sulfoxide N-pentylamide N- (3-quinolylcarbonyl) -R-Methionine-sulfoxide-di-n-penti-1-amide N - (3-quinolylcarbonyl) -R-methionine di- quinolylcarbonyl) -N-phenylthiolcarbonyl-R-Lysine-di-n-pentylamide

N- (3-quinolylcarbonyl) -R-Histidine-di-n-pentylamide dihydrochloride N- (2-indolylcarbonyl) -61-yno-di-n-pentylamide dihydrochloride dihydrochloride N- n-pentylamide

N - (4 ', 8'-dihydroxy-2' '- (3'-quinolinylcarbonyl) -R-phenylglycine di-n-pentylamide N- (3-quinolinecarbonyl) (R) -phenylglycine-di-n-pentylamide N - (5-fluoro-1-naphthyl) pen 1 amide

Dihydro-2-quinolinecarbonyl) -6-ene-di-n-pentylamide N- (2-naphthyl)

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N- (3-methylphenylaminocarbonyl) glycin-di-n-pentylamide N- (4,8-dihydroxy-2-quinolinylcarbonyl) -R- (4-hydroxyphenyl) di-n-pentylamide N- (4,8-dihydroxy-2-quinolylcarbonyl) - (2R, 3S) - (O-benzyl) -

Threonine-di-n-pentylamide N - (3-quinoquinoline-11-carbonyl) -R-methionine-S- (p-hydroxy) N- (8-hydroxy-2-quinolinecarbonyl) -6-ene-di-n-pentiazamide N-methyl-N- (8-hydroxy-2-quinolinecarbonitrile) (3-bromo-1-carbonyl) -Glycine-di-n-pentiazamide and N- (2-indolylcarbonyl) -R-Alanine di -n-pentylamide

The compounds of the invention may be prepared as shown in the following scheme (s). The compounds of the invention having an asymmetric center may exist as separate enantiomers or as mixtures of enantiomers. Compounds of the invention containing two or more asymmetric carbon atoms may exist as pure diastereoisomers, mixtures of diastereoisomers, or racemates of diastereomers or as mixtures of racemates of diastereoisomers. The present invention includes in its scope all isomeric forms.

There are several synthesis routes for the preparation of α-amino acids and derivatives thereof. The invention is not limited to the processes discussed herein for the synthesis of α-amino acids but is intended to include all variations and methods encompassed by the prior art as are discussed in the entire chemical literature. The α-amino acids (ref. Scheme 1) can be prepared directly by displacing the Î ± -halogenated esters (1, X is halo) and the like, or other substituent groups located at Î ±, by ammonia and / or by other substituted amines ( (E.g., carbamates, hydrazines, azides) (e.g., Marvel, Org. Synth., 20, 81, 1940; 106, 1940 The amine group is then demarcated, for example by reduction, and the ester (amide, etc.) group is saponified to give the title compound as a white solid, mp 218-227øC. give the

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Case, in the classical manner.

A second process involves the condensation of an α-ketoester (amide, etc.) with an amine or amine equivalent (e.g., hydroxyamine, hydrazine, carbamate, etc.) and subsequent reduction of this product (2) to give α (e.g., J. Chem., 29, 427, 1951; J. Org. Chem., 38, 822, 1973; J. Org. Chem., 6, 878, 1141) Alternatively, an organometallic reagent may be added to the 2 (imine, etc.) oxime to give either mono-substituted α-amino acids in the case of D being hydrogen, or disubstituted amino acids in the case where D is other than hydrogen (e.g., Tetrahedron Lett. 28, (42), 4973, 1987).

A third process is the alkylation of a resultant carbanion of the compound (3) with an electrophilic nitrogen source (eg diethyl azodicarboxylate). The intermediate product can then be unmasked to give the desired α-amino acid. A similar process involves alkylating the carbanion derived from compound (4) with a suitable alkylating agent. This process also allows the possibility of di-substitution of the center a.

A fifth process involves the Strecker reaction and its modifications. The reaction of cyanide and ammonium on aldehydes and ketones (5) yields the amino acid.

A further process involves the direct reduction of unsaturated heterocyclic carboxylic acids (6) to directly give cyclic amino acids (7) (wherein D and R6 are in the form of a ring).

With suitable available α-amino acids (8) (Scheme 2), the amino group is protected with a NJ protecting group (the most frequent are Boc or Cbz) and, if the carboxylic acid has not been unmasked, it is saponified with a base to give the related carboxylic acid (9). Intermediate:. N-protected, is then coupled with the HNR3 amine using any of the conventional techniques of 3, 4, 5 and 6 (carbodiimide, BOCPC, chloroformate oxalyl chloride; type wherein R 1 and R 2 are alkyl, arylalkyl, aryl or -SO-

Case 4714.P6.Q1 represent another amino acid. The resulting product (10) is then deprotected N, using HCl or trifluoroacetic acid to remove a Boc group and hydrogenolysis, or HBr to remove a Cbz group. The resulting amine (11) is then coupled to aromatic carboxylic acids, aromatic acid halides, heteroaromatic carboxylic acids, aromatic isocyanates, aromatic sulfonic acids, aromatic sulfonyl chlorides and the like using the standard coupling techniques to obtain the products (12), (13), (14) and (15). Preferred acyl coupling partner groups include: quinocarboxylic acids, indole carboxylic acids, substituted benzoic acids and benzoyl chlorides, arylisocyanates and arylisothiocyanates, naphthoic acids, benzothiofuranyl carboxylic acids and the like.

~ 21 ~ J 71 210 Case 4714.PG.01

Scheme I H2mg h o i o

R D

H

V \ 1 R H2 / cataller (R10 = H) R R10M ®10 35

0ÃR 1. " base

R

D 2. «» ΗΗ2 «0 V ^ o

R

1. " base / BX

H I 0

AT 2. r

G B, Λ

Strecker H h ^ v ^ o hho 0 cr

Er 0

R

Cf "

R6 7

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Case 4714.P6.01 " 22 "

Scheme 2

13 15

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Case 4714.P8.01 -25 "

The intermediates in the preparation of the compounds of the formula include those of the formula:

where G is (1) NH2 or substituted (2) amino

R 2 is (1) hydrogen (2) lower alkyl (3) lower alkyl (3) alkyl substituted with carboxy or (4) (1) hydrogen (2) lower alkyl (3) alkyl made functional (4) cycloalkyl (5) aryl (6) oxyalkyl made functional (7) a heterocyclic group or R j taken together with D is (1) C  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (CH2) q â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (CH2) (iv) -N (R 2g) - where R 2g is hydrogen,

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Lower alkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or a protecting group of N or Rg taken together with D is (1) C1-6 alkylene or (2) - (CH2) wherein p is 3, V is defined as above; and P- | is hydrogen or a N-protecting group.

Other intermediates in the preparation of compounds of the formula include those of the formula:

Wherein Z is (1) -C (O) - (2) C (S) - or (3) -S (O) 2B is absent (2) alkylene (3) (5) -R2g "R27" and R26 is absent or is -CH2- and R27 is -O-, -S-, -NH- or -N (lower alkyl) - or (6) - R27 -CH2- where R27 is defined as above

Ar is (1) aryl or (2) a heterocyclic group; and

I 2 is an activator group; or B-Z-Z taken together represent -N = C-Q, -N = C = S, -CH = N = C = O or -CH 2 -M = C = S.

Activating groups are the functional groups which act on a carboxylic acid or sulfonic acid group to couple an amine, forming an amide or sulfonamide linkage. The activating groups z 'include, but are not limited to -HH, -SH, alkoxy, thioalkoxy, halogen, formic acid and acetic acid derivatives, anhydrides derived from alkoxycarbonylhalides as

J 71 210 Case 4714.ΡΘ.01 -25

isobutyloxycarbonyl chloride and the like, esters derived from N-hydroxysuccinimide, esters derived from N-hydroxyphthalimide, esters derived from N-hydroxybenzotriazole, esters derived from M-hydroxy-5-norbornene-2,3-dicarboxamide, esters derived from 4-nitrophenol, esters derived from 2,4,5-trichlorophenol and the like.

The following examples serve to further illustrate the preparation of the novel compounds of this invention.

Example 1 N- (t-butyloxycarbonyl) -R-valine-di-n-pentylamide

Nt-Butyloxycarbonyl-R-Valine (2.5 g, 11.5 mmol) at 0 ° C in 30 mL of methylene chloride (CH2 Cl2) was treated with bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOCPC , 3.5 g, 13.8 mmol) and triethylamine (TE®) 1.5 ml (11.5 mmol). To this reaction mixture was added di-n-pentiamine (11.6 ml, 58 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOCl1 was added after 18 h and the reaction mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo and the residue was taken up in ethyl acetate (EtOAc) and washed with water, 1N hydrochloric acid (HCl) solution, saturated sodium bicarbonate solution (NaHCO 3) and water . The organic solution was dried over magnesium sulfate (MgSO4). After filtration and concentration of the filtrate in vacuo, the residue was chromatographed using ethyl acetate / hexane as solvent system (1: 4). The product was isolated as an oil, 79% yield (3.25

Example 2

The product of Example 1 (0.2 g, 0.6 mmol) was dissolved in 4N HCl in dioxane (10 mL) and stirred under inert atmosphere (N 2) -26 -

J 71 210

Case 4714.ΡΘ.01 for 1 h. When the reaction was complete, confirmed by tlc, the solvents were evaporated in vacuo and hexane and diethyl ether were added. The residue was washed with these two solvents and the solvents were again evaporated in vacuo. This process was repeated several times until a product as a glass was obtained in quantitative yield. MS (CI) m / e 293 (m + H) +.

Example 3 N- (3-quinolinyl) -β-valine-1-n-pentylamide The hydrochloride of example 2 (150 mg, 0.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) 1m EDTA (100 mg), HBOT (135 mg) and quinoline-3-carboxylic acid (88 mg) were stirred at 0% under nitrogen in 5 ml anhydrous CH2 Cl2. To this mixture was added 120 μl of N-methylmorpholine (NMM) and the mixture was stirred overnight (warming to room temperature). The reaction mixture was poured into ethyl acetate and water, and the organic extract was washed successively with water, 10% citric acid solution and saturated aqueous NaHC0 3. The solution was dried over

Filtered, and concentrated. The residue was chromatographed using ethyl acetate (EtOAc) and hexane as eluent to give 110 mg of an oil (54% yield) after removal of the volatiles. [α] D = -14.8 ° (c = 0.5, MeOH). MS (CI) m / e 412 (m + H) +. 1 H NMR (CDCl 3, 300MHz) δ 0.92 (m, 6H), 1.05 (m, 6H), 1.35 (m, 8M), 1.5-1.7 (m, 4H), 2 (M, 1H), 3.05 (m, 1H), 3.3-3.4 (m, 1H), 3. S (m, 1H), 3.65 (m, 1H), 5.08 (d, J = 9 Hz, 1H), 7.62 (t, J = 7 Hz, 1H), 7.8 (t, J = 7 Hz, 1H), 7.91 (d, J = 10Hz, 1H), 8.16 (d, J = 10Hz, 1H), 8.6 (d, J = 3Hz, 1H), 9.35 (d, J = = 3Hz, 1H). Calc'd for C 25 H 37 N 3 O 2: C 72.95, H 9.06, N 10.21; Found: C 72.61, H 9.21, N 9.97.

The product from Example 2 (130 mg, 0.45 mmol), EDCI (90 mg), HOBt (120 mg) and (75 mg) were stirred at 0 ° C under nitrogen in 5 ml of anhydrous CH2 Cl2. To this mixture was added 100 μl of NMM and the mixture was stirred overnight 71 Case 4714.P6.01 -27

(warming to room temperature). The reaction mixture was poured into ethyl acetate and water, and the organic extract was washed successively with water, 10% citric acid solution and saturated aqueous NaHCO3 solution. The solution was dried over MgSO4, filtered and concentrated. The residue was chromatographed using ethyl acetate and hexane as the eluent mixture, yielding 36 mg of the product (yield 75%) after evaporation of the volatiles. mp = 132-4 ° C. [Î ±] D = -9.2Â ° (c = 0.5, MeOH). 1 H NMR (CDCl 3, 300 MHz) δ 0.9 (t, J = 7 Hz, 6 H), 1.0 (m, 6 H), 1.2 (m, 1.4 (m, 8H),

7.65 (d, J = 7 Hz, 1H), 9.3 (br., 1H). C, H, N of the analysis calculated for

The reaction was run in a manner analogous to that of Example 3 using 0.2 g of the hydrochloride of example 2, acid, quinoline-2-carboxylic acid, carboxylic acid (0.12 g), EDCI (0.15 g), HBOT (0.1 g) and NMM (0.18 ml). The product was isolated in 80% yield (0.225 g). mp 78-79 ° C. [α] D = -13.1 ° (c = 1, 1 ', MeOH). NMR (CDCl3, 300MHz) δ0.9 (m, 6H), 1.05 (m, 6H), 1.2-1.4 (m, (m, 8H), 1.55 (m, 4H), 2.22 (m, 1H), 3.08 (m, 1H), 3.4 (m, 2H), 3.64 (m, 1H) (D, J = 7Hz, 1H), 7.62 (t, J = 7Hz, 1H), 7.78 (D, J = 9 Hz, 1H), 8.35 (m, 2H), 8.85 (d, J = 10 Hz, 1H). C, H, N analysis calculated for C 25 H 37 N 3 O 2,

H 2 O: C 72.17, H 8.96, N 10.10; Found: C 72.36, H 8.93, N

(300 mg, 1.03 mmol), EDCI (200 mg), HOBt (280 mg) and α-ethane-4-hydroxycinnamic acid (195 mg)

J 71 210 Case 4714.ΡΘ.01 28

were stirred at 0 ° C under nitrogen in 15 ml of argon. To this mixture 250 μΐ NMM were added and the mixture was stirred overnight (warming to room temperature). The reaction mixture was poured into ethyl acetate and water and the organic extract was washed successively with water, 10% citric acid solution and saturated aqueous NaHC04. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using ethyl acetate and hexane as eluent mixture to give 225 mg of an oily product (yield 57%) after evaporation of the volatiles. [a] p = "4.8" (c = 1.15, MeOH) MS (CI) m / e 428 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ

C, H, N analysis calculated for C 25 H 37 N 3 O 3: C 70.22, H 8.72, N 9.83; Found: C 69.88, H 8. 8.39, N 9.60.

The reaction was conducted in a manner analogous to that of Example 3, using 0.3 g of the hydrochloride of example 2, benzothiophurane-2-carboxylic acid (2-benzothiophuranylcarbonyl) -R-valine di-n-pentylamide (0.22 g), EDCI (0.22 g), HOBt (0.28 g) and NMM (0.22 ml). The oily product was isolated in 58% yield, 0.28 g. [Î ±] 20 = -5.852 (c = 2.0, MeOH). NMR (CDCl3, 300MHz) δ 0.9-1.1 (m, 12H), 1.2-1.3 (m, 3H) ), 1.5-1.6 (m, 4H), 2.15 (m, 1H), 3.05 (m, 1H), 3.3 (m, 1H), 3.42 (m, 1H) , 3.65 (m, 1H), 5.0 (q, J = 3.6Hz, 1H),. 7.00 (d, J = 9 Hz, 1H), 7.41 (m, 2H), 7.80 (s, 1H), 7.86 (m, 2H). C, H, N for the analysis calculated for C 24 H 36 N 2 O 6 úH 2 O: C 68.45, H 8.74, N 6.65; Found: C 68.73, H 3.48, N 6.71.

EXAMPLE 8 N- (4â € ², 8â € ²-dihydroxy-2-guanylcarbonyl) -R-valine-di-n-pentylamide hydrochloride of Example 2 (0.95 g, 3.22 mmol) was stirred in 25 mL of CH2 Cl2 with NMM (0.7 mL) under nitrogen at 0Â ° C. 71 210 Case 4714.Ρθ.01 * " 29

EDCI (0.7 g) and HOBt (0.11 g), followed by addition of 4,8-dihydroxyquinoline-2-carboxylic acid (0.66 g, 3.22 mmol). The reaction mixture was stirred overnight (warming to room temperature). The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed successively with water, 0.1N HCl solution, water and brine. The organic solution was dried over MgSO4 and then filtered. The solvents were evaporated in vacuo and the crude product was subjected to flash chromatography " using ethyl acetate / hexane / methanol as eluent mixture. The product crystallized from methanol / water to give 0.82 g (56%). mp = 233-235Â ° C. [α] D20 = -15.6 S (c = 0.5, MeOH). MS (CI) m / e 444 (m, + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ 0.84 (m, 6H),

The reaction was conducted in a manner analogous to that of Example 8, using 0.3 g of the hydrochloride of example 2, benzofuran-2-carboxylic acid (0.8 g) , 19 g), EDCI (0.22 g), HOBt (0.28 g) and NMM (0.22 ml). The product was isolated in 56% yield (0.225 g). [Î ±] D = -29.2Â ° (c = 1.1, MeOH). MS (CI) m / e 401 (m + H) +. 1 H NMR (CDCl 3, 300MHz) δ 0.9-1.0 (m, 6H), 1.05 (m, 6H), 1.25-1.4 (m, 8H), 1.5-1.68 (m, 4H), 2.15 (m, 1H), 3.1 (m, 1H), 3.28-3.5 (m, 2H), 3.62 (m, 1H), 5.0 (dd, J = 3.6Hz, 1H), 7.28 (t, J = 8Hz, 1H),

7.4 (t, J = 8Hz, 2H), 7.45 (s, 1H), 7.52 (d, J = 9Hz, 1H), 7.65 (d, J = 9Hz, 1H) H, N calculated for ¢ 24 ^ 36 ^ 2% 1 → 1.96, H 9.06, N 6.99; Found: C 72.09, H 9.08, N 6.99.

Example 10 N- [4'-Hydroxy-2'-phenyl-3-quinolinyl] -R-valine-di-n-pentylamide The reaction was conducted analogously to example 8,

71 210

Case 4714.ΡΘ. 0.2 g of the hydrochloride of example 2, 4-hydroxy-2-phenyl-quinoline-3-carboxylic acid (0.18 g), EDCI (0.16 g), HOBt (0.19 g) g) and NMM (0.16 ml), the product was isolated in 64% yield (0.22 g). mp = 154-155 °. [g] -30.0 (c = 0.4,

MeOH). MS (CI) m / e 504 (m + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ 0.82 (m, 14H), 1.2 (m, 8H), 1.38 (m, 4H), 1.94 (m, 1H), 3.02 (m, 2H), 3.2 (m, 1H), 3.4 (m, 1H), 4.55 (m, 1H), 7.43 (m, 5H), 7.7 (m, 2H) (D, J = 7 Hz, 1H), 12.02 (s, 1H), C, H, N analysis calculated for C31 H41 N3 O3: C 73.93, H 8.21, N 8.34, found: C 73 , 73, H, 8.18, N, 8.34.

Example 11

The reaction was conducted in a similar manner to that of Example 8, using 0.21 g of the example hydrochloride (0.8 g) as a pale yellow oil 2, 4-hydroxy-7-trifluoro-quinoline-3-carboxylic acid (0.185 g), EDCI (0.15 g), HOBt (02 g) and NMM (0.16 ml). The product was isolated in 37% yield, 0.16 g. mp 194-195 °. M.p. = 79.2 ° (c = Q, 5, MeOH). MS (CI) m / e 497 (m + H) +. 1 H NMR (DMSOd 6, 300MHz) δ 0.88 (m, 12H), 1.35 (m, 8H), 1.45 (m, 2H) 1.6 (m, 2H), 2.05 (m, 1H 2H), 3.25-3.4 (m, 2H), 3.48 (m, 1H), 4.85 (dd, J = 3, 9Hz, 1H) , 7.8 (d, J = 7 Hz, 1H), 8.1 (s, 1H), 8.45 (d, J = 7 Hz, 1H), 8.9 (s, 1H), 10 , 2 (d, J = 7 Hz, 1H), 12.9 (broad, 1 Η) C, H, N of the analyte calculated for C26 H26 N2 O2: 0.2 H2 O: C 62.56 , H 7.35, N 8.41; Found: C 62.57, H 7.17, N 8.38.

Example 12

The reaction was carried out in a manner analogous to that of Example 8, using 5.0 g of the title compound as a white solid (0.8 g). 1 H NMR (DMSO-d 6):? hydrochloride of Example 2, 4-hydroxy-7-chloroquinoline-3-carboxylic acid (3.8 g), EDCI (3.5 g), HOBt (4.6 g) and NMM (3.8 ml) and 10 ml of DMF. The product was isolated in 54% yield, 4.25 g. mp = 205-206 °. [Î ±] D = -93.8Â ° (c = 0.5, MeOH). 1 H NMR (DMSOd 6, 300 MHz) δ 0.95 (m, 6H), 1.15 (d, J = 8 Hz, 3H), 1.26 (m, d, J = 8Hz, 3H), 1.38 (m, 8H),

J 71 210

1.65 (m, 2H), 1.8 (m, 1H), 2.0 (m, 1H), 2.23 (m, 1H), 3.15 1H), 3.35 (m, 1H), 3.48 (m, 1H), 3.72 (m, 1H) J = 9 Hz, 1H), 7.66 (d, J = 9 Hz, 1H), 7.6 (d, 10.25 (d, J = 6 Hz, 1H), 12.25 (d, J = 9 Hz, 1H) - C, H, N: Analysis calculated for: 25.36%: C 64.98, , 85, N 9.09, Cl 7.67; Found: C 65.16, H 8.04, N 8.94, Cl 7.91.

Example 13 - ζ 4 '-hi d r οχ 1 - 2.' - Quino! The reaction was carried out in a manner analogous to that of Example 8, using 0.2 g of the hydrochloride of example 2, 4-hydroxyquinoline-2-carboxylic acid (0.01 g) 13 g) EDCI. (0.14 g) HOBt (0.19 g) and NMM (0.15 ml). The product was isolated in 71% yield (0.207 g) m.p. 70-71%. [a] D -13.32 (c = 0.6, MeOH). MS (CI) m / e 428 (m + H) +. 1 H NMR (DMSOd 6, 30Hz) δ 0.85-1.1 (m, 12H), 1.2-1.4 (m, 8H), 1.5-1.7 (m, 4H) (M, 1H), 3.25 (m, 1H), 3.45 (m, 1H), 3.64 (m, 1H & (M, 2H), 7.65 (t, J = 7 Hz, 2H), 8.35 (d, 1H) J = 8 Hz, 1 Η), 10.4 (broad s, 1H), C, H, N of the analysis calculated for C25 H17 N2 O2: H, 8.72, N, 9.83; Found: C 69.91, H 8.71, N 9.68.

Example 14 Ν-β '- (N-allylcarbamyl) pyrid-3-carbonitrile (0.20 g, 0.69 mmol) was stirred in 15 ml of CH 2 Cl 2 with NMM (0.15 ml, 1.4 mmol) mmol) under nitrogen at 0 ° C. EDCI (0.135 g, 0.69 mmol) and HOBt (0.19 g, 0.14 mmol) were added followed by the addition of 5-allylcarbamylnicotinic acid (0.142 g, 0.69 mmol). The reaction mixture was stirred overnight (warming to room temperature). The solvents were evaporated in vacuo, the residue taken up in ethyl acetate and washed successively with water, saturated NaHCO3, saturated citric acid solution, water and brine. The organic solution was dried over MgSO4, and then filtered. The solvents were evaporated in vacuo and the crude product was subjected to flash chromatography " using ethyl acetate / hexane as eluent mixture. The title compound was isolated.

71 210

The oily product was obtained in 56% yield (0.17 g). MS (CI), m / e 445 (m + H) +. 1 H NMR (C 13 C 13.300MHz) δ 0.85-1.1 (m, 12H), 1.2-1.4 (m, 8H), 1.5-1.6 (m, 4H), 2.1 (m, 1H), 3.05 (m, 1H), 3.3 (m, 1H). 3.48 (m, 1H), 3.65 (m, 1H), 4.15 (m, 2H), 5.0 (dd, J = 3.6 Hz, 1H), 5.25 (m, 2H), 5.95 (m, 1H), 6.45 (m, 1H), 7.15 (d, J = 9Hz, 1H), 8.48 (s, 1H), 9.15 (s, 2H). C, H, N analysis calculated for C 254 404 4%: C 67.53, H 9.07, N 12.60; Found: C 67.27, H 8.97, N 12.53.

Example ... 15 N- (1'-et11-7'-methyl-4'-oxo-1 ', 8'-naphthyridin-3'-carbonyl) -R-valine-di-n (0.2 g, 0.69 mmol) was stirred in 15 mL of NMM (0.15 mL, 1.4 mmol) under nitrogen at 0 ° C.

EDCI (0.13 g, 0.69 mmol) and HOBt (0.190 g, 1.38 mmol) were added followed by the addition of nalidixic acid (0.160 g, 0.69 mmol). It was stirred. the reaction mixture overnight (warming to room temperature). The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed successively with water, saturated NaHCO3, saturated citric acid solution, water and brine. The organic solution was dried over MgSO4. and then filtered. The solvents were evaporated in vacuo and the crude product was flash chromatographed using ethyl acetate / hexane as eluent. Purification gave 0.19 g (59%) of an oil. MS (CI) m / e 471 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.9 (m, 6H), 1.05 (m, 3H), 1.20-1.4 (m, 10H), 1.48-1.8 (m, 8H), 2.1 (m, 1H), 2.65 (s, 3H), 3.05 (m, 1H), 3.4 (m, 2H), 3.6 (m, 1H) (Dd, J = 3.6Hz, 1H), 7.25 (m, 2H), 8.68 (dd, J = 3.9Hz, m, 1H), 8.85 (m, 1H). C, H, N analysis calculated for C 27 H 42 N 3 N 4, 0.25 H 2 O: C 68.34, H 9.03, N 11.82; Found: C 68.12, H 8.83, N 12.07.

Example 16

The reaction was conducted in a manner analogous to that of example 3 using 0.27 g of the hydrochloride of example 2, (0.16 g) EDCI (0.19 g), HOBt (0.25 g) and NMM (0.21 g)

J 71 210

The oily product was isolated in 58% yield, 0.25 g. [α] D = + 7.1 * (c = 1.1, MeOH), MS (CI) m / e 405 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.82-1.0 (m, 1H), 1.2-1.5 (m, 8H), 1.5-1.7 (m, 4H), 2 (M, 1H), 3.25 (m, 1H), 3.4 (m, 1H), 3.6 (m, 1H), 4.85 (m, 1H), 7.05 (d, J = 42Hz, 1H), 7.1 (d, J = 1Hz, 1H), 7.3- 7.45 (m, 3H), 7.62 (d, J = = 9Hz, 2H). C, H, N. Analysis calculated for C 24 H 37 F 2 N 2: C 71.25, H 9.22, N 6.93; Found: 70.99, H 9.14, N 6.95.

Example 17 N- (2'-naphthol) -R-valine-di-n-pentylamide

The reaction was conducted in a manner analogous to that of example 3, using 0.2 g. hydrochloride of Example 2, 2-naphthoic acid (0.12 g), EDCI (0.13 g) HOBt (0.18 g) and NMM (0.16 ml). The product was isolated as an oil in 72% yield, 0.2 g. [α] D13 -13.0 (c = 1.0, MeOH). MS (CI) m / e 411 (m + H) +. 1 H NMR (CDCl 3, 300MHz) δ 0.8-0.9 (m, 6H), 1.1 (m, 6H), 1.2-1.4 (m, 8H) 67 (m, 4H), 2.13 (m, 1H), 3.0-3.1 (m, 1H), 3.25-3.3 (m, 1H), 3.5 (m, 1H (D, J = 9 Hz, 1H), 7.52 (m, 2H), 7.92 (m, 1H) 9 (m, 4H), 8.33 (s, 1H). C, H, N analysis calculated for C 26 H 38 N 2 O 2: C 76> 05 H 9.33, N 6.82; Found: C 76.20, H 9.32, M 6.98.

Example 18

(3-chlorophenyl) propyl] -2-oxo-3-methyl-pentylamide A The reaction was conducted in a manner analogous to that of Example 3, using 0.3 g of the hydrochloride of Example 2, 3- (3-pyridyl) acrylic acid (0.17 g), EDCI (0.22 g), HOBt ( 0.28 g) and NMM (0.22 ml). An oil was isolated in 76% yield, 0.3 g. [.oc) q

= + 10.0 ° (c 0.85, MeOH). MS (CI) m / e 388 (m + H) +. 1 H NMR (CDCl 3 300MHz) δ 0.8-1.05 (m, 12H), 1.2-1.4 (m, 8H), 1.45-1.72 (m, 4H) 06 (m, 1H), 3.1 (m, 1H), 3.2-3.5 (m, 2H), 3.5-3.65 (m, 1), 4.92 (dd, J (D, J = 9Hz, 1H), 7.3 (m, 1H), 7.6 (d, J = 15Hz, 1H) = 15 Hz, 1H), 7.8 (d, J = 9 Hz, 1 Η), 8.58 (d, J = 6 Hz, 1H), 8.74 (d, J = 2 Hz, 1H). C, H, N analysis calculated for C 23 H 37 N 3 O 2, 0.75 H 2 O: C 68.88, H 9.68, N 10.48; Found: C 68.74, H 9.31,

71 210

Case 4714.Ρθ.01 N 10.21.

Example 19

The reaction was carried out in a manner similar to that of example 3, using 250 (1 H, 2 H) -6- (4-methoxyphenyl) mg of the hydrochloride of example 2, NL-1, 2,3,4-tetrahydro-harmano-3-carboxylic acid (270 mg), EDCI (160 mg), HBOT (235 mg) and NMM (190 ml) . The oily product was isolated in 38% yield (148 mg). [a] " 5.5δ (c = Q, 2, MeOH). MS (CI) m / e 455 (m + H) +. 1 H NMR (CDCl3, 300 MHz) δ 0.8-1.0 (m, 12H), 1.2-1.35 (m, 8H), 1.5 (m, 4H), 1.6 (m, 1H), 2.05 (m, 1H), 2.55-2.8 (m, 1H), 3.1-3.4 (m, 4H), 3.55 (m, 2H) , 4.1 (m, 1H), 4.75 (m, 1H), 7.0-7.15 (m, 2H), 7.25 (d, J = 9 Hz, 1H), 7.45 , J = 9 Hz, 1H), 7.8 (broad s, 1H), 7.85 (br s, 1H), 8.26 (s, 1H). C, H, N of the analysis calculated for C 27 H 42 N 4 O 2 · 75h 2 O: C 69.27, H 9.36, N 11.97; Found: C 69.58, H 9.16, N 11.91,

Example 20 N-Î''-hydroxy-2'-naphtho1) -R-valine-di-n-pentylamide

The reaction was run in a manner analogous to that of example 3, using 250 mg of the hydrochloride of example 2, 1-hydroxy-2-naphthoic acid (160 mg), EDCI (180 mg), HOBt (240 mg) and NMM (200 μ ). The product was isolated in 85% yield (310 mg). m.p. = 85-86%. [a] D = +90.52 (c = 0.6, MeOH). MS (CI) m / e 427 (m + H) +. 1 H NMR (CDCl 3, 300MHz) δ 0.9 (m, 6H), 1.05 (m, 6H), 1.25-1.4 (m, 8H), 1.5-1.7 (m, 4H), 2.15 (m, 1H), 3.05 (m, 1H), 3.25 (m, 1H), 3.5 (m, 1H), 3.65 (m, 1H) (D, J = 9 Hz, 1H), 7.35 (d, J = 10 Hz, 1 H), 7.45 (d, J = 10 Hz, 1 H) Δ), 7.5 (dd, J = 3.6Hz, 1 Η), 7.6 (dd, J = 3.6Hz, 1H), 7.75 (d, J = 7Hz, 1H), 8.4 (d, J = 9 Hz, 1H), 10.6 (broad s, 1H), C, H, N of the analysis calculated for: C 73.20, H 8.98, N 6.57; Found: C 73.24, H 9.02, N 6.55.

EXAMPLE 1 (R) - (t-butyloxycarbonyl) -1-R-norleucine di-n-pentylamide

N - (t-butyloxycarbonyl) -R-Norleucine (1.2 g, 5.2

J 71 210

(50 mL) and CH 2 Cl 2 (0.5 g, 5.9 mmol) and TEA (0.7 mL, 5.2 mmol) were added. To this reaction mixture was added d1 -n-pentyllamine (2.5 mL, 10.5 mmol). The mixture was stirred overnight and allowed to warm to room temperature. After 18 h, an additional equivalent of BOCPC1 was added and the reaction mixture was stirred for one day at room temperature. The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed with water, 1 N HCl, saturated NaHCO 3 solution, water and then the organic solution was dried over MgSO 4. After filtration and concentration of the filtrate in vacuo, the residue was chromatographed using ethyl acetate / hexane as solvent system in the ratio (1: 4). The product was isolated as an oil, yield 75% (1.45 g). NMR (CDCl3, 300MHz) δ 0.9-1.2 (m, 9H), 1.24-1.35 (m, 12H), 1.32 (m, 5 (s, 9H), 1.55-1.6 (m, 4H), 1.88 (m, 2H), 3.1 (m, 1H), 3.32 (m, 1H), 3.42 (m, 1H), 3.6 (m, 1H), 5.15 (m, 1H), 6.9 (d, J = 10 Hz, 1H).

Example 22 R-norleucine-dl-n-pentyllamide hydrochloride

The product of Example 21 (1.4 g, 3.8 mmol) was dissolved in 4N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. When the reaction was quenched with tlc, the solvents were evaporated in vacuo and hexane and ether were added. The residue was triturated with these solvents and the solid product was collected by filtration in quantitative yield. [Î ±] D1 = 1.4S (c = 0.6, MeOH), MS (CI) m / e 271 (m + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ0.87 (m, 9H), 1.2-1.4 (m, 12H), 1.42-1.6 (m, 4H), 1.7 (m, 2 H), 3.0 (m, 1H), 3.1-3.3 (m, 2H), 3.53 (m, 1H), 4.14 (br. S, 1H), 8.25 (br s , 2H).

Example 23 N- (3-methoxycarbonyl) -R-norleucine-d1-n-pentylamide The hydrochloride of example 22 (240 mg, 0.87 mmol), EDCI (170 mg), HOBt (240 mg) and quinol- 3-carboxylic acid (150 mg) were stirred at 0 ° C under nitrogen in 20 ml anhydrous CH 2 Cl 2. To this mixture was added 200 μM NMM and the mixture agitated

J 71 210 Case 4714.ΡΘ.01

overnight (warming to room temperature). The reaction mixture was poured into ethyl acetate and water and the organic extract was washed successively with water, 10% solution of citric acid and saturated aqueous NaHCO3 solution. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using ethyl acetate / hexane as eluent to afford 200 mg of the title product (yield 54%) after evaporation of the volatiles. [oc] q = -10.5 "(c = 1.0, MeOH). MS (CI) m / e 426 (m + H) +, 1 H NMR (C 13 C 13.300MHz) δ 0.9 (m, 9H), 1.35 (m, 12H),

The hydrochloride of example 22 (0.30 g, 1.0 mmol) was stirred in 10 ml of methylene chloride in dichloromethane of CH2 Cl2 with NMM (0.2 mL, 2.0 mmol) under nitrogen at 0Â ° C. EDCI (0.2 g, 1.1 mmol) and HOBt (0.27 g, 2.0 mmol) were added followed by addition of indole-2-carboxylic acid (0.162 g, 1.0 mmol). The reaction mixture was stirred overnight (warming to room temperature). The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed successively with water, saturated NaHCO 3, saturated methanol, water and brine. The organic solution was dried over MgSO4, and then filtered. The solvents were evaporated in vacuo and the crude product was subjected to flash chromatography " using ethyl acetate / hexane as eluent mixture. The product crystallized from ethyl acetate and hexane to give a vitreous product 0.285 g (69%). [Î ±] D = -10.6Â ° (c = 0.8, MeOH). MS (CI) m / e

Calc'd for C 25 H 39 N 3 O 2, 0.75 H 2 O: C 70.30, H 9.55, N 9.84;

J 71 210

Case 4714.ΡΘ.01 " 37 " N, 9.84; Found: C 70.38, H 9.20, -N 9.85.

EXAMPLE 25 N- (t-butyloxycarbonyl) -R- (Θ-benzyl) serine-di-n-pentylamide

(3.0 g, 10.15 mmol) in 50 mL of CH 2 Cl 2 was stirred with (2-chloro-4-methyl- 11 mmol) and 2.0 ml (1.5 mmol) of TEA. To this reaction mixture was added di-n-pentylamine (7 mL, 35 mmol). The mixture was stirred overnight and allowed to warm to room temperature. After 18 h 1 additional equivalent of BOCPC1 was added and the reaction mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed with water, 1N HCl, saturated NaHCO3, water, and then the organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as eluent system in the ratio (1: 4). The product was isolated as an oil in 44% yield (1.9 g). MS (CI) m / e 435 (ε · η + Ή) +. NMR (CDCl3, 300 MHz) δ 0.89 (m, 6H), 1.28 (m, 8H), 1.4 (s, 9H), 1.55 (m, 4H), 3.05-3 , 4.5 (m, 2H), 4.85 (m, 1H), 5.35 (d, J = 7 Hz, 1 H) , 7.31 (m, 5H).

The product from Example 25 (0.43 g, 1.0 mmol) was dissolved in 4N HCl in dioxane (10 ml) and stirred at -78 DEG C. atmosphere (N2) for one hour. When the reaction was quenched with tlc, the solvents were evaporated in vacuo and hexane and diethyl ether were added. The residue was triturated with these two solvents and the solvents were removed again in vacuo. This process was repeated several times until the product was obtained as a solid, glass, in 93% yield (0.35 g). [gQq * + 1.6 (c = 0.5, MeOH). MS (CI) m / e 335 (m + H) +.

Example 27 1 N- (3-quinolinecarbonyl) -R- (Q-benzyl) serine-di-n-pentylamide

J 71 210 Cas® 4714.Ρβ.01

The hydrochloride of example 26 (0.35 g, 0.95 mmol) was stirred in 25 mL CH 2 Cl 2 with NMM (0.22 mL, 2 mmol) under Mg at < EDCI (0.19 g, 1.0 mmol) and HOBt (Q, 27 g, 2 mmol) were added followed by the addition of quinoline-4-carboxylic acid (0.165 g, 0.95 mmol). The reaction mixture was stirred overnight (warming to room temperature). The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed successively with water, saturated NaHCO3, saturated citric acid solution, water and brine. The organic solution was dried over MgSO4 and then filtered. The solvents were evaporated in vacuo and the crude product was flash chromatographed using ethyl acetate / hexane as eluent. The product was crystallized from ethyl acetate and hexane to give a semisolid substance, 0.44 g (94%). [a] p = -4.0 " (c = 0.45

MeOH). MS (CI) m / e 490 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 9.9 (m, 6H),

calc'd for C 20 H 9 N 2 O 6, 0.75 H 2 O: C 71.61, H 8.11, M 8.35; Found: C 71.73, H 8.01, N 8.21.

Example 28 N- (t-butyloxycarbonyl) -R-phenylalanine-1-n-pentanamide The reaction was conducted analogously to example 2 using N- (t-butyloxycarbonyl) -R-phenylalanine (0.8 g; 3.1 mmol), BOCPC (1.2 g, 4.06 mmol), dententamine (3.1 mL, 15 mmol) and TEA (0.4 mL, 3.1 mmol). The oily product was isolated in 65.5% yield (0.87 g). [α] ρ = (c = 1.0, MeOH). MS (CI) m / e 405 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 0.85 (m, 6H), 1.15-1.45 (m, 8H), 1.5 (s, 9H), 1.55-1.6 (m, 4H ), 2.9-3.1 (m, 5H), 3.5 (m, 1H), 4.25 (m, 1H), 5.3 (d, J = 9 Hz, 1H), 7.25 (m, m).

Example ... N- (t-butyloxycarbonyl) - (2R, 3S) - (O-benzyl) threonine-d1-n-pentylamide

J 71 210 Case 4714.ΡΘ.01

The reaction was run in a manner analogous to that of Example 1 using N - (t-butyloxycarbonyl) -D- (O-benzyl) -Treonine (5 g, 16.2 mmol), BOPP1 (8.2 g, 2 mmol), dipentylamine (16 mL, 78.5 mmol) and ΪΕΛ (2.1 mL, 16.2 mmol). The product was isolated in 58% yield (4.15 g). MS (CI) 449 (M + H) ". 1 H NMR (CDCl3, 300 MHz) δ 0.85 (t, J = 6 Hz, 6 H), 1.18 (d, J = 6 Hz, 3H), 1.2~1.35 (m, 8H), 1.45 (s, 9H), 1.5-1.6 (m, 4H), 3.0-3.18 (m, 2H), 3.41-3.63 (m, 2H) (D, J = 9Hz, 1H), 7.30 (m, 1H), 4.57 (dd, J = 12.18Hz, 2H) 5H).

Example 30 (2R, 3R) - (O-benzyl) threonine-di-n-pentylamide hydrochloride The product of example 29 (1 g, 2.22 mmol) was deprotected and isolated in a manner analogous to example 2. The product was isolated as an oil. [Î ±] D30 + 13.3Â ° (c = 1.1, MeOH). MS (CI) m / e 359 (m + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ 0.86 (m, 6H), 1.08-1.32 (m, 11H), 1.48 (m, 4H), 3.03 (m, 2H) (M, 2H), 7.35 (m, 5H), 8.35 (m, 2H) (bs, 2H).

The hydrochloride of example 30 (0.25 g, 0.65 mmol) was stirred in methylene chloride to give the title compound as a white solid (0.25 g, 0.65 mmol) in dichloromethane. 15 ml of CH 2 Cl 2 with NMM (0.175 ml, 1.3 mmol) under nitrogen at 0Â ° C. EDCI (0.15 g, 0.8 mmol) and HOBt (0.18 g, 1.3 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.115 g, 0.65 mmol). The reaction mixture was stirred overnight (warming to room temperature). The solvents were evaporated in vacuo, the residue taken up in ethyl acetate and washed successively with water, saturated NaHCO3, saturated citric acid solution, water and brine. The organic solution was dried over MgSO4, and then filtered. The solvents were evaporated in vacuo and the crude product was subjected to flash chromatography " using ethyl acetate / hexane as eluent mixture. An oily product was isolated, in 62% yield (0.2 g). [Î ±] 20 P

J 71 210

Case 4714.P8.01

40-

8.63 (d, J = 2 Hz, 1H), 9.35 (d, J = 3 Hz, 1H). C, H, N analysis calculated for C 31 H 41 N 3 G 3, 1.62 H 2 O: C 69.92% H 7.89, N 8.37; Found: C 69.81, H 7.78, N 8.08.

The product from example 31 (1 g, 2 mmol) was stirred in 20 ml of methanol (50 ml) and recrystallized from toluene

(1.0 M solution in trifluoroacetic acid) at 0Â ° C. The mixture was stirred for about 1 h. The tlc showed some Initial material and therefore 5 ml of tristrifluoroacetate was added. of boron; 5 ml of trifluoroacetic acid. The reaction was continued overnight until its end by tlc. The reaction mixture was diluted with MeOH and then concentrated in vacuo. The residue was purified by chromatography using ethyl acetate / hexane as eluent. The pure fractions were mixed and the desired product was characterized as the salt of dl-trifluoroacetic acid. mp = 84-6 ° C. -11.6 " (c = 0.55, MeOH). MS (CI) m / e 414 (m + H) +. 1 H NMR (CDCl 3, 300MHz) δH, 85 (m, 6H),

1H). C, H, N analysis calculated for 824 Η 35 Ν 303, 2 CF 3 CO 2 H: C 52.42, H 5.81, N 6.55; Found: C 5.2.31, H 5.62, N 6.66.

Example 33 N- (3'-indolol-11-carbonyl) - (2R, 3S) - (O-acetyl) threonine di-n-pentyl

The product of Example 32 (51 mg, 0.125 mmol) was dissolved in acetonitrile (2 mL) and the reaction mixture was stirred overnight at room temperature. Ethyl acetate and ethyl acetate were added.

This solution was washed successively with water and brine. The organic solution was dried over MgSO 4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as eluent system in the ratio (4: 1). The product was isolated, Vitriol, 44% yield (25 mg). MS (CI) m / e 456 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ

9.35 (d, J = 3 Hz, 1H). C, H, N for the analysis calculated for C 26 H 37 N 3 O 4 • 0.4H 2 O: C 67.48, H 8.23, N 9.08; Found: C 67.69, H 8.20, N 8.60.

Example 34 N- (3-Quinolylcarbonyl) - (2R, 3S) - (Q-methyl) threonine-1-n-pentylamide

Lithium bis (trimethylsilyl) amide in THF (0.15 mL of a 1.0 M solution in THF) was added to a cooled (~ 10 ° C) solution of the product of example 32 (55 mg, 0.14 mmol ) in 2 ml of tetrahydrofuran (THF) and then methyl iodide (0.015 ml) was added. The reaction mixture was stirred for about 1 h and was warmed to room temperature. Tlc showed some starting material and therefore another equivalent of methyl iodide (1.01 ml) was added. The reaction was then continued until tlc terminated. The reaction mixture was concentrated in vacuo. Ethyl acetate was added to the residue, which was then washed with water and brine. The ethyl acetate extract was dried over

Filtration and concentration of the filtrate in vacuo,

there was obtained a residue which was purified by chromatography using ethyl acetate / hexane as eluent mixture. An oil was isolated in 47% yield (28 mg). MS (CI) m / e 428 (m + H) +. ^ H

71 210

Case 4714.ββ-8-8.6 (d, J = 3 Hz, 1H), 9.35 (d, J = 3 Hz, 1H).

Exemp35

N-t-butyl (oxocarbonyl) -3- (2-chlorophenyl) -R-alanine di-n-pentylamide

N - (t-butyloxycarbonyl) -R-3- (2-thienyl) -anine (0.78 g, 3.25 mmol) was stirred at 0 ° C in 25 mL CH 2 Cl 2 with BOCPC (0.44 g, 3.25 mmol) and 0.5 ml (3.25 mmol) TEA. To this reaction mixture Di-n-pentylamine (2 ml, 10 mmol) was added. The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOClCl was added after 18 h and the reaction mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed with water, 1N HCl solution, saturated NaHCO 3 solution, water, and then the organic solution was dried over magnesium sulfate. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as solvent system (1: 4). The product was isolated as an oil, in 57% yield (0.76 g). J = 7.5 Hz), 2.27 (c = 0.66,

MeOH) MS (CI) m / e 411 (m + H) +, 355, 311 1 H NMR (CDCl3, 300MHz) Î'0.85 (m, 6H), 1.15-1.38 (m, 10H (M, 2H), 3.1 (t, 4H), 3.22 (m, 1H), 3.4 (m, 1H) (D, J = 9Hz, 1H), 6.83 (d, J = 6Hz, 1H), 6.9 (t, J = , 7.15 (d, J = 6 Hz, 1H).

The product of example 35 (0.22 g, 0.54 mmol) was deprotected and isolated in the same manner as example 2 in quantitative yield. MS (CI) m / e 327 (M + H) +.

Example ..... N- (3'-guinolylcarbonyl) -3- (2'-thienyl) -R-alanine di-n-pentylamide

The reaction was conducted in a similar manner to that of Example 3 using (80 mg, 0.23 mmol) the hydrochloride of example 36, quinoline-3-carboxylic acid (40 mg), EDCI (50 mg), HOBt (62 mg) and NMM 43 71 210

Case 4714.Ρβ.01 (51 μΐ). An oil was isolated in 45% yield (48 mg). MS (CI) m / e 466 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.9 (m, 6H), 1.2-1.4 (m, 8H), 1.45-1.65 (m, 4H), 3.05-3, 4 (m, 4H), 3.45-3.6 (m, 2H), 5.35 (dd, J = 6.7Hz, 1H), 6.87 (d, J = 3Hz, 1H), 6 7.4 (d, J = 9 Hz, 1 H), 7.63 (dd, J = 3.7 Hz, 1 H), 7.83 (d, J = 9 Hz, 1H) 7.8 (dd, J = 3.7Hz, 1H), 7.9 (d, J = 8Hz, 1H), 8.15 (d, J = 8Hz, 1H), 8.6 (d, J = 3Hz , 1H), 9.32 (d, J = 3 Hz, 1H). C, H, N analysis calculated for C27 H30 N3 O2 S: 0.9 H2 O: C 67.29, H 7.70, N 8.72; Found: C 67.60, H 7.47, N 8.98.

The reaction and the isolation of the product were conducted in a similar manner to that of example 1 using N- (t-butyloxycarbonyl) -8-naphthyridine (3.5 g, 13.8 mmol) and diperitylamine (11.6 mL, 58 mmol) and TEA (1.6 g) ml, 12 mmol). The oily product was isolated in 55% yield (2.25 g).

-21.1 (c = 1.0, MeOH). MS (CI) m / e 357 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 0.9 (m, 6 H), 1.05 (m, 6H), 1.25-1.35 (m, 8H), 1.45 (s, 9H), 1.5-1.55 (m, 4H), 1.95 (m, 1H), 3.0 (m, 1H), 3.2 (m, 1H), 3.36 (m, , 6 (m, 1H), 4.4 (dt, J = 3.7Hz, 1H), 5.24 (d, J = 9Hz, 1H).

S-valine-di-n-pentylamide The product of example 38 (0.2 g, 0.57 mmol) was deprotected and the product isolated as in Example 2, with quantitative yield. MS (CI) m / e 257 (rHH-b1) 1 ".

Example 40 N- (3-Amino-guanyl) -11-carbonyl) -S-valine-di-n-penylamide The reaction was conducted in a similar manner to example 3, using 175 mg of hydrochloride of example 39, quino acid; 3-carboxylic acid (110 mg), EDCI (125 mg), HOBt (165 mg) and NMM (75 μ). The glass product was isolated in 80% yield (198 mg). [Î ±] D + + 12.95Â ° (c = 0.8, MeOH). MS (CI) m / e 412 (m + H) +. 1 H NMR (CDCl 3,300MHz) δ0.8-1.05 (m, 12H), 1.2-1.44 (m, 8H),

71 210

Case 4714.P3.01 44

Analysis calculated for C 25 H 37 N 3 O 25 0.25 H 2 O: C 72.16, H 9.09, N 10.10; Found: C 72.41, H 9.21, N 9.97.

Example 41 N - (t-butyloxycarbonyl) -N- (N -methyl) -N-t-butyloxycarbonyl-R- (4.95 g, 12.6 mmol) was stirred at 0 ° C in 50 mL of ΒΗ2012 with BOCPC (3.2 g, 12.6 mmol) and 1.65 mL (12.2 mmol) 6 mmol) of TEA. To this reaction mixture was added di-n-pentylamine (7.7 mL, 38 mmol). The mixture was stirred overnight and allowed to warm to room temperature. One more B0PC1 equivalent was added after 18 h, and the reaction mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed with water, 1N HCl solution, saturated NaHCO3 solution, water. The organic solution was dried over MgSO 4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as solvent system (1: 4). The product was isolated as an oil, in 75% yield (5.1 g). [Î ±] D * -1-8.8Â ° (e * 1.0, MeOH). MS (CI) m / e 549 (m + H) +. 1 H NMR (DMSOd6,300MHz) δ0.85 (m, 6H), 1.05-1.46 (m, 21H), 2.42 (s, 3H), 2.67 (m, 2H) 03-3.15 (m, 4H), 4.52 (m, 1H), 7.0 (s, 1H),

C, H, N for the analysis calculated for C28 H28 N4 O4: C 61.28, H 8.08, N 10.21; Found: C 61.04, H 8.05, N 10.10.

To a solution of the product of example 41 (6.7 g, 12.21 mmol) in CH 2 Cl 2 (100 mL) was added trifluoroacetic acid (TFA , 40-50 ml). The reaction mixture was stirred at room temperature for 60 minutes. When it was found by tlc that the reaction was

J 71 210 Case 4714.Ρβ.01 -45

The solvents were evaporated several times in vacuo and CH 2 Cl 2 was combined with saturated NaHCO 3 solution. The reaction mixture was vigorously stirred for a further 1 h and, after separation of layers, the organic layer was washed several times with water and brine. The CH2 Cl2 layers and washings were dried over magnesium sulfate. The product was then concentrated in vacuo. A semi-solid product was isolated and dried in vacuum oven over P 2 Og at room temperature, 5.1 g (9.3% yield).

The compound of example 42 (170 mg, 0.5 mmol), EDCI (105 mg), HOBt (135 mg) and i-propionic acid 2-carboxylic acid (85 mg) were stirred at 0 DEG under nitrogen in 10 ml anhydrous. To this mixture 110 μl were added! of NMM and the mixture was stirred overnight (warming to room temperature). The reaction mixture was poured into ethyl acetate and water and the organic extract was washed successively with water, 10% citric acid solution and saturated aqueous NaHCO3 solution. The solution was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using chloroform / methanol / ammonia as the eluent mixture to give 98 mg of the semi-solid product (45% yield) after evaporation of the volatiles. [c] q + 9.8 (c = 0.46,

J 71 210 Case 4 / Ι4.ΡΘ.01 "46

Example 44

(Benzyloxycarbonyl) -N- (benzyloxycarbonyl) -R-1-isine-dimethylpentylamide The reaction was conducted in a manner analogous to that of Example 1, useful (5 g, 13.15 mmol), BOClCl (6.7 g, 26.3 mmol), di-n-pentylamine (26 g), potassium carbonate

mL, 131 mmol) and TEA (1.8 mL, 13.5 mmol) in CH2 Cl2 (25 mL). The oily product was isolated in 64.5% yield (4.4 g). [α] D +65.3 - (c * Q, 15, MeOH). MS (CI) m / e 520 (m + H) +. 1H

Example 45 N- (t-butyloxycarbonyl) -3- (1-naphthyl) -R-alanine-d1-n-pentylamine N - (t-butyloxycarbonyl) -3- (1-naphthyl) 1.1 mmol) was stirred at 0Â ° C in 25 mL of BOCPC (0.3 g, 1.2 mmol) and 0.15 mL of TEA (1.2 mmol). To this reaction mixture was added di-n-pentylamine (0.8 ml, 4 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOClCl was added after 18 h and the reaction mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo, and the residue was taken. in ethyl acetate and washed with water, 1N HCl solution, saturated NaHCO 3 solution, water, and then the organic solution was dried over MgSO 4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as solvent system (1: 4). The product was isolated as an oil, with

65% yield (0.25 g). MS (CI) m / e 455 (m + H) +. ^ H

J 71 210

Case 4714.ΡΘ.01

47

Example 46 (0.32 g, 0.72 mmol) was dissolved in 4N HCl in dioxane (10 mL) and the product of Example 45 (0.32 g, 0.72 mmol) ) and stirred under inert atmosphere (Nj) for 1 h. When the reaction was checked for tlc, the solvents were evaporated in vacuo and hexane and diethyl ether were added. The residue was triturated with these two solvents to provide the solid, vitreous product in quantitative yield.

The hydrochloride of example 46 (200 mg, 0.52 mmol), EDCI, HBOT (70 mg) and quinoline-3-carboxylic acid (90 mg) were stirred at 0Â ° C under nitrogen in 5 ml of anhydrous CH2 Cl2. To this was added 10 μM NMM and the mixture was stirred overnight (warming to room temperature). The reaction mixture was poured into ethyl acetate and water and then the separated organic extract was washed successively with water, 10% citric acid solution and saturated aqueous NaHCO 3 solution. The solution was dried over MgSO 4, filtered and concentrated. The residue was purified by chromatography using ethyl acetate / hexane as eluent to give 180 mg of the oily product (68% yield) after removal of the volatiles. MS (CI) m / e 510 (m + H) +,

9.4 (d, J = 3 Hz, 1H).

J 71 210

Case 4714.PG.01 -48-

Example 48 N- (t-butyloxycarbonyl) -3- (2-naphthyl) -R-Alanine (0) - N - (t-Butyloxycarbonyl) -3- (2-naphthyl) -R-alanine di-n-pentylamide , 31 g, 1.0 mmol) was stirred at 0 ° C in 25 mL of CH2 Cl2, with BQPC1 (0.38 g, 1.5 mmol) and 0.2 mL of TEA (1.5 mmol). To this reaction mixture was added di-n-pentylamine (0.7 mL, 3.5 mmol). The mixture was stirred overnight and allowed to warm to room temperature. An additional equivalent of BOCl1 was added after 18 h and the reaction mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo, the residue taken up in ethyl acetate and washed with water, 1N HCl solution, saturated NaHCO 3 solution, and water. The organic solution was dried over MgSO 4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as solvent system (1: 4). The product was isolated as an oil, in 62% yield (0.28 g). MS (CI) m / e 455 (m + H) +, 355.

Example 49 (0.28 g, 0.6 mmol) was dissolved in 4N HCl in dioxane (10 mL). The product from Example 48 (0.28 g, 0.6 mmol) was dissolved in 4N HCl in dioxane (10 mL) ) and stirred under N 2 for one hour. When the reaction was checked for tlc, the solvents were evaporated in vacuo and then hexane and diethyl ether were added. The residue was triturated with these two solvents to give the product, solid, glass, in 93% yield. MS (CI) m / e 355 (m + H) +.

Example 50 N- (3'-quinolylcarbonyl) -R-histidine-di-n-pentylamide The free base of example 42 (3.7 g, 9.26 mmol), EDCI (1.7 g, 9 mmol), HOBt (3.65 g), 1.5 g of quinoline-3-carboxylic acid, were stirred at 0 ° C in 50 ml of anhydrous dimethylformamide (DMF) / CH 2 Cl 2 (1: 1) the reaction mixture was allowed to evaporate under vacuum and the residue was dissolved in a large excess of ethyl acetate (300 ml). Water and

71 210

Case 4714.R8.01 < 4 > the organic extract was washed with 10% citric acid solution, and saturated NaKCO3 solution. The solution was dried over MgSOâ, ", filtered and concentrated. The residue was purified by chromatography using chloroform / methanol / ammonium hydroxide as the eluent mixture to give 1.98 g (68.3%) of product. [Î ±] D = -6.4Â ° (c * 0.25, MeOH), MS (CI) m / e 450 (m + H) +, 156. 1 H NMR (CDCl3, 6H), 1.29 (m, 8H), 1.45-1.6 (m, 4H), 3.08-3.2 (m, 3H), 3.23-3.4 (m, 2H), 3.5-3.6 (m, 1H), 5.3 (app q, J 9Hz, 1H), 6.85 (s, 1H), 7.6 (m, 3H) (d, J = 8 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 8.16 (d, J = 8 Hz, 1H), 7.88 H), 8.6 (d, J = 3 Hz, 1 Η), 9.3 (d, J = 3 Hz, 1H). N- (3'-quinolinylcarbonyl) - (hP 2 -tosyl) -R-Histidine-di-n-pentylamide (0.2 g) was also isolated; see, example 51.

Example 51 N-3- [1- The title compound of Example 51 was isolated as a by-product in the procedure of example 50. [Î ±] 20 = +13 (+) - , 3 '(c = 1, G5,

MeOH), MS (CI) m / e 604 (m + H) +, 450. 1 H NMR (CDCl 3, 300 MHz) δ0.9 (m, 6H), 1.3 (m, 8H), 1.45-1.7 (m, 4H), 2.25 (s, 3H) , 3.35 (m, 1H), 3.5 (m, 1H), 5.36 (app q, J = 6 Hz, 1H 7.6 (t, J = 7 Hz, 2H), 7.7 (d, J = 9 Hz, 2H), 7.8-7.9 (m, 2H), 7.15 (m, 3H). (D, J = 7 Hz, 1H), 8.45 (d, J = 3 Hz, 1H), 9.18 (d, J = 3Hz, 1H). C, H, N analysis calculated for C 33 H 41 N 5 O 4 S: C 65.64, H 6.85, N 11.60; Found: C 65.58, H 6.84, N 11.50.

Example 52 Ne- (benzyloxycarbonyl) -R-lysine-di-n-pentylamide hydrochloride The compound was prepared analogously to example 2 by deprotecting the product of example 44 using 4N HCl in dioxane. The product was isolated in quantitative yield. MS (CI) m / e 420 (m + H) +.

Example 53

The reaction was conducted in a manner analogous to that of Example 3, except that, for example,

J 71 210 Case 4714.PG.01 50-

(0.38 g), EDCI (0.45 g), HOBt (0.6 g) and NMM (0.48 ml). The oily product was isolated in 72% yield. [a] n ~ + 2.7S (c = Q, 7, MeOH). MS (CI) m / e 575 (m + H) +. 1 H NMR (CDCl 3, 300 MHz)

Example 1 To a suspension of 0.5 g of 10% -Pd / C in methanol (MeOH, methanol, methanol, methanol, dichloromethane, 25 ml) -cyclohexadiene (3 ml), under nitrogen, was added a solution of the product of example 53 (0.51 g, 0.89 mmol) in methanol by cannula. The reaction mixture is stirred at room temperature. Cyclohexadiene (2 ml) was added and the reaction was continued overnight. The mixture was filtered through celite and washed several times with methanol. The filtrate and washings were combined and concentrated in vacuo. The residue was subjected to flash chromatography " using chloroform / methanol / ammonium hydroxide (90: 10: 1) as the eluent mixture. The product was obtained by lyophilization in 64% yield (0.25 g). MS (CI) m / e 441 (m + H) +.

calc'd for C 26 H 40 N 4 O 2 • H 2 O: C 69.45, H 8.97, N 12.46; Found: C 69.48, H 8.76, N 12.03.

Example 55

(5 g, 18.7 mmol), BOCEP (5.1 g, 20 mmol), diphenylamine (5 g, 18.7 mmol), potassium carbonate 8 ml; 37

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) And TEA (2.6 mL). The product was isolated in 78% yield, (5.99). MS (CI) m / e 407 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 0.85 (m, 6H), 1.1, 1.35 (m, 8H), 1.3 (s, 3H), 1.45-1.58 (m, 4H (D, J = 9 Hz, 1 Η), 6.02 (d, J = 9 Hz, 1H) (D, J = 9 Hz, 1H), 6.5 (s, 1H), 6.75 (d, J = 9 Hz, 2H), 7.18 (d, J = 9 Hz, 2H).

EXAMPLE 56 N- (8'-Hydroxy-2-guinolylcarbonyl) -R-valine-di-n-pentylamide The title compound was prepared analogously to example 3. mp = 143-4 ° C. 1 H NMR (CDCl 3, 300 MHz) δ 8.58 (d, J = 10 Hz, 1H), 8.31 (s, 2H), 8.09 (s, 1H) (Dd, J = 7.1 Hz, 1H), 7.54 (m, 1H), 5.01 (dd, J = 7.1 Hz, 1H) , 3.65 (dt, J = 7.16Hz, 1H), 3.28-3.55 (m, 2H), 3. QS (dt, Jâ,ƒ7.14Hz, 1H), 2.22 (septet, J = 7 Hz, 1H), 1.50-1.75 (m, 4H), 1.25-1.42 (m, 8H), 1.06 (d, J = 7 Hz, 3H), 1.03 d, J = 7Hz, 3H), 0.92 (t, J = 7Hz, 3H), 0.89 (t, J = 7Hz, 3H), calculated for C25H37N3O3, 0.1 H2O : C 69.93, H 8.73, N 9.79, found: C 69.78, H 8.51, N 9.61.

The compound was prepared analogously to example 2 by deprotection of Nt-butyloxycarbonyl-R-phenylalanine-di-n-pentylamide, the product of example 28, using N -butyloxycarbonyl-R-phenylalanine di-n-pentylamide hydrochloride. 4N HCl in dioxane. The product was isolated in quantitative yield. MS (CI) m / e 305 (m + H) +.

The hydrochloride of example 57 (870 mg, 2.46 mmol), EDCI (550 mg), HOBt (300 mg) and quino acid were stirred for 2 hours at reflux temperature for 1 hour. 3-carboxylic acid (430 mg) were stirred at 0 ° C under nitrogen in 25 ml of dry CH2 Cl2. To this mixture was added 550 μΐ NMM and the mixture was stirred overnight (warming to room temperature). The reaction mixture was poured into ethyl acetate and water and the organic solution was separated, the organic extract was washed successively with

water, 10% citric acid solution and saturated aqueous NaHCO3. The solution was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography using ethyl acetate / hexane as the eluent mixture, yielding 870 mg of the product (77%) after removal of the volatiles. [oqq- + 12.9 (¢ = 1.05, MeOH). MS (CI) m / e 460 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.9 (m, 6H), 1.15-1.4 (m, 8H), 1.5-1.55 (m, 4H) 2H), 3.48-3.6 (m, 1H), 5.35 (m, 1H), 7.27 (m, 5H), 7.2 (m, (D, J = 8Hz, 1H), 7.9 (d, J = 8Hz, 1H), 7.62 ), 8.15 (d, J = 9 Hz, 1H), 8.55 (d, J = 3H2, 1H), 9.38 (d, J = 3 Hz, 1H). C, H, N of

calc'd for C 29 H 37 N 3 O 2 • H 3 O: C 74.32, H 8.39, N 8.97; Found: C 73.92, H 8.05, N 8.83.

Example 59 N- (2-metylphenylaminocarbonyl) -R-valine-dl-n-pentyllamide

A solution of the hydrochloride of example 2 (0.15 g, 0.52 mmol), 2-methyl-1-phenisoclanate (0.1 g) and triethyllamine (0.1 ml) was allowed to react at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. Water was added and the mixture was extracted several times with EtOAc. The ethyl acetate extracts were combined, washed with brine and dried over MgSOâ, ". The volatiles were removed in vacuo and the residue purged by chromatography. The oily product was isolated in 80% yield. Coe] O + 1.5 S (c = 0.4, MeOH). MS (CI) m / e 396 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.8-1.0 (m, 12H), 1.12-1.41 (m, 8H), 1.42-1.78 (m, 4H) 2H), 3.51 (m, 1H), 4.7 (m, 1H), 2.22 (s, 3H), 3.25 (m, 1H) (D, J = 6 Hz, 1H), 6.76 (m, 2H), 7.53 (d, J = 9Hz, 1H). C, H, N analysis calculated for. C 23 H 39 N 3 O 2: C 70.91, H 10.09, N 10.79; Found: C 70.57, H 9.46, N 10.57.

Example 60

N - (t-butyloxycarbonyl) -N g- (2'-chlorobenzyloxycarbonyl) -R-lysna-1-n-pentylamide

Na- (t-butyloxy) carbonyl) -N- (2-chlorobenzyloxycarbonyl) -R-Lysine (1.0 g, 2.4 mmol) was suspended in 25 ml of

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CH2 Cl2 with BQPC1 (0.65 g, 2.6 mmol) and TEA (0.35 mL, 2.4 mmol). To this reaction mixture was added di-n-pentylamine (2.5 mL, 12 mmol). The mixture was stirred overnight and allowed to warm to room temperature. One more B0PC1 equivalent was added after 18 h, and the mixture was stirred for a further day at room temperature. The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed with water, 1N HCl, saturated NaHCO3, and water. The organic solution was dried over MgSO4. After filtration and concentration of the filtrate in vacuo, the residue was purified by chromatography using ethyl acetate / hexane as solvent system (1: 4). The product was isolated as an oil, in 53% yield (0.7 g). 1 H NMR (CDCl 3, 300 MHz) δ 0.9 (m, 6H), 1.2-1.38 (m, 12H), 1.42 (m, (s, 9H), 1.5-1.7 (m, 4H), 3.02-3.45 (m, 4H), 3.48 (m, 4H), 4.5 (m, 1H) (M, 1H), 5.2 (s, 2H), 5.4 (d, J = 9Hz, 1H), Î'.25 (m, 2H), 7.3-7.45 (m, ,2 M).

The compound was prepared analogously to example 2 by deprotection of the product of example 60 using 4N HCl in dioxane. The product was isolated in quantitative yield, MS (CI) m / e 454 (m + H) +, free base.

Example 62

(2-chlorobenzyloxycarbonyl) -R-1-isine-di-n-pentamide The hydrochloride of example 61 (0.5 g, 1.02 mmol) mmol) was stirred in 15 mL of CH2 Cl2 with MMM (0.24 mL, 2.2 mmol) under N2 at 0Â ° C. EDCI (0.25 g, 1.3 mmol) and HOBt (0.3 g, 2.2 mmol) were added followed by the addition of quinoline-3-carboxylic acid (0.1 g, 1 mmol). The reaction mixture was stirred overnight and allowed to warm slowly to ambient temperature. The solvents were evaporated in vacuo, the residue was taken up in ethyl acetate and washed successively with water, saturated NaHCO 3, solution

J 71 210

Case 4714.PG.01 saturated with citric acid, water and brine. The organic solution was dried over MgSO4, and then filtered. The solvents were evaporated in vacuo and the crude product was subjected to " flash " using ethyl acetate / hexane as eluent mixture. The product was isolated as an oil, 0.46 g (74%). MS (CI) m / e 609 (m + H) +. 1H). NMR (CDCl 3, 300 MHz) δ 0.8-0.96 (m, 6H), 1.16-1.42 (m, 12H), 1.45-1.6 (m, 2H), 1,8- 2.0 (m, 2H), 2.7 (m, 2H), 3.07-3.45 (m, 4H), 3.5-3.65 (m, 2H), 5.15 1H), 7.2 (d, J = 9Hz, 2H), 7.4 (d, J = 9Hz, 2H), 7.6 (m, 2H), 6.85 (d, J = ),

7.8 (t, J = 7 Hz, 1H), 7.9 (t, J = 7 Hz, 1H), 8.15 (d, J = 9 Hz, 1 Η), 8.6 (s, 1H), 9 , Δ (d, J = 3 Hz, 1H). C, H, N analysis calculated for C34 H45 ClN4 O4, 0.6 H2 O: C 65.86, H 7.41, N 9.04; Found: C 65.63, H 7.29, N 9.42.

The reaction was carried out in a manner analogous to that of example 3, using 75 mg of the hydrochloride of Example (2) 49, quinoline-3-carboxylic acid (34 mg), EDCI (40 mg), HOBt (50 mg) and NMM (22 μ). The oily product was isolated in 31% yield (32 mg). MS (CI) m / e 510 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 0.85 (m, 6H), 1.06-3.75 (m, 12H), 2.85 (m, 1H), 3.0 (m, 2H), 3.35 (m, 2H), 3.55 (m, 1H), 5.45 (app q, J = 7 Hz, 1H), 7.32-7.5 (m, 4H), 7.62 (t , J = 6 Hz, 1H), 7.68-7.82 (m, 5H), 7.88 (d, J = 7 Hz, 1H), 8.15 (d, J = , 52 (d, J = 2 Hz, 1H).

The compound was prepared analogously to Example 2 by deprotection of the product of example 55 using 4-Hexahydro-4-hydroxyphenylglycine di-n-pentylamide hydrochloride. N in dioxane. The oily product was isolated in 90% yield,

[α] D = -87.0 (c = 0.2, MeOH); MS (CI) m / e 307 (m + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ 0.82 (m, 6H), 1.02-1.2 (m, 8H), 1.3-1.5 (m, 4H), 3.05-3.3 (m, 2H), 3.32-3.4 (m, 2H), 5.22 (broad s, 1H), 6.83 (d, J = 9Hz, 2H), 7.25 (d, J = 9Hz, 2H), 8.4 (broad s, 3H).

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Case 4714.P0.O1 -55 "

The reaction was carried out in a manner analogous to that of Example 3 using (2-chloro-4-methoxyphenyl) -1- (300 mg, 2.6 mmol) of the hydrochloride of example 64, quinoline-3-carboxylic acid (450 mg), EDCI (550 mg), HGBt (380 mg) and NMM (0.62 ml). The product was isolated in 53% yield (0.78 g). mp. 79-80 ° C. [Î ±] D + = 99.6Â ° (c = 1, G, MeOH). MS (CI) m / e 462 (m-1-H) +. 1 H NMR (CDCl3, 300MHz) δ 0.85 (t, J = 7Hz, 6H), 1.1-1.3 (m, 10H), 1.4-1.5 (m, 2H), (M, 2H), 5.9 (d, J = 9Hz, 1H), 6.6 (d, J = 9Hz, 2H) (D, J = 7 Hz, 1H), 7.85 (t, J = 7 Hz, 1H), 8.08 (d, J = 9 Hz, (D, J = 3 Hz, 1H), 9.1 (d, J = 6 Hz, 1H), 9.25 (d, J = 3 Hz, 1H), 9.53 (s, , 1H). Ο, Η, Ν analysis calculated for C28-35% 33: C 72.85, H 7.64, N 9.10; Found: C 72.65, H 7.65, N 9.08.

Example 66

The reaction was run in a manner analogous to that of example 33 using 60 mg of the product of example 54 and pyridine with acetic anhydride. The oily product was purified by standard chromatography and isolated in 33% yield (22mg) [Î ±] p = (c = 0.5, MeOH). MS (CI) m / e 483 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.92 (m, 6H), 1.23-1.4 (m, 8H), 1.45-1.7 (m, 8H), 1.8 (m, 2H (M, 1H), 3.25 (m, 2H), 3.32 (m, 1H), 3.6 (m, 2H), 5.8 (s, 3H) , 7.5 (broad s, 1H), 7.5 (d, J = 8 Hz, 1 Η), 7.65 (t, J = 6 Hz, 1 Η), δ (D, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1H), 8.62 (d, J = 2 Hz, 1H), 9.36 (d, 2 Hz, 1H).

Example 67

5-Hydroxy-indole-2-carboxylic acid (95 mg), the hydrochloride of example 2 (150 mg) was dissolved in dichloromethane NMM (0.12 ml), HQBt (70 mg), and EDCI (105 mg) were reacted under conditions analogous to those described in example 3. The product was isolated in 74% yield. MS (CI) m / e 416 (m + H) +. 1 H NMR (CDCl 3, 300 MHz), δ 0.9 (m, 6H), 1.0 (app q, J = 7 Hz.6H), 1.3-2 (m, 8H), 1.62 (m, 4H ), 2.11 (m, 1H), 3.15 (m, 1H), 3.2 (m, 1H),

J 71 210 Case 4714.PG.01

-5-

The hydrochloride of example 2 (60 mg, 0.22 mmol), N-methyl (25 μ), was dissolved in 10 ml of methylene chloride. ml of CH2 Cl2. 4-Chlorophenylsulfonyl chloride (46 mg) was added to this reaction mixture and stirred overnight (warming to room temperature). The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water, both in large excess. The organic extracts were washed successively with saturated aqueous NaHCO 3, 0.1 N HCl solution and brine. The combined extracts were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography using ethyl acetate / hexane as eluents. The pure product was isolated in 75% yield (59 mg). m.p. =

89-90-C. [Î ±] D = -61.8Â ° (c 0.5, MeOH). MS (CI) m / e 431 (m + H) +. 1H

To a solution of 4-chlorocinnamic acid (0.8 g, 4.38 mmol) in CH 2 N 2 was added N-hydroxysuccinimide (0.55 g) 4.8 mmol) and EDCI, and the reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo and the residue dissolved in ethyl acetate and water. The combined EtOAc extracts were dried over MgSO4 and the solution was concentrated in vacuo. The residue was crystallized from an ethyl acetate / hexane mixture. The product was isolated in 72% yield (0.88 g). p, f = 192-

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7.92 (d, J = 9 Hz, 2H), 7.93 (d, J = 17 Hz, 1H).

Example 70 Nα- (3 '' - 9 '') carbonyl) -N '- [3' - (4 " -chlorophenyl) prop-2-enoyl)] - To a solution of Example 54 (60 mg, 0.14 mmol) in dimethylformamide (8 mL), cooled to 0 ° C, was added NMM (35 μ) and the active ester of Example 69 (40 mg, 0.14 mmol). The mixture was stirred overnight, warming to room temperature. The DMF was removed in vacuo and the residue was chromatographed on silica, using ethyl acetate / hexane as eluent. The oily product was isolated in 40% yield (35 mg). MS (CI) m / e 605 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.92 (m, 6H), 1.3 (m, 8H), 1.62 (m, 8H), 1.83 (m, 2H), 3.14 (m, 1H), 3.35 (m, 4H), 3.58 (m, 1H), 5.15 (m, 1H), 6.18 (m, 1H), 6.35 (d, J = 17 Hz, 1H), 7.62 (t, J = 8 Hz, 1 H), 7.83 (t, J = (D, J = 9 Hz, 1H), 8.62 (d, J = 2 Hz, 1H), 9.37 (d, J = 2 Hz, 1H).

Example 71 N- (t-butyloxycarbonyl) -R-tyrosine-di-n-pentylamide

Nt-Butyloxycarbonyl-R-Tyrosine (4.5 g, 15.4 mmol) was stirred with BOCPC (3.92 g, 15.4 mmol) and dipentylamine (7.9 mL, 39 mmol) in 100 mL tetra (THF) at 4 ° C and allowed to warm to room temperature overnight. After 1 day, more B0PC1 (800 mg) was added and, two days later, the volatiles were evaporated. The residue, dissolved in EtOAc, was extracted with 0.1 M citric acid solution, 0.1 M sodium carbonate solution, and water; then dried over magnesium sulfate (MgSO4), filtered and concentrated in vacuo to give an oil, 5.67 g,

13.4 mmol (87.4%). Rf = 0.45 (2: 1 hexanes-EtOAc). [Î ±] D + 2.8Â ° (c = 0.76, MeOH). MS (CI) m / e 421 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 0.88 (app q, J = 7 Hz, 6H), 1.15-1.32 (m, 10H), 1.36-1.47 (m, 11H) (D, J = 8 Hz, 1 H), 5.83 (m, 5H), 3.38-3.48 (m, 1H), 4.72 (app q, , 6.70 (d, J = 8 Hz, 2H), 7.02 (d, J = 8 Hz, 2H).

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Case 4714.P0.O1

-58-

The product of example 71 (2.0 g, 4.75 mmol) was dissolved in 4N HCl in dioxane (20 mL, 80 mmol) which was precooled to give 4- to 4¾. Three hours later the excess reagent was evaporated and the oily residue was placed under high vacuum overnight to give a glass product, 1.5 g; 4.2 mmol (87%). [α] D = -42.8 ° (c = 1.2, MeOH). MS (CI) m / e 321 (m + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ0.82-0.89 (m, 6H), 1.1-1.4 (m, 1H), 2.70-3.04 (m, 5H) (Dd, J = 5.7Hz, 1H), 6.70 (d, J = 8Hz, 2H), 6.99 (d, J = 8Hz, 2H) ), 8.37 (br s, 3H), 9.48 (s, 1H).

The product of Example 72 (357 mg, 1 mmol), quinoline-3-carboxylic acid (173 mg, 1 mmol), HOBt (13 mg, 0.1 mmol) and TEA (279 μ, 2 mmol) , were dissolved in 10 ml of methylene chloride, and EDCI (191 mg, 1 mmol) was added in one portion. Three days later the volatiles were evaporated and the residue in Et 2 O was extracted as in Example 71. The residue was then purified by chromatography on silica gel eluted with 1% ethanol in chloroform to give the first mono- (19 mg, see Example 80) followed by an oily product (108 mg, 0.17 mmol, 17% yield). Rf = 0.36 (18: 1 chloroform / ethanol). [α] D = + 5.8 ° (c = 0.5, CHCl3). [g] d + 53.2 ° (c = 0.73, MeOH). MS (CI) m / e 631 (m + H) +, 518, 458, 446, 368. NMR (CDCl3, 300MHz) δ0.88-0.94 (m, 6H), 1.22-1.41 (m, 10H), 1.50-1.59 (m, 2H), 2.96-3.30 (m, 5H),

Calc'd for C 39 H 42 N 4 O 4, H 2 O: C 72.20, H 6.84, N 8.64; Found: C 72.38, H 6.62, N 8.50.

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Case 4714.ΡΘ.01 -59-

Example 74 (N-quot; (2-indolylcarbonyl) -R-tyrosine-di) in 111 ml -1 was added the product of example 72 (200 mmol), indole-2-carboxylic acid (97 mg, 0.6 mmol) and TEA (84 μ, 0.6 mmol) were dissolved in 5 ml of methylene chloride and treated with EDCI (115 mg, 0.6 mmol) at room temperature. Three days later, the solvent was evaporated and the residue was extracted as in Example 71. Column chromatography on silica gel eluted with 1% ethanol in methylene chloride yielded the product. 0.38 (18: 1 methylene chloride / ethanol). m.p. = 124-7 ° C. [α] ρ = +21.4 "(c = 1.17, MeOH). MS (CI) m / e 464 (m + H) +. 1 H NMR (CDCl 3, 300MHz) δ 0.88 (app q, 8 Hz, 6H), 1.15-1.56 (m, 12H), 2.46-3.22 (m, 5H) (M, 1H), 6.12 (s, 1H), 6.70 (d, J = 8 Hz, 2H), 6.95 (m, d, J = 1Hz, 1H), 7.05 (d, J = 8Hz, 2H), 7.13 (dt, J = (Dt, J = 1.7Hz, 1H), 7.40 (d, J = 8Hz, 1H), 7.64 (d, J = 8Hz, 1H), 9.22 (s, 1H) . C, H, N analysis calculated for C 28 H 37 N 3 O 3: C 72.54 > H 8.05, N 9.06; Found: C 72.37, H 8.10, N 8.80,

The product of example 72 (103 mg, 0.29 mmol) was dissolved in 5 ml of methylene chloride and treated with dichloromethane of 3,4-dichlorobenzoyl (126 mg, 0.6 mmol) and TEA (84 μ, 0.6 mmol) at room temperature. Two hours later more acid chloride (13 mg) and TEA (8 μl) were added and the mixture was stirred overnight. The volatiles were evaporated and the residue, in EtOAc, was extracted with 0.1% citric acid, H2O; then dried over MgSO4, filtered and concentrated in vacuo. The resulting diacyl residue was dissolved in 10 mL THF / methanol (1: 1) and treated with 1 N NaOH (290 mL, 0.29 mmol). One hour later, the tlc showed the end of the reaction and the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and acidified with 0.1 cit citric acid. The EtOAc layer was then washed until neutral, dried over MgSO 4, filtered and concentrated in vacuo. The residue was heated with 80% aqueous ethanol and cooled overnight to give

J 71 210 Case 4714.ΡΘ.01

60- a solid product, 64 mg; 0.13 mmol (45% yield). m.p. 148-172 ° C. [Î ±] D = + 15.6Â ° (c = 1.0, MeOH). MS (CI) m / e 493 (m + H) +.

of the analysis calculated for C26 H34 N2 O2: C, 63.38; H, 6.94; N, 5.68; Found: C 63.39, H 7.00, N 5.54.

The product of example 72 (100 mg, 0.28 mmol) was acylated with 2-naphthoic acid (52 mg, 0.30 mmol) in dichloromethane in the presence of TEA (39 μl, 0.28 mmol) and EDCI (57 mg, 030 mmol) in 5 ml of methylene chloride. The reaction and extractive work were conducted as in Example 71 to give 120 mg; 0.25 mmol (89%). m.p. = 128-133 ° C. [a] q + 11.8 S (c = 0.68, MeOH). MS (CI) m / e 475 (m + H) +, 303, 290. 1 H NMR (CD30D, 300MHz) δ 0.88-0.93 (m, 6H), 1.19- (M, 3H), 2.99 (dd, J = 7.13Hz, 1H), 3.08-3.29 (m, 4H), 3.37- (D, J = 8 Hz, 2H), 7.12 (d, J = 8 Hz, 2H) (M, 3H), 8.37 (s, 1H), 7.83 (d, J = . C, H, N analysis calculated for C 75.91, H 8.07, N 5.90; Found: C 75.57, H 7.97, N 5.83.

Example 77 N-t-butyloxycarbonyl- (O-benzyl) -R-thiourea di-n-pentylamine

Nt-Butyloxycarbonyl- (O-benzyl) -R-Tyrosine (3.71 g, 10 mmol) was stirred with di-n-pentylamine (5.1 mL, 25 mmol), H2 O (1.4 g, 10 mmol) and TEA (1.4 mL, 10 mmol) in 150 mL of methylene chloride at 4 ° C and then BOClCl (2.6 g, 10 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. One day later B0PC1 (260 mg) and TEA (140 μΐ) were added. Two days later the volatiles were evaporated and the residue (in EtOAc) was extracted with 0.1 M HCl, 0.1 M Na2 CO3, b20; then dried over MgSO4, filtered and concentrated in vacuo.

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Case 4714.PG.01 -61-

The residue was chromatographed on silica gel eluting with 2: 1 hexanes / EtOAc to give an oil, 1.3 g, 2.55 mmol (25%), [gc] = +5.8 (c = 1.5, MeOH). MS (CI) m / e 511 (m + H) +, 456, 393. 1 H NMR (CDCl3, 300MHz) δ0.84-0.93 (m, 6H), 1.1-1.35 (m, 12H), 1.41 (s, 9H), 2.81-3.04 (m, 5H), 3.36-3.46 (m, 1H), 4.15-4.23 (m, 1H (D, J = 8Hz, 1H), 6.87 (d, J = 8Hz, 2H), 7.11 (d, J = 8Hz, 2H), 5.03 (s, 2H), 5.32 7.32-7.43 (m, 5H).

The product of example 77 (1.3 g, 2.55 mmol) was treated with 5 ml of 4N HCl in dioxane, pre-cooled to 0 DEG C. The reaction mixture was allowed to warm to room temperature. After 1 hr, the reaction mixture was evaporated and the residue was evaporated in vacuo, (Gc] MeOH), MS (m / z): 1 H NMR (DMSO-d6): δ Cl) m / e 411 (m + H) +, 1 H NMR (DMSOdd, 300MHz) Î'0.85 (app q, J = 7 Hz, 6H), 1.07-1.38 (m, 1H), 2 (M, 2H), 4.27 (dd, J = 5.13, z, 1H), 3.32-3.42 (m, 1H), 5.09 (s, 2H), 6.93 (d, J = 8 Hz, 2H), 7.12 (d, J = 8 Hz, 2H), 7.32-7.43 (m, 5H), 8.37 (s, 3H).

Example 7.9 N- (3-quinolylcarbonyl) - (O-benzyl) -R-tyrosine-di-n-pentylamide

EDCI (290 mg, 1.5 mmol) was added to a cooled (4 ° C) solution of quinoline-3-carboxylic acid (260 mg, 1.5 mmol) of the product of example 78 (650 mg , 1.35 mmol) and TEA (418 μΐ, 3.0 mmol) in 5 mL of ethylene chloride. The stirred reaction mixture was allowed to warm to room temperature overnight. After evaporation of the volatiles, the residue was dissolved in EtOAc and extracted with 0.1M H 3 PO 4 (3x), 0.1 N NaOH (3x), brine (3x); then dried over MgSO4, filtered, and concentrated in vacuo to give an oil, 650 mg; 1.15 mmol (85%). 0.77 (18: 1 chloroform / ethanol), 0.40 (1: 1 hexanes / EtOAc). [Î ±]

H + 0.21 " (c = 0.47, CHCl3). MS (FAB) m / e 566 (m + H) +, 393, 381. 1

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1 H NMR (CDCl3, 300 MHz) δ 0.91 (app q, J7 Hz, 6H), 1.17-1.38 (m, 10H), 1.43-1.6 , 2H), 2.86-3.17 (m, 5H), 3.49-3.59 (m, 1H), 5.03 (s, 2H), 5.26-5.33 (m, 1H J = 8Hz, 2H), 7.28-7.43 (m, 6H), 7.62 (dt, J = 8Hz, 1H), 7.82 (dt, J = 1.8 Hz, 1 Η), 7.90 (d, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1 Η), 8.54 (d, J = 2 Hz, 1H),

9.32 (d, J = 2 Hz, 1H). C, H, N analysis calculated for C 76.55, H 7.88, N 7.29; Found: C 76.43, H 7.66, N 7.43.

Example 80 N- (3'-quinolinylcarbonyl) -R-tyrosine-di-n-pentylamide The product of example 79 (614 mg, 1.09 mmol) was dissolved in 30 ml of methanol and treated with 10% Pd / C (200 mg, pre-wet with solvent under nitrogen) under hydrogen atmosphere. Another 200 mg of catalyst was added after 4 h, and the reaction mixture was stirred overnight. The mixture was then filtered and the filtrate concentrated in vacuo. Chromatography on silica gel column (eluted with 2: 1 to 1: 1 hexane / EtOAc, gradient in step) gave 270 mg; 0.57 mmol (52% yield). mp. 135-37 ° C. [Î ±] D = + 12.6 (c = 0.5, MeOH). MS (CI) m / e 476 (m + H) +, 347, 321, 291. 1 H NMR (CDCl 3, 300 MHz) δ0.91 (t, J = 7 Hz.6H), 1.24-1.38 (m, 8H), 1.48-1.62 (m, 4H), 3.0 (M, 5H), 3.51-3.61 (m, 1H), 5.30-5.38 (m, 1H), 6.72 (d, J = 8 Hz, 2H), 6 , 7.78 (d, J = 8 Hz, 1 H), 7.60 (t, J = 7 Hz, 1 H), 7.96 (d, (D, J = 8 Hz, 1 Η), 8.15 (d, J = 9 Hz, 1H), 8.58 (d, J = 2 Hz, 1H), 9.27 (d, J = 2 Hz, 1H). C, H, N analysis calculated for C 29 H 37 N 303: C 73.23, H 7.84, N 8.38; Found: C 73.23, H 7.89, N 8.76.

The product from example 80 (59 mg, 0.12 mmol) was dissolved in 2 ml of DMF in dichloromethane (2 ml) and the product of Example 80 (59 mg, 0.12 mmol) was dissolved in 2 ml of DMF and treated with freshly prepared pyridine / sulfur trioxide complex (HCReitz et al., J.Amer.Chem.Soc. 68, 1031-5, 1946) overnight at room temperature. The pyridine was evaporated in vacuo and the solution was poured into DMF over water and

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Case 4714.PG.01 was adjusted to pH 7 with 1 N NaOH. The homogeneous solution was then frozen and lyophilized. By preparative C-18 chromatography of the residue, eluting with a gradient from 100% aqueous buffer (0.05 M ammonium acetate, pH 6.2) to 50% acetonitrile / aqueous buffer over 10 min, the product fractions were obtained, which were mixed, frozen and lyophilized to give 48 mg, 0.08 mmol (67%). m.p. = 113-6 " C.

[c] D = + 12.2 " (¢ = 0.88, MeOH). MS (FAB) m / e 554 (m-H) +, 368, 302, 2.98. 1 H NMR (D 20, 300 MHz) δ 0.68-0.75 (m, 6H), 0.98-1.43 (m, 1 2H), 2.98-3.28 (m, 6H) (D, J = 8 Hz, 2H), 7.30 (d, J = 8 Hz, 2H), 7.44 (t, J = 8 Hz, 1 H) , 7.62 (d, J = 8 Hz, 1 H), 7.69 (t, J = 8 Hz, 1 H), 7.82 ), 8.78 (s, 1H). C, H, N analysis calculated for CjgH Q QN₂O j · 0.6H₂O: 0.50 H2O: C 59.88, H 7.10, N 9.63; Found: C 59.77, H 6.82, N 9.11.

Example 82 (3,5-diiodo-N- (3-quinolinylcarbonyl) -R-Tyr-di-n-pentylamide

Uel 3-iodo-N- (3-furylylcarbonyl) -R-Tyr-di-n-pentylamide

Iodine (27 mg, 0.11 mmol) was combined with morpholine (40 μ, 0.46 mmol) in 5 mL of methanol and the product of Example 80 (50 mg, 0.11 mmol) in 15 mL methanol at room temperature. The mixture was stirred until tlc indicated the end of the reaction. After evaporation of the solvent, step chromatography on silica gel eluted with a gradient from chloroform to 1% ethanol in chloroform gave the diiodo product followed first by the mono-iodo product. Diiodo product (a); [Î ±] D +18Â ° (¢ = 0.11, MeOH), MS (CI) m / e 728 (m + H) +, 602. 1 H NMR (CDCl3, 300 MHz) J = 7Hz, 6H), 1.2-1.45 (m, 12H), 2.92-3.13 (m, 5H), 3.53-3.67 (m, 1H), 5.22-5, (Dt, J = 8 Hz, 1H), 7.56 (s, 2H), 7.63 (dt, J = 8 Hz, 1 H) , 7.83 (dt, J = 1.8 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 8.18 (d, J = 8 Hz, 1H),

8.55 (d, J = 2 Hz, 1H), 9.33 (d, J = 2 Hz, 1H). C, H, N analysis calculated for C 29 H 35 I 2 H 3 O 3, 0.4 EtOAc: C 48.19, H 5.05, N 5.51; obtained: C-64 71 210

Case 4714.Ρθ.01 48.43, δ 5.03, N 5.79. Mono-iodine product (b): m.p. = 75-85 ° C. 1 H NMR (CDCl3, 500 MHz) δ 0.84 (apparent q, 7 Hz, 6H), 1.13-1.35 (m, 9H), 1.37-1.53 (m, 3H), 2.90-2.98 (m, 3H), 3.02-3.08 (m, 2H), 3.48-3.55 (m, m), 5.18-5.23 (m, 1H), 6.83 (d, J = 8Hz, 1H), 7.05 (dd, J = 1.8Hz, 1H), 7.22 (dt, J = 1.8Hz, 1H), 7.76 (dt, J = 1.8Hz, 1H), 7.46 (dt, J = 1H), 7.84 (d, J = 8Hz, 1H), 8.11 (d, J = 8Hz, 1H), 8.48 (d, J * 2Hz, 1H), 9.24 (d, J = 2Hz, 1 Η). C, H, N analysis calculated for Î "Hggl NgCl3, 1.5 H2 O: C 55.42, H 5.25, H 6.69; Found: C 55.19, H 5.95, N 6.17.

Example 83

The product of example 80 (25 mg, 0.053 mmol) was dissolved in 1 ml of acetone and the combined organic extracts were dried (MgSO4) and evaporated to dryness K 2 CO 3 (8 mg, 0.058 mmol) and methyl iodide (5 μ, 0.08 mmol). After 3 h reflux, more methyl iodide (5 ml) and acetone (2 ml) were added. Two days later, the volatiles were evaporated and the residue, EtOAc, was extracted with 0.1% aqueous citric acid and with water; then dried over MgSO4, filtered and concentrated in vacuo. (M + H) +, 490 (M + H) +, 476, 361, 347, 317. 1 H NMR (CDCl 3, .delta. 56 (m, 12H), 2.42-3.15 (m, 5H), 3.49-3.59 (m, 1H), 3.78 (s, 3H), 5.27-5.34 (d, J = 8 Hz, 1 Η), 6.82 (d, J = 8 Hz, 1H), 7.08 (d, J = 8 Hz, 1 Η), 7.1 (M, 1H), 7.56-7.63 (m, 1H), 7.76-7.82 (m, 1H) , 7.83-7.88 (m, 1H), 8.14 (d, J = 8 Hz, 1 Η), 8.53 (d, J = 2 Hz, 1H), 9.29 (t, J = 2 Hz , 1H).

Example 84 Nt-Butyloxycarbonyl- (O-benzyl) -R-tyrosyl-S-phenylglycinate of methyl Nt-butyloxycarbonyl- (O-benzyl) ) -R-Tyrosine (1.0 g, 2.7 mmol), methyl S-phenylglycinate hydrochloride (540 mg, 2.7 mmol), HOBt (362 mg, 2.7 mmol) and TEA (374 μ, 2.7 mmol) were dissolved in 20 mL of THF and treated with BOPCI (682 mg, 2.7 mmol). The reaction was followed by tlc (18: 1, chloroform / ethane1) and more BOCPC1 (200 mg) and TEA (374 μ1) were added after 1.2 and 4

J 71 210

Case 4714.PG.01 -65- days. Two days later methylene chloride (20 ml) was also added. After 1 week, the volatiles were evaporated in vacuo, e. the residue in EtOAc was extracted as in Example 71. Chromatography of the residue on silica gel eluted with a gradient gradient from 9: 1 to 2: 1 hexanes / EtOAc afforded 485 mg, , 13 mmol) (42%). m.p. 138-39 ° C. [Î ±] D + 48.7Â ° (c = 1, Q,

MeOH). NMR (CDCl3, 300MHz) δ 1.41 (s, 9H), 2.92-3.04 (m, 2H) , 3.71 (s, 3H), 4.35 (br s, 1H), 5.01 (s, 3H), 5.43-5.46 (m, 1H), 6.78 (d, J = 7Hz, 1H), 6.82 (d, J = 8Hz, 2H), 7.02 (d, J = 8Hz, 2H), 7.19-7.23 (m, 1H), 7.30-7, 45 (m, 10H).

The product of example 84 (450 mg, 1.05 mmol) was dissolved in 4N HCl in dioxane (5 mL, 20 mmol) in methylene chloride (20 mL). moll) precooled to 4 ° C. After 1 h, the excess regent was evaporated in vacuo and the product was used directly in the next step. m.p. = 163-6 ° C. [< z] q =

+ 43.7 (c = 0.76, MeOH). MS (FAB) m / e 419 (m + H) +, 403.225 1 H NMR (DMSOd 6, 300MHz) δ 2.86-3.00 (m, 2H), 3.67 (s, 3H), 4.13 (bt, J * 5Hz, 1H), 5.03 (s, 2H), 5.45 (d, J = 7 Hz, 1H), 6.88 (d, J = 8Hz, 2H), 7.05 (d, J = 8Hz, 2H), 7.22-7.25 (m, 2H), 7.33-7.46 (m, 8H ), 8.28 (s, 3H), 9.35 (d, J = 7 Hz, 1H).

Example 86 Methyl 3-quinolinecarboxylic acid (182 mg, 1.05 mmol) in dichloromethane , TEA (146 μl, 1.05 mmol) and the product of example 85 (1.05 mmol) were dissolved in 20 ml of methylene chloride and EDCI (201 mg, 1.05 mmol) was added to room temperature. . After 4 days, the volatiles were evaporated and the residue was extracted as in Example 71. The solvents were evaporated in vacuo to give 407 mg, 0.71 mmol (68% yield), m.p. 153-8Â ° C. [α] D + = 73.0 (c = 1.2,

1 H-NMR (CDCl3, 300 MHz) δ 3.06 (dd, J = 8.14 Hz, 1 Η H-NMR (CDCl3, 300 MHz) δ 3.06 (dd, J = 8.14 Hz, ), 3.20 (dd, J = 5.14 Hz, 1 Η), 3.70 (s, 3H), 4.94-5.02 (m, 3H), 5.53 (d, J = 1 Η), 6.78 (d, J = 8 Hz, 2H),

J 71 210

(D, J = 7 Hz, 1H), 7.01 (d, J = 8 Hz, 2 H), 7.14 (d, J = 7 Hz, 1H), 7.97 (M, 2H), 7.33-7.36 (m, 4H), 7.39-7.44 (m, 4H), 7.62 (dt, J = 1) (Dt, J = 1.7Hz, 1H), 7.88 (d, J = 8Hz, 1H), 8.15 (d, J = 8Hz, 1H), 8.54 1H), 9.28 (d, J = 2 Hz, 1H), C, H, N of the analysis calculated for C31 H30 N2 O5 Â · 0.5 H2 O: C 72.15, H 5.54, N 7.21, found: C 72.05, H 5.63, N 6.88.

The product from example 86 (200 mg, 0.35 mmol) was dissolved in 10 ml of methylene chloride and treated with iodide (0.8 g, 0.05 mole) in dichloromethane of trimethylsilyl (TMSI, 198 μ, 1.39 mmol) at room temperature.

Additional TMSI (198 μl) is added after 1 day. Three days later the reaction was quenched with methanol, 5 minutes, then poured into 0.1M citric acid, and extracted with ethyl acetate (3x). All the ethyl acetate solutions were combined and washed with water, then dried over MgSO 4, filtered and concentrated in vacuo. vacuum. The crude solid product was purified one by chromatography on gradient eluted silica gel. from 1 to 5% ethanol in methylene chloride and then crystallized from EtOAc and hexane to give 51 mg (30%). m.p. = 238-40 ° C. Ca] D +72.62 (c = 0.23, MeOH). MS (CI) m / e 484 (m + H) +, 319. 1 H NMR (CDCl3, δ CD30D, 300MHz) δ 3.0-3.16 (m, 2H), 3.72 (s, 3H), 4 (D, J = 8 Hz, 1 H), 6.67 (d, J = 8 Hz, 2H), 6.99 (d, J = 8 Hz, , 7.28-7.24 (m, 2H), 7.35-7.38 (m, 3H), 7.40 (s, 1H), 7.68 (dt, J = 1.7 Hz, 1H) , 7.86 (dt, J = 1.7 Hz, 1H), 7.98 (d, J = 8 Hz, 1 Η), 8.12 (d, J = 8 Hz, J = 8 Hz, 1H), 8.68 (d, J = 2 Hz, 1H), 9.21 (d, J = 2 Hz, 1H). C, H, N analysis calculated for C 28 H 25 N 3 O 5: C 69.55, H 5.21, N 8.69; Found: C 69.20, H 5.29, N 8.60.

N-benzyloxycarbonyl-R-methionine (283 mg, 1.0 mmol) and Î ± -iodoacetamide (555 mg, 3.0 mmol) were dissolved in 6 ml of 50% aqueous ethanol and heated at 42 ° C for 4 days. Joined 3 71 210 Case 471.4.Ρθ. 01 67-

citric acid (3 ml of a 0.1 M solution) and the mixture was refluxed for 4 h. After evaporation of the volatiles, the residue was poured into water and extracted with ethyl acetate (3x). The ethyl acetate solutions together were extracted with 0.5 N HCl and water, then dried and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with hexanes / ethyl acetate (1: 1) to give 106 mg, 0.52 mmol (52%). (cf. Ozinskas, A.J., Rosenthal, J., J. Organ. Chem., 51, 5047,

The product of example 88 (620 mg, 2.8 mmol) and dipentylamine (1.4 mL, 7 mmol) were dissolved in 60 mL of acetonitrile and then heated under reflux overnight. After evaporation of the volatiles, the residue was chromatographed on silica gel eluting with a gradient in step from chloroform to 1% ethanol in chloroform to give an oil, 580 mg, 1.6 mmol (56%). [α] β =

Example ...... 90 N '- (2-fluoro-11) - (2 R,) -aminobutyrolactone

EDCI (191 mg, 1.0 mmol) was added to a solution of indole-2-carboxylic acid (161 mg, 1.0 mmol), Î ± -aminobutyrolactone hydrobromide (182 mg, 1.0 mmol) , HOBt (135 mg, 1.0 mmol) and TEA (279 μl, 2.0 mmol) in 15 mL of methylene chloride at room temperature. Additional EDCI (120 mg) and TEA (56 μΐ) were added one day later. After 5 days, the volatiles were evaporated and the residue, EtOAc, was extracted with 1M H 3 PO 4, 0.1 M Na 2 CO 4

71 210

Case 4714.60. The solution was dried over Na2 SO4, filtered and concentrated in vacuo. The product was crystallized from EtOAc to give 147 mg, 0.6 mmol, 60%. Rf = 0.17 (1: 1 hexanes / EtOAc). m.p. = 235-62C. MS (CI) m / e 245 (m + H) +, 144. 1 H NMR (CDCl3 - CD3 OD, 300MHz) Î'1.86-2.51 (m, TH), 2.19-2.79 (dt, J = 2.11 Hz, 1H), 4.82 (dd, J = 8.11Hz, 1H), 4.62 (m, 1H) , 7.18 (d, J = 1.8 Hz, 1H), 7.4 (s, 0.5H), 7.46 (d, J = 8 Hz, 1H), 7.66 (d, J = 8 Hz, 1H).

The product of example 90 (25 mg, 0.1 mmol) and diphenylamine (50 μl, 0.25 mmol) were dried over magnesium sulfate and evaporated to dryness. dissolved in 2 ml of THF and heated to 50Â ° C. After a few hours, more dipentylamine (250 μΊ) was added. Four days later, the volatiles were evaporated and the residue was chromatographed on silica eluting with hexanes / EtOAc (2: 1). Yield: 26 mg, 0.06 mmol, 60%. mp. 128 - 139 ° C. MS (CI) m / e 402 (m + H) +, 158.1H NMR (CDCl3, 300MHz) δ0.92 (t, J = 6 Hz, 6H), 1.26-1.40 (M, 3H), 1.98-2.11 (m, 1H), 2.69 (t, J = 8 Hz, 1H), 3.06-3, (M, 1H), 3.60-3.77 (m, 3H), 5.12-5.20 (m, 1H) 1H), 7.31 (dt, J = 1.7Hz, 1H), 7.42 (dd, J = 1.8Hz, 1H) 1.8 Hz, 1H), 7.48 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 9.13 (s, 1H). C, H, N for the analysis calculated for C 23 H 35 N 3 O 3 ú2 H 2 O:: 67.28, H 8.84, N 10.24; Found: C 67.42, H 8.64, N 10.10.

Example ...... 92 M '" (3'-quinolinyl) carbonyl) (2, R, S) -aminobutyrolactone

The quinoline-3-carboxylic acid (5.2 g, 30 mmol) was coupled to α-aminobutyrolactone (5.5 g, 30 mmol) analogously to example 90 to give 2.62 g, 10.2 mmol (34% yield). Another extraction of the aqueous layer with EtOAc gave another 820 mg, 3.2 mmol (10.7%). Rf 0.26 (18: 1 chloroform / ethanol). m.p. 160-63 ° C. MS (CI) m / e 257 (m + H) +. 1 H NMR (CDCl 3, 30Hz): δ 2.32-2.46 (m, 1H), 2.91-3.01 (m, 1H), 4.35-4.43 (m, 1H) (Dt, J = 2.10 Hz, 1H), 4.83-4.92 (m, 1H), 7.36 (d, J = 6 Hz, 1H),

71 210

Case 4714.ΡΘ.01 69

C, H, N analysis calculated for C14 H12 N2 O: C 65.61, H 4.72, N 10.93; Found: C 65.42, H 4.82, N 10.82.

Example 93 N- (3-Amino-1-carbonyl) -R, S-homoserine di-n-penti-1-amide The product of example 92 (500 mg, 2.0 mmol) was treated with dipentylamine (1.5 mL, 7.4 mmol) in 25 mL of toluene and refluxed. Two days later, more than 1 ml of dipentylamine e. continued heating. One week later, the volatiles were evaporated in vacuo and the excess amine was removed by Kugelrohr distillation. The residue was then chromatographed on silica gel eluted with a gradient gradient from chloroform to 4% ethanol in chloroform to give An oil, 611 mg, 1.48 mmol (74%) was added. MS (CI) m / e 414 (m + H) +. 1 H NMR (CDCl 3, 300

The product of example 92 (200 mg, 0.8 mmol) and the product of Example 92 (200 mg, 0.8 mmol) were refluxed for 2 hours. n-pentylamine (232 μL, 2.0 mmol) were dissolved in 20 mL THF / acetonitrile (1: 1) and stirred at room temperature until all of the starting material was consumed (tlc: 18: 1 chloroform / ethanol).

The volatiles were evaporated in vacuo. The residue was mixed with hexanes and the product separated by filtration, yielding 273 mg,

0.79 mmol (99%). m.p. * 181 ° C. MS (CI) m / e 344 (m + H) +. 1H

J

71 210

J = 3 Hz, 1H), 7.64 (dt, J = 1.5 Hz, 1H), 7.83 (dt, J = .1.6 Hz, 1H (D, J = 6 Hz, 1H), 8.10 (d, J = 6 Hz, 1 H), 8.15 (d, J = 7 Hz, 2 Hz, 1H), 9.37 (d, J = 1 Hz, 1H). C, H, N analysis calculated for C 252: 83, 0.25 CHCl 3: C 61.13, H 6.82, N 11.26; Found: C 60.82, H 6.88, N 11.16.

Example 95 N-t-butyloxycarbonyl-R-methionine-di-n-pentylamide

To a cooled (4 ° C) solution of Nt-butyloxycarbonyl-R-Methionine (5.0 g, 20 mmol), dipentylamine (8.0 mL, 40 mmol) was added B0PC1 (5.1 g, 20 mmol) in 60 ml of dry THF was added and the stirred reaction mixture allowed to reach room temperature overnight. The volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and extracted successively with 1M H3PQ4 (3x), 1N Na2 -CO3 (3x), brine (3x); then dried over MgSO4, filtered and concentrated in vacuo to give an oil: 4.6 g, 11.7 mmol (59%). Rf = 0.81 (1: 1 hexanes / EtOAc).

[< z] D * + -27.5 " (c = 2.7, IleOH). MS (CI) m / e 389 (m + H) +, 333, 311, 258, 219, 202, 158, 1 H NMR (C 13 C 13.300 MHz) δ 0.86-0.93 (m, 6H), 1. , 21-31.7 (m, 9 H), 1.42 (s, 9H), 1.43-1.66 (m, 3H), 1.76-1.66 (m, 2H), J = 7Hz, 2H), 3.06-3.15 (m, 1H), 3.19-3.29 (m, 1H), 3.12 (s, 3H) (M, 1H), 4.68-4.75 (m, 1H), 5.37 (d, J = 9 Hz, 1H) ).

Example 96 1 N - (3-quinolylcarbonyl) - (O-methyl) -N, S-homoserine-di-n-pentamide The product of example 93 was methylated analogously to example 34 to give the title compound. after purification by chromatography.

Example 97

The product of example 93 was benzylated in the same manner as in Example 34, using the title compound as a white solid (0.8 g). benzyl bromide as the

71 210

The title compound was obtained after purification by flash chromatography.

The product of example 95 (4 g, 10.3 mmol) was dissolved in 30 ml of methanol, dried over sodium sulfate and evaporated to dryness. of trifluoroacetic acid precooled to 4 ° C. Two hours later, the excess reagent was evaporated and the residue was placed under high vacuum overnight. [α] d] + = 5,1S (c = 1.4, MeOH). MS (CI) m / e 289 (m + H) +. 1 H NMR (DMSOd 6, 300 MHz) δ 0.88 (app q, J = 8 Hz, 6H), 1.18-1.35 (m, 8H), 1.42-1.58 (m, 4H) (Br m, 2H), 2.08 (s, 3H), 2.43-2.67 (m, 2H), 3.00-3.09 (m, 1H), 3.13 -3.23 (m, 1H), 3.28-3.38 (m, 1H), 3.48-3.57 (m, 1H), 4.2-4.28 (m, 1H), 8.17 (s, 3H).

Example 99 N- (3-guanylcarbonyl) -R-methionine di-n-pentylamide Quinoline-3-carboxylic acid (0.43 g, 2.5 mmol), the product of example 98 (1.0 g , 2.5 mmol) and TEA (697 μl, 5 mmol) were dissolved in 15 ml of methylene chloride cooled to 42 ° C and EDCI (0.48 mg, 2.5 mmol) was added. The reaction mixture stirred solution was allowed to reach room temperature overnight. The volatiles were evaporated and the residue was extracted into EtOAc with 0.1 M citric acid, 0.1 M NaCl, and with water; then dried over MgSOâ, ", filtered and concentrated in vacuo. Chromatography on silica gel eluted residue with a step gradient from chloroform to 0.5% ethanol in chloroform afforded an oil, 572 mg, 1.29 mmol (52%), Rf = 0 , 19 (1: 1 hexanes / ethyl acetate), Kajq = + 8.0.0 (¢ = 0.85, MeOH), MS (CI) m / e 444 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ0.91 (t, J = 7 Hz, 3H), 0.93 (t, J = 7 Hz, 3H), 1.23-1.42 (m, 8H), 1.52 - 1.62 (m, 2H), 1.63-1.75 (m, 2H), 2.02-2.17 (m, 5H), 2.56-2.72 (m, 2H), 3. , Δ (t, J = 8Hz, 0.5H), 3.14 (t, J = 8Hz, 0.5H), 3.25-3.35 (m, 1H), 3.46-3.55 m, 1H), 3.59 (t, J = 8Hz, 0.5H), 3.63 (t, J = 8Hz, 0.5H), 5.28-5.36 (m, 1H (Dt, J = 1.8Hz, 1H), 7.55 (dt, J = 8Hz, 1H), 7.12 (dt, 88 (dd, J = 1.8 Hz, 1H), 8.15 (d, J = 8 Hz, 1H),

J

71 210

 € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ " C, H, N analysis calculated for C 25 H 37 N 3 O 2 S · 0.5 H 2 O: C 66.33, H 8.46, -N 9.28; Found: C 66.33, H 8.19, N 9.25.

The product of example 99 (100 mg, 0.23 mmol) was dissolved in 5 ml of THF and added to the temperature (0.25 g, 0.6 mmol) in dichloromethane The solvent was evaporated in vacuo to give the title compound as a white solid (0.25 g, 0.8 mmol) in dichloromethane The residue was purified by chromatography on silica gel eluting with methylene chloride / ethanol to give the title compound as a white solid (0.25 g). MS (CI) m / e 460 (m + H) +, 396. 1 H NMR (CDCl 3, 300 MHz) δ 0.9 (m / z), 1.26-1.40 (m, 10H), 1.52-1.73 (m, 3H), 2.14-2.26 (m, 1H), 2.39-2.52 (m, 1H), 2.71-3.22 (m, 3H), 3.08-3.18 (m, 1H), 3.23-3.35 (m, 1H), 3.38-3.52 (m, 1H), 3.58-3.68 (m, 1H), 5.20-5.34 (m, 1 Η), 7.62 (dt, J = 7 Hz, 1 Η), 7.83 (tt, J = 1.8 Hz, 1 Η), 7.92 (d, J = 8Hz 1H), 8.17 (d, J = 8 Hz, 1 H), 8.62 (dd, J = 2.5, 1H), 9.35 (dd, J = 2.3 Hz, 1H). C, H, N analysis calculated for C25 H37 N3 O3 S: Et0 Ac: C 65.13, H 8.13, N 8.97; obtained; C 65.31, H 8.30, N 8.73.

Example 101 M-t-butyloxycarbonyl-R-proline-dimethyl-amide

To a cooled (4-C) solution of Nt-butyloxycarbonyl-R-Proline (1.0 g, 4.64 mmol), dipentyl amine (2.18 g, 4.64 mmol) , 5 mT, 12.5 mmol) in 50 mL of dry THF. The cooling bath was removed and the stirred reaction mixture was allowed to gradually warm to ambient temperature. After 5 hours, the volatiles were evaporated in vacuo. The residue was dissolved in EtOAc and extracted in succession with 1M H 3 PO 4 (3x), Na 2 SO 4 (3x), brine (3x), then dried over MgSO 4, filtered and concentrated, dried over magnesium sulfate in vacuo to give an oil, 880 mg,

J 71 210 Case 4714.ΡΘ.01 73-

2.48 mmol (54%). Rf = 0.28 (2: 1 hexanes / EtOAc). [Î ±] D = + 28.7Â ° (c * 1.0, MeOH), MS (CI) m / e 355 (m + H) +, 299.255. 1 H

The product of Example 11 (800 mg, 2.3 mmol) was mixed with HCl / dioxane (12.5 mL, 50 mmol, precooled at 4Â ° C) in toluene. atmosphere at room temperature. One hour later, the volatiles were evaporated in vacuo, the residue was mixed with toluene and concentrated (2x) and placed under high vacuum overnight. The residue was used directly.

Example 103 N- (2-indolylcarbonyl) -R-proline-di-n-pentylamide

EDCI (440 mg, 2.3 mmol) was added to a cooled (4C) solution of indole-2-carboxylic acid (371 mg, 2.3 mmol), the product of example 102 (2.3 mmol supposed), (311 mg, 2.3 mmol) and TEA (321 μl, 2.3 mmol) in 10 mL of methylene chloride. The stirred solution was allowed to warm to room temperature overnight. The volatiles were evaporated, the residue was dissolved in EtOAc and extracted with 1M Hâ,,O (3x), 1M Na2 CO3 (3x) and brine (3x); then dried over MgSO 4, filtered and concentrated to an orange oil, the crude product was purified by flash chromatography eluting with hexanes / EtOAc (2: 1) to give 0.92 g, 2.4 mmol (92%) of slightly yellowish v-tail product. Rf = 0.22 (2: 1 hexanes / EtOAc). The product was dissolved in hot hexanes / EtOAc and then cooled slowly to ~ 20 ° C. An oil was removed which after 24 hours solidified. The solution was decanted and the solid product was collected using hexane to give 769 mg

-74-

J 71 210

(M, 3H), 1.80-1.43 (m, 8H), 1.50-1.75 (m, 3H), 1.80 (M, 3H), 2.32-2.45 (m, 1H), 3.16-3.37 (m, 2H). (M, 2H), 4.0-4.08 (m, 1H), 4.12-4.2 (m, 1H), 5.02 (dd, J = 4.8Hz, 1H), 6.96 (br s, 1H), 7.12 (dt, J = 1, SHz, 1 H), 7.28 (dt, J = 7 Hz, 1H), 7.48 (dd, (D, J = 8 Hz, 1H), 9.30 (s, 1H) C, H, N of the analysis calculated for C 24 H 35 N 3 O 2: C 72, 50, H 8.87, N 10.57; Found: C 72.55, H 8.91, N 10.49.

Example 104 2- (3'-Cholylcarbonylamino) -2-methylpropionate, methyl quinoline-3-carboxylic acid (1.12 g, 6.5 mmol) (1.0 g, 6.5 mmol) and TEA (1.8 mL, 1.3 mmol) were dissolved in 50 mL of methylene chloride and treated with EDCI (1: 2 g, 6.5 mmol) over night. The solvent was evaporated and the residue was extracted as in Example 71 to give a white solid, 660 mg, 2.58 mmol (40%). m.p. = 138-140 ° C. MS (CI) m / e 273 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 1.75 (s, 6H), 3.82 (s, 3H), 7.06 (s, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.81 (dt, J = 1.7Hz, 1H), 7.91 (dd, J 1.8, z, 1H), 8.15 (d, J = 8Hz, 1H), 8.58 , J = 2 Hz, 1 Η), 9.28 (d, J = 2 Hz, 1H).

The product from Example 104 (620 mg, 2.42 mmol) was dissolved in 50 mL of methanol and treated with 1 N NaOH (2.5 mL, 2.5 mmole) mmol). After 1 day, an additional 2.5 ml was added. After 2 days the solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate. The aqueous phase was then acidified and extracted with ethyl acetate. This second layer of EtOAc was dried over MgSO4, filtered and evaporated to give 406 mg, 1.67 mmol (69%) Rf = 0.3 (80:20: 1 CHCl3 / CH3 OH / NH4 OH)

The product of example 105 (100 mg, 0.413 mmol), dipentylamine (202 μl, 1.0 mmol) and TEA (59 μl, 0%) , 42 mmol) were dissolved in

J 71 210

15 ml of methylene chloride, treated with EDCI (80 mg, 0.42 mmol) and stirred overnight at room temperature. The solvent was evaporated, the residue was dissolved in ethyl acetate and extracted as in Example 71. NMR indicated the presence of undesirable dehydrated product (oxazolone). MS (CI) m / e 241 (m + H) +. 1 H NMR (D 3 O 3 300 MHz) δ 1.61 (s, 6H), 7.66 (dt, J = 1.7 Hz, 1H), 7.86 (dt, J = (Dd, J = 8Hz, 1H), 8.20 (d, J = 8Hz, 1H), 8.74 (d, J = 2Hz, 1H), 8.98 (d, J = 2Hz, 1H). The crude, dehydrated product was redissolved in 25 mL THE and treated with dipentylamine (202 μ, 1.0 mmol). Another 400 ml of diphenylamine was added to the 2S and 4-day. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluted with 4: 1 to 1: 1 (gradient in hexane) of hexane / ethyl acetate to give 51 mg, 0.13 mmol, ( 32%). m.p. = 134-5 ° C. NMR (CDCl3, 300 MHz) δ 0.92 (t, J = 7 Hz, 6H), 1.25-1.49 (m, 1H) (Dt, J = 1.7 Hz, 1H), 7.8 (dt, J = 1.7 Hz, 1H), 1.90 (s, 6H) 8.69 (s, 1H), 8.92 (d, J = 8 Hz, 1H) , 9.37 (d, J = 2 Hz, 1H). C, H, N for analysis calculated for C 24 H 35 N 3 O 2 • 0.25 H 2 O: C 71.69, H 8.90, N 10.45; Found: C 71.65, H 8.74, N 10.39. The product from example 62 (1.61 g, 2.64 mmol) was obtained as a white solid (0.25 g, 0.6 mmol) in dichloromethane. treated with 15 ml of HBr in HOAc (1.1 N, 16.5 mmol) for 2 h under inert atmosphere. The solvent was evaporated and the residue was purified by chromatography on silica gel eluted with a gradient from methylene chloride to 1% ethanol in CH 2 Cl 2 to give 1.25 g, 2.39 mmol (91%) as a yellow vitreous product. m.p. = 85-95Â ° C. 1 H NMR (DMSOd 6, 300 MHz) δ 0.85 (t, J = 7 Hz, 6H), 1.23-1.83 (m, 18H), 2.78 (t, J = 7 Hz, 2H) (M, 1H), 3.28-3.44 (m, 3H), 4 ', 85.4-4.3 (m, 1H), 7.57 (bs, 2H) (Dt, J = 1.7Hz, 1H), 8.10 (d, J = 8Hz, 2H), 8.92 (dt, J = J = 2 Hz, 1 Η), 9.02 (d, J = 8 Hz, 1H), 9.32 (d, J = 2 Hz, 1H). -76-

Case 4714.Ρθ.01

The product of example 107 (20 mg, 0.045 mmol) was treated with carbonyl demi-idazole (8.1 mg, 0.05 mmol) in 10 ml of dimethylsulfoxide ml methylene chloride at room temperature overnight. Thiophenol (10.3 μ, 0.10 mmol) and 10 ml of THF were added and the mixture was warmed to 60 ° C. After 1 day, the mixture was eluted on silica gel " with 1% ethanol in methylene chloride to give an oil. MS (CI) m / e 577 (m + H) +, 467, 420. 1 H NMR (DCD 13.300MHz) δ 0.88-0.96 (m, 6H), 1.23-1.86 (m, 18H), 3.12 (dt, J = 7.13 Hz, 1H), 3.22 - 3.44 (m, 4H), 3.59 (dt, J = 7.13 Hz, (M, 1H), 5.70 (t, J = 5 Hz, 1H), 7.32-7.37 (m, 3H), 7.47-7.51 (m, 3H ), 7.62 (dt, J = 1, 7Hz), 7.91 (dd, J = 1.8, 1H) , 16 (d, J = 8 Hz, 1 Η), 8.63 (d, J = 2 Hz, 1 Η), 9.37 (s, J = 2 Hz, 1H).

N-benzyloxycarbonyl-R-phenylglycine (1.0 g, 3.5 mmol), 2-propylpiperidine (1 mL, 6.64 mmol), HGBt (475 mg, 0.75 mmol), and N-benzylcarbonyldiimidazole The title compound was prepared according to the procedure described in Example 1, which was dissolved in 25 ml of 80% CaCl2 (80 mg, 3.5 mmol) and TEA (490 μl, 3.5 mmol) The solvent was evaporated and the crude product was purified by chromatography on silica gel eluting with 9: 1 to 4: 1 hexane / acetic acid (490 μl) and BOCl (890 mg) (step gradient 1 to give 179 mg, 0.454 mmol, (13%) mp = 100-115Â ° C. [Î ±] 13.5S (c = 1.0, MeOH ) MS (CI) m / e 395 (m + H) +, 261 1 H NMR (CDCl3, 300 MHz) δ 0.52 (t, J = 7 Hz, 1H), 0.92 (t, J = 7 Hz, 2H), 1.18-1.70 (m, 10H), 2.56-2.67 (m, 0.33H), 3.01 (dd, J = 2.13Hz, 0.67H) (D br, J = 12Hz, 0.67H), 3.80 (br s, 0.33H), 4.51 (brd, J = 13Hz, 0.33H), 4.78 (bs, (D, J = 11 Hz, 1H), 5.12 (d, J = 11 Hz, 1 Η), 5.54 (d, J = 7 Hz, 58 (d, J = 7 Hz, 0.33H), 6.4 6.56 (m, 1 H), 7.28-7.43 (m, 1 OH).

Example 110 1R-phenylglycine- (2-propylpiperidinediamide 71 210

The product of example 109 (150 mg, 0.38 mmol) was treated with 25 mg of 10¾ Pd / C in 5 ml of methanol under a hydrogen atmosphere for 24 h. The catalyst was filtered off and the filtrate evaporated to give the product.

EXAMPLE 111 N- (3-chloro-1H-imidazol-1-yl) -carbamic acid tert-butyl ester 3-carboxylic acid (38.1 mg, 0.22 mmol), the product of example 110 (31 mg, 0.22 mmol) and TEA (31 μ, 0.22 mmol) were dissolved in 4 mL of 1: 1 DMF And treated with EDCI (42.1 mg, 0.22 mmol) under stirring overnight at room temperature. The solvent was evaporated and the residue extracted as in Example 71. 0.4 (1: 1 hexanes /

et. MS (CI) m / e 416 (m + H) +, Î'1.154, 128. 1 H NMR (CDCl3, 300MHz) Î'0.55 (t, J = 1Hz, 1H), 0.94 (t, J = 7Hz, 2H), 1.23-1.2 (m, 1H), 2.71 (dt, J = 2.13Hz, 0.33H), 3.08 (dt, J = J = 13Hz, 0.67H), 3.93 (br s, 0.33H), 4.58 (d, broad, J = 13Hz, J = 13Hz, 0.67H), 3.68 , 6.73 (d, J = 7 Hz, 0.67H), 6.07 (d, J = 7 Hz, Q, 33H), 7.3 (Dt, J = 1.7 Hz, 1 H), 7.90 (d, J = 8 Hz, 1H) 8.28 (t, J = 6 Hz, 1 H), 8.59 (d, J = 2 Hz, 1 H), 8.18 (d, J = 8 Hz, 1H);

9.34 (d, J = 2 Hz, 1H). C, H, N analysis calculated for C 26 H 29 N 3 O 2 • 0.5 H 2 O: C 73.56, H 7.12, H 9.90; Found: C 73.60, H 7.10, N 9.61.

Example 112

(45 mg, 0.01 mole) of 4-methyl-4-hydroxy-2-carboxylic acid (45 mg, 22 mmol), the product of example 110 (52 mg, 0.20 mmol) and TEA (31 μ, 0.22 mmol) were dissolved in 4 ml of 1: 1 DMF / methylene chloride and treated with EDCI (42 ml). mg, 0.22 mmol) under stirring overnight. The mixture was then poured into ethyl acetate and extracted as in Example 71. The resulting residue was

J 71 210 Case 4714.PG.01

Chromatography on silica gel eluted with 1% to 9% (step gradient) of ethanol in methylene chloride. MS (CI)

Example ...... 113

N-benzyloxycarbonyl-N-benzyloxycarbonyl-R-phenylglycine (285 mg, 1.0 mmol), N-benzyloxycarbonyl-N-benzyl- - (benzylamino) propionyltrityl (391 μ, 2.5 mmol) and TEA (139 μl, 1.0 mmol) were dissolved in 10 ml CH 2 Cl 2; and treated with B0PC1 (256 mg, 1.0 mmol). After 1 day, another 139 μΐ TEA was added. After 2 days, more B0PC1 (256 mg), amine (391 μl) and DMF (5 ml) were added. After 3 days, the solvents were evaporated and the residue was extracted as in Example 71. The crude residue was recrystallized from hexanes / ethyl acetate to give 314 mg, 0.74 mmol (74%). Rf = 0.75 (1: 1 hexanes / ethyl acetate). m.p. = 114-150 ° C. [Î ±] D = -9.4Â ° (c = 0.67, 1: 1 DMF-MeOH). MS (CI) m / e 428 (m + H) +, 445, 384, 375. 1 H NMR (CDCl3, 3.30), 2.45-2.66 (m, 2H), 3. (M, 0.5H), 3.66-3.75 (m, 1H), 4.38 (d, J = 16, z, 1H), 4.43-4.5 (m, 0.5H), 4.63 (d, J = 16Hz, 1H),

The product of example 113 (225 mg, 0.53 mmol) was dissolved in 25 ml of ethanol and treated with 100 mg of 10% Pd / C at room temperature. After 1.5 h, the catalyst was filtered and the

J 71 210

The title compound was obtained, yielding 158 mg, 0.54 mmol (quantitative). MS (CI) m / e 294 (m + H) +, 241.

Example 115 N- (3'-quinolylcarbonyl) -R-phenylglycine- (N-benzyl, N-2'-cyanoethyl) amide quinoline-3-carboxylic acid (35 mg, 0.20 mmol) and the product of Example 114 (53 mg, 0.18 mmol) were dissolved in 10 mL of methylene chloride and treated with EDCI (38 mg, 0.20 mmol). After 1 day the solvent was evaporated and the residue was extracted as in Example 71 to give 54 mg, 0.12 mmol (67%). [Α] ρ = -0.42% (e = 2 , 6, CHCl3), p, f. 57-63Â ° C, MS (CI) m / e 449 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ1.90-2.02 (m, 0.25H), 2.27-2.38 (m, 0.25H), 2.49-2.72 (m, 5H), 3.42 (dt, J = 7.13Hz, 1H), 3.81 (dt, J7.73Hz, 1H), 4.46 (d, J = (d, J = 18Hz, 1H), 6.11 (d, J = 6Hz, 0.25H), 6.16 (d, J = 7Hz, 0.75H), 6.98-7.72 (m, 2H), 7.19-7.22 (m, 0.5H), 7.30-7.33 (m, 2.5H), 7.38-7.46 (m, 3H), 7.53 7.64 (m, 3H), 7.82 (dt, J = 1.7, 1H), 7.85-7.94 (m, 2H), 8.15 (d, 1 H, J = 8 Hz) ), 8.61 (d, J = 1 Hz, 1 Η), 9.33 (d, J = 1 Hz, 1H), C, H, N of the analysis calculated for C28 H24 N4 O2 0.7 H 2 O: C 72.93, H 5.55, W 12.15; Found: C 72.86, H 5.58, N 11.77,

Example 116 N - (4 ', 8'-Dihydroxy-2-quinolylcarbonyl) -R-phenylglycine- (N-benzyl, N-2-cyanoethyl) amide 4,8-Dihydroxyquinoline-2-carboxylic acid (41 mg, 0.20 mmol), the product of example 114 (53 mg, 0.18 mmol) and TEA (28 μ, Ι, 0.20 mmol) were dissolved in 5 ml EDCI-treated DMF (38 ml). mg, 0.20 mmol). After 2 h and one day more TEA (28 μ) and EDCI (38 mg) were added. After 2 days, HOBt (27 mg, 0.20 mmol) was added to the reaction mixture. After 3 days the solvent was evaporated and the residue was extracted with 0.1 M citric acid and water, the organic solution was dried over MgSOâ, ", then filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 1: 1 hexanes / ethyl acetate to give 22.6 mg, 0.05 mmol (26%). m.p. = 218-222 ° C. [Î ±] D = -80-

-71- J 71 210

Case 4714.PG.01

-4.8fi (¢ = 0.42, MeOH). MS (CI) -m / e 481 (m + H) +, 428. 1 H NMR (CD 3 OD, 300 MHz) δ 2.47-2.58 (m, 0.33H), 2.6-2.82 (m, 2H), 3.33-3.62 (m, 2.33H) , 3.68-3.78 (m, 0.33H), 3.82-3.91 (m, 1 Η), 4.53 (d, J = 16Hz, 1H), 4.62 (d, J = = 14Hz, 0.33H), 4.76 (d, J = 16Hz, 1H), 4.87 (s, H2O), 4.92 (d, J = 5Hz, 0.33H), 6.18 (s, 1H), 7.10 (dd, J = 1.7 Hz, 1H), 7.2-7.35 (m, 7H), 7.39-7.46 (m, 3H), 7.51 - 7.60 (m, 2H), 7.67 (dd, J = 1.8 Hz, 1H).

The product of example 80 (1.5 g, 3.0 mmol) was treated with 1,4 N HCl in dloxane (11 mL) , 15 mmol) over 10 minutes. The excess reagent was evaporated and the oily residue was triturated with diethyl ether and filtered to give 1.3 g, 2.6 mmol (87%) of a pale yellow, solid product. . 1 H NMR (DMSOd 6, 300 MHz) δ 0.84 (t, J = 7 Hz, 6H), 1.15-1.62 (m, 12H ), 2.87-3.22 (m, 3H), 3.29-3.40 (m, 3H), 5.02 (app q, J = 7 Hz, 1 Η), 6.66 (d, J (Dt, J = 1.8 Hz, 1H), 7.96 (dt, J = 1.8 Hz, 1H), 7.11 (d, J = 8 Hz, 2H), 7.78 8.17 (t, J = 7 Hz, 2H),

9.04 (d, J = 2 Hz, 1H), 9.22 (d, J = 8 Hz, 1H), 9.33 (d, J = 2 Hz, 1H). C, H, N for the analysis calculated for C 29 H 37 N 3 O 11 1.3 HCl: C 66.60, H 7.38, N 8.03; Found: C 66.43, H 7.38, N 7.99.

The product from example 50 (800 mg, 1 mmol) was dissolved in dichloromethane (50 ml). , 78 mmol) was dissolved in 13 ml of 1.4 M HCl in acetic acid for 10 min and the volatiles were then evaporated to remove excess reagent. The oily residue was dissolved in a small amount of CH 2 Cl 2 and the product precipitated with hexanes. The solid product, 824 mg, 1.58 mmol (89%) was collected. MS (CI) m / e 458 (m + H) + - 1 H NMR (DMSOd 6300MHz) δ 0.74 (t, J = 7 Hz, 3H), 0.85 (t, J = 7 Hz, 3H). 1.12-1.32 (m, 3H), 1.41-1.52 (m, 4H), 3.08-3.43 (m, 6H), 5.24-5.31 (m, 1H) (Dt, J = 1.7 Hz, 1H), 7.94 (dt, J = 1.7 Hz, 1H), 8.15 (dt, J = 9Hz, 2H), 9.02 (s, 2H), 9.31-

J 71 210

(M, 2H), 14.18 (s, 1H), 14.57 (s, 1H). C, H, N for the analysis calculated for C 26 H 35 N 5 O 2: 2.6 HCl: C 57.36, H 6.96, N 12.87; Found: C 57.30, H 6.96, N 12.86.

Example 119 Methyl (4,8-dihydroxy-2-guanylcarbonyl) -R- (4-hydroxyphenyl) -glycine-di-n-pentylamide The reaction was carried out analogously (0.2 g), EDCI (0.21 g) HOBt (0.13 g) was added dropwise to the solution of Example 8 using 0.3 g of the compound of Example 64, 4,8-dihydroxyquinoline- ) and NMM (0.22 ml). The product was isolated in 75% yield (0.37 g). NMR (DMSOd6, 300 MHz) δ 0.85 (m, 6H), 1.1-1.35 (m, 10H), 1.38-1.30 (D, J = 9 Hz, 1 H), 6.76 (d, J = 9 Hz, 2 H), 7.08 (d, J = 9Hz, 1H), 7.23 (d, J = 9Hz, 2H), 7.4 (t, J = 9Hz, 1H), 7.55 (m, 2H), 9.5 1H), 9.75 (d, J = 10 Hz, 1H). C, H, N calculated for Η 28Η35% ° 5 '0.5 H2 O: C 66.91, H 7.22, N 8.36; Found: C 66.76, H 7.20, N 8.18.

The compound was prepared analogously to Example 1 using N-t-butyloxycarbonyl-Glycine. Example 20 1-Benzyloxycarbonyl-glycinyl-di-n-pentylamide. 1 H NMR (CDCl 3, 300 MHz): δ 7.30-7.40 (m, 5H), 5.86 (bs, 1H), 5.12 (br s, 2H), 4.0 (brd, J = 4.5Hz, 2H), 3.32 (t, J = 7.5Hz, 2H), 3.15 J = 7.5 Hz, 2H), 1.50-1.70 (m, 4H), 1.20-1.40 (m, 8H), 0.9 (m, 6H),

Example 121 N- (2-indolylcarbonyl) -glycine-di-n-pentylamide The product of example 120 was deprotected in an analogous manner to example 80. The free amine was then coupled with indole-2-carboxylic acid as in example 4. mp (CDCl 3, 300 MHz) δ 9.27 (s, 1H), 7.67 (d, J = 6 Hz, 1H) J = 7 Hz, 2H), 7.29 (dt, J = 1.6 Hz, 1H), 7.14 (dt, J = 1.6 Hz, 1H), 6 2H), 3.89 (broad t, J = 7 Hz, 2H), 3.25 (broad t, J = 7 Hz, 2H), 1.98 (s, 1H), 4.27 (d, J = , 55-170 (m, 4H), 1,25-

J

71 210

(1H, m), 0.93 (t, J = 6 Hz, 3H), 0.91 (t, J = 6 Hz, 3H). Analysis calculated for C21 H31 N3 O2 S 0.3H2 O: 69 > 51 > H 8.78, N 11.58; Found: C 69.45, H 8.58, N 11.47 *

N-t-butyloxycarbonylglycine and ethyl N-benzylglycinate were ligated in a similar manner to that of Example 1 yielding the title product.

Example 123 N- (3-quinolylcarbonyl) glycine 1 (N-benzyl) glycinate of ethyl

The product of example 122 was deprotected in an analogous manner to example 2 and then attached in a manner analogous to that of the example. NMR: (CDCl3, 300 MHz) δ 9.37 (d, J = 2 Hz, 0.33) 1 H), 9.35 (d, J = 2 Hz, Q 67), 8.65 (broad, 1H), 8.18 (broad d, J = (M, 1H), 7.43-7.55 (m, 1H), 7.30-7.40 (m, 3H), 7.25 (m, 2H) (D, J = 4Hz, 1.33H), 4.33 (d, J = 4Hz, J = 4Hz), 4.37 (s, 0.67H), 4.67 (s, (M, 2H), 4.13 (s, 1.33H), 4.00 (s, 0.67H), 1.28 (m, 3H).

Example 124 N-t-butyloxycarbonyl) -R-homophenylalanine-di-n-pentylamide The product was prepared analogously to example 1 using t-butyloxycarbonyl-R-homophenyl alanine. MS (CI) m / e 419 (m + H) +, 363, 345, 319. 1 H NMR (CDCl3,300MHz) δ 7.85 (m, 1H), 7.48 (m, 1H), 7.18 J = 9Hz, 1H), 4.56 (m, 1H), 3.48 (dt, J = 7.14Hz, 1H) (M, 2H), 1.68 (m, 2H), 1.45 (s, 9H), 1.38 (m, 2H) 20-1.35 (m, 8H), 1.13 (m, 2H), 0.88 (m, 6H).

Example 125 N- (3-quinolinecarbonyl) -R-homophenylalanine di-n-pentamide The product was prepared analogously to example 2 and 3 using the product of example 124 as the starting reagent, MS (CI) m / e 474 (m + H) +, 369, 319, 305, 289. 1 H NMR (CDCl 3, 300 MHz) δ

J

71 210

(D, J = 8 Hz, 1H), 8.53 (d, J = 2 Hz, 1H), 8.16 (dd, J = 1.8Hz, 1H), 7.82 (m, 1H), 7.62 (m, 1H), 7.40 (broad d, J = 8Hz, 1H), 7.30 (m, 4H), 7.20 (m, 1H), 5.19 (m, 1B), 3.55-3.70 (m, 1H), 3.05-3.20 (m, 3H). 2H), 2.15 (m, 2H), 1.50-1.65 (m, 4H), 1.15-1.35 (m, 8H) , 0.90 (m, 6H).

Example 126 N- (3-amino-11-chlorobenzyl) -quinoline; Carboxylic acid methyl ester hydrochloride and methyl bromide hydrochloride were ligated in a similar manner to Example 3, the resulting product was subjected to metal saponification with NaOH. The desired product was extracted with EtOAc from the acidified solution or , alternatively, allowed to precipitate slowly from the acidified solution. NMR (DMSOd6, 300 MHz) δ 12.72 (broad s, 1H), 9.32 (d, J = 4 Hz, 1 Η), 9.41 (m, J = 7Hz, 1H), 8.87 (d, J = 3Hz, 1H), 8.12 (t, J = , 7.71 (t, J = 7 Hz, 1H), 4.03 (bs, 2H).

The product of example 126 and d1-n-pentylamine were ligated in a similar manner to that of example 1. The product was isolated by chromatography and solidified upon concentration. m.p. = 36-37 ° C. MS (CI) m / e 370 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 9.38 (d, J = 2 Hz, 1H). 8.65 (d, J = 1.8Hz, 1H), 8.18 (d, J = 8.5Hz, 1H), 7.93 (dd, 1H), 7.64 (m, 2H), 4.32 (d, J = 3.7Hz, 2H), 3.41 (bt, J = 8Hz, 2H), 3.27 (broad t, 8Hz, 2H), 1.62 (m, 4H), 1.30-1.45 (m, 8H), 0.95 (t, J = 7 Hz, 3H), 0.92 (t, J = 7 Hz, 3H). C, H, N analysis calculated for C39 H31 N3 O2: C 71.49, H 8.46, N 11.37; Found: C 71.28, H 8.42, N 11.36.

EXAMPLE 128 The acid of Example 126 and 4-propylpyridine were ligated as in Example 1. mp 126 DEG-149 DEG C. EXAMPLE 12 N- (3-Amino-4-methoxyphenyl) * 116-117%. MS (CI) m / e 340 (m + H) +, 279, 254, 201.1H NMR (CDCl3, 300 MHz) δ 9.36 (d, J = 2 Hz, 1 Η),

J 71 210

8.63 (d, J = 2 Hz, 1 Η), 8.16 (d, J = 8.5 Hz, 1H), 7.93 (dd, J = 7.63 (m, 1H), 4.61 (dt, J = 213 Hz, 1H), 4.31 (m, 1H) 2H), 3.79 (brd, J = 10Hz, 1H), 3.07 (dt, J = 313Hz, 1H), 2.70 (dt, J = m, 2H), 1.55 (m, 1H), 1.05-1.40 (m, 6H), 0.92 (t, J = 7 Hz, 3H). C, H, N analysis calculated for C 20 H 25 N 3 O 2 • 1 • 1 h 2 O: C 70.40 > H 7.44, N 12.31; Found: C 70.19, H 7.44, N 12.15.

The product was obtained by the coupling of N-benzyloxycarbonyl-R-phenylglycine and N-benzyloxycarbonyl-R-phenylglycine and N -benzyloxycarbonyl-R-phenylglycine. di-n-pentylamine as in example 1. MS (CI) m / e 426 (M + +) +, 333.31, 29.1 1H NMR (CDCl3, 300 MHz) (D, J = 7.5 Hz, 1H), 5.12 (d, J = 7.5 Hz, 1H) J = 12Hz, 1H), 3.48 (m, 1H), 3.18 (m, 2H), 2.97 (m, 1H), 1.25 (M, 8H), 0.87 (t, J = 7.5Hz, 3H), 0.84 (t, J = 7.5Hz, 3H) .

The product resulted from the hydrogenolysis of the product of example 129. MS (Cl) m / e 291 (m + H) +, 158. 1 H NMR (CDCl 3 300MHz) δ 7.25 1H), 3.52 (m, 1H), 3.08-3.22 (m, 2H), 2.92 (m, 1H), 2.02 (br s, 2H), 1.50 (m, 3H), 1.10-1.35 (m, 9H), 0.88 (t, J = 7Hz, 3H), , 85 (t, J = 7 Hz, 3H).

Example 139 N- (3-quinolylcarbonyl) -R-phenylglycine-di-n-pentylamide The product of example 130 was coupled in a similar manner to example 3 to give the title product. MS (CI) m / e 446 (m + H) +. 1 H NMR (CDCl 3, 300) δ 9.33 (d, J = 2 Hz, 1H), 8.58 (d, J * 2Hz, 1H), 8.13 (broad t, J * 8Hz, 2H) (M, 1H), 7.62 (m, 1H), 7.55 (m, 2H), 7.32-7.42 (m, 3H (M, 9H), 0.90 (t, J = 7 Hz, 3H), 6.03 (d, J = 6 Hz, 1 H) , 0.86 (t, J = 7 Hz, 3H).

-85-

The product of example 130 was ligated analogously to example 8 to give the title compound. 1H NMR (DMSO-d6):? mp. 89-91 °. NMR (DMSOd 6300MHz) Î'9.91 (brd, J = 8 Hz, 1H), 7.55 (m, 2H), 7.52 (m, 1H). 7.35 (1H, d), 7.35 (1H, d, J = 7 Hz), 7.35-7.45 (m, 7H) (m, 4H), 1.60 (m, 1H), 1.48 (m, 2H), 1.13-1.35 (m, 9H), 0.85 (t, J = 7 Hz, 3H), G, 78 (t, J = 7 Hz, 3H). C, H, N analysis calculated for C 28 H 35 N 3 O 4, 0.3 H 2 O: C 69.63, H 7.43, N 8.70; Found: C 69.61, H 7.40, N 8.65.

Example 133 N- (3-chlorophenylaminocarbonyl) -R-phenylglycine-di-n-pentylamide The product of example 130 was reacted with 3-chlorophenylisocyanate to give the title compound. MS (CI) m / e 444 (m + H) +, 425, 317, 291, 259, 242. 1H NMR (CDCl3, 300MHz) δ 7.95 (bs, 1H), 7.42 (m, 1H 7.08 (m, 2H), 6.89 (m, 1H), 7.52 (m, 1H), 7.28-7.34 (m, 5H) (M, 1H), 3.00-3.30 (m, 4H), 1.43-1.63 (m, 3H), 1.10- 1.30 (m, 8H), 0.84 (t, J = 7 Hz, 3H), 0.78 (t, J = 7 Hz, 3H).

Example 134 N- (3-methylphenylaminocarbonyl) -R-phenylglycine-di-n-pentylamide The product of example 130 was reacted with 3-methylphenylisocyanate to give the title compound. MS (CI) m / e 424 (m + H) +, 374, 317, 291, 276, 239, 228. 1 H NMR (CDCl3, 300 MHz) δ 7.27-7.48 (m, 5H) (D, J = 8 Hz, 1H), 7.06 (d, J = 8 Hz, 1H) J = 8 Hz, 1H), 5.87 (d, J = 8 Hz, 1 Η), 3.51 (m, 1H), 3.20 (m, 2H), 3.04 (m, (M, 8H), 0.84 (t, J = 7 Hz, 3H), 0.82 (t, 3H) J = 7 Hz, 3H).

Example 135 N- (5-chloroindolylcarbonyl) -R-phenylglycyan-di-n-pentamine The product of example 130 was reacted with 5-fluoroindole-2-carboxylic acid in analogy as in Example 4 to give the desired product. mp = 94-6 ° C. MS (CI) m / e 452 (m + H) +, 276, 267, 184. 86 71 210

1 H NMR (CDCl 3, 300 MHz) δ 9.36 (broad s, 1H), 7.96 (d, J = 7 Hz, 1H), 7.50 (m, 2H), 7.30 7.40 (m, 3H), 7.36 (s, 1H), 7.33 (m, 1H), 6.98 (dt, J = 2.59Hz, 1H), 6.91 (m, 1H ), 5.94 (d, J = 7 Hz, 1H), 3.53 (m, 1H), 3.13, 3.30 (m, 2H), 3.04 (m, 1H), 1.45 1.65 (m, 4H), 1.10-1.40 (m, 8H), 0.89 (t, J = 7 Hz, 3H), 0.85 (t, J = 7 Hz, 3H). C, H, N analysis calculated for C 27 H 34 FN 3 O 2: C 71.81, H 7.59, N 9.31; Found: C 71.53, H 7.50, N 9.30.

Example 136

The product of Example 130 was reacted with 5-chloroindole-2-carboxylic acid in a manner analogous to that of example 4, the title compound is obtained. MS (CI) m / e 468 (m + H) +, 434, 302, 276, 212, 1 H NMR (CDCl3, 300MHz) Î'9.36 (broad s, 1H), 7.97 (d, J = 7 Hz 1H), 7.59 (m, 1H), 7.50 (m, 2H), 7.35 (m, 3H), 7.22 (m, 2H), 6.89 (m, (D, J = 7 Hz, 1 Η), 3.53 (m, 1H), 3.15-3.30 (m, 2H), 3.44 (m, 1H) 60 (m, 4H), 1.10-1.40 (m, 8H), 0.89 (t, J = 7 Hz, 3H), 0.85 (t, J = 7 Hz, 3H). C, H, N for the analysis calculated for C27 H34 N3 O2: C 69.29, H 7.32, N 8.98; Found: C 69.44, H 7.36, N 8.95.

Example 137 N- (2-methoxyphenyl) -R-phenylalanine methyl ester The product from example 130 was coupled in an analogous manner to example 5, yielding the desired compound. m.p. 116-117 ° C. MS (CI) m / e 446 (m + H) +, 289, 277, 261, 246. 1 H NMR (CDCl 3, 300 MHz) δ 9.62 (d, J = 8 Hz, 1H), 8.24 J = 8Hz, 1H), 7.83 (d, J = 8Hz, 1H), 7.74 (m, 1H), 7.59 (m, 3H), 7 (M, 1H), 3.0-3.0 (m, 1H), 3.65 (m, 1H) 2H), 1.50-1.65 (m, 4H), 1.15-1.40 (m, 8H), 0.89 (t, J = 7 Hz, 3H), 0.87 (m, t, J = 7 Hz, 3H). C, H, N for the analysis calculated for C28 H28 N3 O5: C, 75.47; H, 7.92; N, 9.43; Found: C 75.45, H 7.91, N 9.43.

Example 138 1 N - [(t-butyloxycarbonyl) -1-amino-cyclohexane- (di-n-pentyl) carboxamide The product was prepared as in example 1 from

71 210

Case 4714.Ρθ.01 "87 " dl-n-pentyllamine e. of N-t-butyloxycarbonyl-1-amino-1-cyclohexanecarboxylic acid. MS (CI) m / e 383 (M +) 11. â € ƒâ € ƒâ € ƒ1 H NMR (CDCl3,300MHz) Î'4.70 (br s, 1H), 3.20-3.50 (m, 4H), 1.85-2.0 (m, 4H), 1.45 (M, 8H), 1.42 (br s, 9H), 1.20-1.40 (m, 10H), 0.92 (t, broad, J = 7 Hz, 6H).

Example ... 130 N '- (3'-guinole Ucarbonyl-1-amine Î ± -cyclohexanecarboxamide The expected product was prepared by deprotecting the desired product. The product of Example 138 (analogously to example 2) and by attachment to quinoline-1-carboxylic acid as Example 3, mp 136-137%.

EXAMPLE 140 N '- (t-Butoxycarbonyl) -1-amino-cyclohexane-N-pentyl) carboxamide The product was prepared by coupling N-1-butyloxycarbonyl- 1-amlno-cyclohexane carboxylic acid and pentylamine as in example 1. MS (CI) m / e 313 (M + H) +, 257, 239, 213, 198. NMR (CDCl3, 300MHz) δ 6.70 (s, 1H), 4.52 (br s, 1H), 3.23 (m, 2H), 1.80-2.05 (m, 4H), 1.65 (m, 4H), 1.44 (s, 9H), 1.25-1.38 < m, 8H), Q 88 (t, J = 7 Hz, 3H).

Example 141

The product was obtained in an analogous manner to that of example 139, using the product of example 140 as a reagent Initial. MS (CI) m / e 368 (m + H) +. 1 H NMR (CDCl 3, 300 MHz) δ 9.38 (d, J = 2Bz, 1H), 3.58 (d, J = 2 Hz, 1H), 8.18 (d, J = 8 Hz, 1H) H), 7.94 (broad d, J = 8 Hz, 1H), 7.83 (m, 1H), 7.65 (m, 1H) 27 (br s, 1H), 3.38 (m, 2H), 2.34 (m, 2H), 2.03 (m, 2H), 1.65-1.80 (m, 4H), 1.50-1.60 (m, 4H), 1.25-1.40 (m, 4H), 0.88 (t, J = 7 Hz, 3H). C, H, N for analysis calculated for C22 H29 N3 O2: C 71.91, H 7.95, N 11.43; Found: C 71.73, H 7.95, N 11.33,

J 71 21 Ο

Case 4714., Ρβ. 01

Example 142

(4-hydroxy-2-hydroxy-1-carbonyl) glycine di-n-pent-1 arthritis

The product of example 120 was deprotected in a similar manner to that of example 80 and the resulting amine was then ligated analogously to example 8 to give the title compound. mp = 158.5-159.5 ° C. MS (FAB) m / e 402 (m + H) +, 386, 245, 217. 1 H NMR (DMSOd 6, 300 MHz) δ 9.90 (bs, 1H), 9.80 (bs, 1H), 7.55 (broad s, 1H), 7.42 (m, 1H), 7.11 (broad d, J = 8 Hz, 1H), 7.55 (t, broad, J = 8 Hz, 1H), 4.20 (broad d, J = 6 Hz, 2H), 3.36 (br s, H2 O), 3.20-3.33 (m, 4H), 1.58 (m, 2H), 1.48 m, 2H), 1.20-1.33 (m, 8H), 0.85 (m, 1H). C, H, N for analysis calculated for C22 H31 N3 O4 • H2 O: C 62.99, H 7.93, N 10.02; Found: C 63.12, H 8.02, N 10.01.

Example 143 N- (2apos; -naphthyl) glycine-di-n-pentylamide The product of example 120 was deprotected analogously to example 80 and the resulting amine was then ligated analogously to example 17 to give (m + H) +, 200, 184, 172. 1 H NMR (CDCl 3, 300 MHz) δ 8.38 (s, 1H), 7.85-7.95 (m, m, 4H), 7.50-7.60 (m, 3H), 4.30 (d, J = 4Hz, 2H), 3.40 (t, J = 7.5H 2.2H), (T, J = 7 Hz, 3H), 1.60 (m, 4H), 1.25-1.45 (m, 8H), 0.94 (t, J = , 0.92 (t, J = 7 Hz, 3H), CHN of the calculated calculated for C23 H22 N2 O4: 21.94, 4.96, H 8.75, N 7.68, found: C 74.44, The product from example 120 was deprotected in a manner analogous to that of example 80, and the product from Example 120 was deprotected in a manner analogous to that of Example 80 and the title compound as a white solid (0.25 g). the resulting amine was then attached to the 6-hydroxy-2-naphthoic acid in a manner analogous to that of example 17 to give the title compound. MS (CI) m / e 385 (m-1 H) +, 228 , 200, 184. NMR (DMSOd6, 300 MHz) δ 8.58 (broad 1, J = 6 Hz, 1H), 8.36 (br s, 1H), 7.86 (m, 2H) , 7.63 (d, J = 8 Hz, 1 Η), δ, 15 (m, 2H), 4.14 (d, J = 5 Hz, 2H), 3.20-3.3 δ (m, 4H), (M, 2H), 1.45 (m, 2H), 1.20-1.35 (m, 8H), 0.89 (t, J = 7 Hz, 3H), 0.6 (t, J = 7 Hz, 3H). C, H, N of the calculated analysis

J 71 210

For C 23 H 32 N 2 O 3: C 71.84, H 8.39, N 7.29; Found: C 71.73, H 8.36, N 7.21.

The product of example 120 was deprotected in a manner analogous to that in Example 1 (a) to give the title compound as a white solid.

of example 80 and the resulting amine was then attached to the 3-methylphenylisocyanate to give the title compound. m.p. = 66-7Â ° C. 1 H NMR (CDCl3,300MHz) δ 7.08-7.20 (m, 3H), 7.96 (m, 1H) 1H), 6.86 (d, broad, J = 7 Hz, 1H), 6.21 (bs, 1H), 4.13 (br., 2H), 3.32 J = 7.5 Hz, 2H), 2.3 (s, 3H), 1.45-1.65 (m, 4H), 1.20 (t, 1.40 (m, 8H), 0.92 (t, J = 7 Hz, 3H), 0.86 (t, J = 7 Hz, 3H). C, H, N analysis calculated for C20 H33 N3 O2: C, 69.13, H 9.57, N 12.09; obtained; C 68.99, H 9.56, N 12.04.

The reaction was run in a manner analogous to that of the above example using 0.35 g of the hydrochloride of the title compound as a white solid (0.8 g). 1 H NMR (CDCl3): δ Example 30, 2-

(0.16 g) and TEA (0.135 ml). The product was purified using chloroform / methanol as the solvent mixture. The oily product was isolated in 83% yield (0.42 g), [alpha] + 21.8 S (e = 0.11, MeOH). MS (CI) m / e 502 (m + H) +. (M, 6H), 1.23 (m, 11H >, 1.43-1.65 (m, 4H) > 3.0-3.21 (m, 2H), 3.55 (m, 2H), 3.33 (m, 1H), 4.57 (d, J = 15Hz, 1H), 4.63 (d, J = 15Hz, 1H), 4.98 6.95 (t, J = 7 Hz, 1 H), 7.2 (m, 2 H), 7.3 (m, 6 H), 6.48 (d, J = 9 Hz, 8.11 (d, J = 9 Hz, 1H), C, H, N of the analysis calculated for ¢ 28 ^ 40 ^^ 3 * 0.3 CHCl3: C 63.19, N 7.55, N 7.81; found: C 63.21, H 7.34, N 7.82.

Example 147 N- (4 ', 8'-dihydroxy-2-guineo) carbon 11) - (2R, 3S) - (Pr.benzyl) threonine di-n-pentylamide

The reaction was conducted in a manner analogous to that of Example 8 using 0.35 g of the hydrochloride of example 30, 4,8-dihydroxyquinalnanoic acid (0.21 g), EDCI ( 0.22 g), HOBt (0.14 g) and DIMM (0.22 g). The oily product was isolated in 60% yield (0.32 g). [a] D = +8.02 (c = 0.125, MeOH). MS (CI) m / e 536 (m + H) + 1 H NMR (OMSOd 6,300MHz) δ0.82 (m, 6H), 1.15-1.3 (m, 11H), 1.4-1 , 6 (m, 4H), 3.2-3.65 (m, 4H), 4.08 (m, 1H), 4.52 (d, J = 12Hz, 1H), 4.63 (br. (T, J = 9 Hz, 1 H), 7.12 (m, 5H), 7.42 (t, J = 9 Hz, 1H), 7.55 (m, , 2H), Î', 8 (d, J = 9 Hz, 1H), 10.4 (broad s, 1H), II, 72 (broad s, 2H). C, H, N analysis calculated for C 31 H 41 N 3 G 5, H 2 O: C 67.25, H 7.83, H 7.59; Found: C 67.19, H 7.60, N 7.38.

Example 148 Methyl 6α-R-methyne-β- (p-hydroxy) -phenylglycinate

Boc-R-Methionine (250 mg, 1 mmol), methyl β-hydroxylphenylglycinate hydrochloride (217 mg, 1 mmol) and triethylamine (139 μl, 1 mmol) were combined in 10 ml dichloromethane at 0 ° C and treated with B0PC1 (254 mg, 1 mmol). After 1 day, more B0PC1 (254 mg) and TEA (134 μΐ) were added. After 2 days, the reaction mixture was poured into EtOAc and extracted successively with 0.1% citric acid, 0.1 M NaHC04 and water. The solution was then dried over MgSO4, filtered and evaporated, yielding 288 mg, 0.7 mmol (70%). Rf = 0.56 (1: 1 hexanes / EtOAc). m.p. = 1582C (dec). 1 H-NMR (CDCl 3, 300 MHz) d 1.43 (s, 9H), 3.72 (s, 3H), 6.73 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.33 (bs, 1H).

The product of example 148 (250 mg, 0.6 mmol) was treated with 5 ml of 4N HCl in dioxane at room temperature under a nitrogen atmosphere. After 30 min the excess reagent was evaporated to give the product quantitatively.

J 71 210 Case 4714.ΡΘ.01

Example 150 Methyl-N- (S -quinolylcarbonyl) -R-methionine-S- (p-hydroxy) -phenylglycinate of example 149 (50 mg, 0.14 mmol), 3- (26 mg, 0.15 mmol) and TEA (21 μl, 0.15 mmol) were dissolved in 5 ml of methylene chloride and treated with EDCI (29 mg, 0.15 mmol) for 4 hours. H. The mixture was poured into EtOAc, extracted with 0.1% citric acid and water and then dried over MgSOâ, ". The resulting filtrate was concentrated and chromatographed over silica gel eluting with 2: 1 to 1: 2 hexane / EtOAc (gradient) to give 29 mg, 0.06 mmol (44%). MS (CI) m / e 468 (m + H) +, 393, 287. 1 H-NMR (CDCl3 .30Hz) δ

9.30 (d, J = 2 Hz, 1H). C, H, N of the analysis calculated for C 24 H 25 N 3 O 5 S 5 • 5

Example 15 (0.11 g, 0.145 mmol) was added to the product of Example 27 (71 mg, 0.145 mmol dissolved) in dichloromethane in 2 ml of methylene chloride, a further 1 ml of methylene chloride was added and the reaction was monitored by tlc After 20 min stirring at ambient temperature the starting reagent was consumed and the solvents were evaporated with methanol, The residue was purified by chromatography on silica gel using EtOAc / hexane (1: 1) as eluents, and an oily product was isolated in 69% yield (40 mg). 1 H-NMR (CD 3 OD, 300MHz) δ 0.94 (m, 6H), 1.26-1.44 (m, 8H), 1.54-1 (M, 3H), 3.25-3.35 (m, 1H), 3.43-3.62 (m, 3H), 3.8 (M, 2H), 5.22 (t, J = 6 Hz, 1H), 7.73 (t, J = 6 Hz, 1H),

71 210

Case 4714.P8.01 -92 "

Example 152 N- (8-Hydroxy-2-quinol-11-carboryl) glycine-di-n-pentamide In a similar manner to example 121, the product of example 120 was deprotected and linked to 8-hydroxy-2-quinolinecarboxylic acid in a conventional manner, using EDCI, etc, to give the product. EH (Cl) m / e 386 (m + H) +. 1 H-NMR (CDCl 3, 300 MHz) δ 8.96 (br s, 1H), 8.23 (s, 2H), 8.02 (s, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.36 (dd, J = 11.5Hz, 1H), 7.23 (dd, J = 7.5Hz, 1H), 4.34 (d, J = 5Hz, 2H), 3.42 J = 8 Hz, 2H), 3.28 (br t, J = 8 Hz, 2H), 1.55-1.70 (m, 4H),

1.25-1.40 (m, 8H), 0.93 (app q, 6H). C, H, M analysis calculated for 0.2 H2 O: C 67.91, H 8.13, N 10.80; Found: C 67.90, H 8.14, N 10.69.

Example 153 N-methyl-N- (3-guanylcarbonyl) -glucine-dl-n-pentamide The product of example 127 was mixed using bis-trimethylsilyl amide and methyl iodide in THF at -78 By heating to ambient temperature, yielding the product after the classic treatment and its purification. MS (CI) m / e 384 (m + H) +.

Example 154

N- (3-iodo-2-indolylcarbonyl) glycine-di-n-pentylamide The product from example 121 was iodinated with N-iodo-succinimide to give the desired product after chromatographic purification. MS (CI) m / e 484 (m + H) +. C, H, N analysis calculated for C 21 H 30 N 3 O 3: C 52.18, H 6.25, N 8.69; Found: C 52.04, H 6.21, N 8.49.

Example 155 1 N- (2-indolylcarbonyl) -R-alanine-di-n-pentamide

In an analogous manner to examples 57 and 58, the product was prepared from the corresponding R-alanyl-di-n-pentylamide hydrochloride and 3-quinoline carboxylic acid. MS (CI) m / e 372 (m + -H) +. C, H, N analysis calculated for the title product: C 71.1, H 8.95, N 11.31; Found: C 70.76, H 9.03, N

J 71 210

Case 4714.ΡΘ.01 11.17. The ability of the compounds of Formula I to interact with CCK & of CCK antagonists can be demonstrated by using the following protocols, Pharmacological Procedures: CCK g [Asp-T1r (SOgH) -Met-Gl-Trp-Met-Asp-Fen-NH2] was purchased from Peptlde International (Loulsvllle, KY) or Cambryld Research Research (Atlantic Beach, NY), ΕΘΤΑ, HEPES and BSA were purchased from Sigma Chemical Co. (St. Louis, MO). [Specific activity, 2200 C1 / mmol)] and the Aquasol-2 scintillation cocktail were obtained from the New England Nuclear (Boston, MA). Bestatlra and " phosphoramldon " were purchased from Peptlde International. Male cobalts, 250 to 325 g, were obtained from the Sclentlflc Small Animal Laboratory and Farm (Arnoldton, IL).

Protocol of ...... Tests ... of Radlo-1Igandos Connection 1 - Preparations of ...... Pancreatic Membranes and ...... Cortlcals ....... of Cobala Brain .

Cortical and pancreatic membranes were prepared as described (Lln and Miller, J. Pharmnol Exp Ther. 232, 775-780, 1985). Briefly, the cortex and pancreas were removed and washed with ice-cold saline. The visible fat and the connective tissues were removed from the pancreas. The tissues were weighed and homogenized separately in about 25 ml of ice cold 50 mM HCl-Trls buffer pH 7.4 at 4 ° C with a Brinkmann Poloytron for 30 seconds at position 7. homogenates were centrifuged for 10 ml at 10 g and pellets were discarded. The supernatants were centrifuged at 38,000 x g for 20 ml. The resulting pellets were re-homogenized in 25 ml of 50 mM HCl-Trls buffer with a Teflon-voldro homogeniser with 5 strokes up and down. The homogenates were again centrifuged at 38,730 x g for 20 ml. The pellets were then resuspended in 20 mM HEPES, containing 1 mM E8TA, 118 mM MaCl, KCl-94-

-71- J 71 210

4.7mM Case 4714.ΡΘ.01 4.7mM MgCl? 5 mM, 100 μM bestatin, " phosphoramidon " 3 μΜ, pH 7.4 to 22%, with a Teflon-glass homogenizer, with 15 strokes up and down. The volume of suspension was 15-18 ml per gram of original wet weight for the cortex and 60 ml per gram for the pancreas. Incubation Conditions Bull (CCKg) (I-BH-CCKg) and the compounds to be tested were diluted with HEPES-EGTA-sa1 buffer (see above) containing 0.5% bovine serum albumin % (BSA). To 1 ml polystyrene tubes, Skatron, 25 μl of [125 I] BH-CCKg and 200 μl of membrane suspension were added. The final BSA concentration was 0.1%. The cortical tissues were incubated at 30 ° C for 150 min and the pancreatic tissues were incubated at 37 ° C for 30 min. The incubations were terminated by filtration using the Skatron Cell Harvester and SS32 microfiber filter plates. The specific binding of BH-CCKg, defined as the difference between binding in the absence and presence of 1 μg CCKg, was 85-90% of the total binding in the cortex and 90-95% in the pancreas . ICgg values were determined by Hill analysis. The results of these binding assays are shown in Table 1.

Amiodase Liberation Protocol

This assay was performed using the modified product of Lin et al., J. Pharmacol., Exp. 236, 729-734, 1986. Preparation of Guinean Acinos

Guinea pigs were prepared by the method of Bruzzone et al. (Boc et al., 226, 621-624, 1985) as follows.

The pancreas was dissected and the connective tissues and blood vessels removed. The pancreas were cut into small pieces (2 mm) with a cutter and placed in a 15 ml plastic conical tube containing 2.5 ml Krebs-Ringer HEPES buffer (KRH) plus 400 units-per ml collagenase. The composition of the KRH buffer was: HEPES, 12.5 mM; NaCl, 118 mM; KCl, 4.8 mM; CCC12, 1 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 5 mM; glucose, 10 mM at pH 7.4. The tarnham was supplemented with 1% MEM vitamins, 1% amino-

• 95- J 71 210

Case 4714.PG.01 g hand up to 5 MEM acids and 0.001% aprotinin were added. The suspension tube was homogenous, usually 5-6min. ml KRH, without collagenase ® 0.1% BSA, and centrifuged at 50Â ° C for 35 seconds, the supernatant was discarded and 6 ml of KRH were added to the pellet of cells. The cells were pooled with a glass pipette and centrifuged at K 9 for 35 seconds. The washing process was repeated once. Cell pellet from the last centrifugation was then resuspended in 15 ml of KRH containing 0.1% BSA. The contents were filtered through a double nylon mesh, size 275 and 75 μΜ. The filtrate containing the acin was centrifuged at 50Â ° C for 2 min. The acin was then resuspended in 5 ml of KRH-BSA buffer for 30 min at 37Â ° C under 100% oxygen with a fresh buffer change at 15 min. 2 - Assay ^ da A mi ase

After 30 min of incubation, the acini were resuspended in 100 volumes of KRH-BSA buffer, containing 3 μΜ of " phosphoramidon " and 100 μg of bestatin. While stirring, 400 μΐ of acini were added to 1.5 ml microcentrifuge tubes containing 50 μl! of CCKq, buffer or assay kits. The final volume of the assay was 500 μΐ. The tubes were vortexed and placed in a 37 ° C water bath, under 100% O, for 30 min. The tubes were then centrifuged at 10,000 x g for 1 min. The supernatant and pellet cell analysis activity was determined separately, after appropriate dilutions in 0.1% Triton-X-100, 10 mM Na2CO4, pH 7.4, by the Abbot Amylase A-gent assay using the Abbot Bichromatic Analyzer 200. The reference concentration for CCKg in the determination of the ICg of the compounds of Formula I was 3 x 10 IUM. The results of this test are shown in Table 2.

Results ........ in Vitro

Preferred compounds of Formula I are those which inhibit the specific binding [125] -βΗ-CCKg in a concentration-dependent manner. The analysis of [Î ± 5 I] -BH-CCK receptor binding, in the absence and presence of the compounds of formula I, indicated that the β-

Case 4714.P8.01 Formula I compounds inhibit CCI receptive specific binding <0. The IC 50 values of the compounds of Formula in Table 1 are shown in Table 1. Compound of the compounds of Formula I in Table 1 Table 1: Binding [1251] -BH-CCK8 iC50 Table 10 Example Pancreas Cortex * 5 0 40 17,000 4 100> 10,000> 27,000 290 &gt; 10 000 8 12 &lt; 10,000 13 190 1-10 000 17 200 &quot; 100,000 2% 87 &quot; 10 000 24 170 &gt; 10 000 27 140 7200 31 73 &quot; 10 000 33 30 &quot; 10 000 34 9 &gt; 10 000 37 210 &quot; 10 000 43 48 1 400 47 320 &quot; 10 000 50 19 2 400 53 24 &quot; 10 000 56 530 &gt; 10 000 62 140 5 200 65 41 &lt; 10,000 66 T5Q 1-10 000 70 260 &quot; 10 000 73 180 &gt; 10 000 74 70 &quot; 10 000

J 71 210 Case 4714.ΡΘ.01

75 160 &gt; 10 000 76 92 &gt; 10 000 80 37 &quot; 10 000 81 120 5 300 82a 250 &gt; 100 63 &quot; 10 000 117 74 28 000 118 42 3 300 119 110 6 200 125 160 &quot; 10 000 131 9.3 1 600 1 1 w / C *. 3,1 1 700 133 210 &quot; 10 000 135 69 6,000 142 160 &gt; 10 000 143 130 145 100 147 86 2 900 150 980 &gt; 10 000 151 51 152 520 &gt; 10 000 155 230 &lt; 10,000

These results also indicate that the compounds of the invention have selectivity over pancreatic (type A) receptors of CCK.

J 71 210

Case 4714.P6.01 -98-Table 2

Inhibition of release

Compound of amylase-induced Example 3 290 4 <100,000 8 <100,000 17 <30,000 31 <100,000 32 <1 000 34 <100,000 43,140 <100,000 54 * 0,000 65 100 000 74 <100 000 80 <100 000 80 <10 000 81 <10 000 91 <10 000 99 <10 000 131 <100 000 132 <100 000 141 <30 000 151 <10 000 These results indicate that iritagonists. the compounds of the invention are In vivo Results The ability of the compounds of Formula I to interact with CCK receptors and antagonize CCK In vivo can be demonstrated using the following protocols.

Inhibition do ...... ...... ...... Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es Es .osto. to rehearse. CCKg (80æg / kg s.c.) was given before 60 min, five minutes later, oral "flour" was given. of coal

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(0.1 ml of 10% suspension). The animals were sacrificed in the following 5 minutes. Gastric emptying, defined by the presence of charcoal in the intestine beyond the pyloric sphincter, is inhibited by CCKg. Gastric emptying observed in 2 or 3 mice (greater than 1) indicates antagonism of CCKg,

Compound NS of mice with example .......................................... Dose ( po) Gastric emptying 118 100 mg / kg 2

Measure .... .... Nível of Level .... .... ... ... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... .... ....

a compound of Formula I. The ability of the compounds of Formula I to antagonize CCK-induced hyperinsulinemia can be demonstrated in vivo using following protocol.

Male mice, 20-30 g, were used in all experiments. The animals and laboratory and mare at ease. I.p. the compound of Formula I (1-100 mg / kg in 0.2 ml of 0.9% saline). 10 minutes later CCKg (0.2 to 200 nmole / kg in 0.2 ml of 0.9% saline) was injected or saline was injected into the tail vein. Two minutes later the animals were sacrificed and blood was collected in heparinized 1.5 ml polypropylene tubes. The tubes were centrifuged at 10,000 x g for 2 min. Insulin levels were determined in the supernatant (plasma) by a RIA method using &quot; Kits &quot; of Radioassay Systems Laboratory (Carson, CA) or Novo Biolabs (MA).

Antagonism of Behavioral Effect Mediated by CCK, in

Mice ....... with ...... Compounds ....... of ...... Formula ...... I

Male Swiss CD-1 mice (Charles River) (22-2? G) were given abundant food. . &lt; Pufifrâ "¢ Lab) and water to the time of being injected with the test compounds.

ICV injections were given by hand by a method similar to that previously described (Haley and McCormick, Br. J. Pharmacol.

(CDCl3): Î'12.15 (1957)). The aids were placed in a slightly raised metal grate and were secured between the thumb and forefinger at the level of the shoulders, thus immobilizing their heads. Injections were applied with a stopper measuring needle 30 consisting of a bit of tygon tube to limit needle penetration to about 4.5 mm below the skin surface. The needle was inserted perpendicular to the skull at a midpoint equidistant from the eyes and at a posterior equal distance from the eye level so that the injection site and the two eyes formed an equilateral triangle. The injection volume (5'μΐ) was gently expelled for a period of approximately 1 second.

Immediately after the injections, the mice were placed in their cages and left within 15 minutes of recovery before the beginning of the observations on their behavior.

For behavioral observations, the mice were placed in transparent cages. ; (&quot; clear &quot;) plastic.

Each cage was 19 x 26 x 15 centimeters and contained a 60-tube polypropylene test tube rack (NALGENE # 5970-0020) placed on foot. no: middle of the box to allow exploratory sceneries. Observations were made every 30 s over a period of 30 minutes.

The behavior between drug treated and CCKq mice was compared; CCKg-treated mice; and mice treated with equal volume of vehicle (usually 0.9% saline or 5% dimethylsulfoxide in water). The locomotion described here consisted of locomotion on the hill or active climb on the shelf. Differences between groups were analyzed by the Newman-Kewels analysis and a level of probability of p &lt; 0.05. Each group tested consisted of 10 animals. The results of this assay indicate that the compounds of Formula I are antagonists of CCK in vivo. The minimally effective dose

(MED) is defined as the dose at which a statistically significant reversal of inactivity induced by CCK

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Case 4714, ΡΘ.01 -101 when the test compound of formula I and CCK6 were administered.

Compound ..... of ...... Example 43 .................. Dose ...... of ...... CCKg 3 nmol

MED 3. .nmol

The compounds of Formula I antagonize CCK which makes the compounds useful in the treatment and prevention of diseases in majmorrhoids (especially man) where CCK or gastrin may be involved, e.g., in disorders. - gastrointestinal disorders such as irritable bowel syndrome, ulcers, excess pancreatic or gastric secretion, hyperinsulinemia, acute pancreatitis, cancers (especially cancers of the gallbladder and pancreas), disorders of motility, pain (potentiation of analgesia of narcotics), central nervous system disorders caused by interaction of CCK with dopamine. such as neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychoses, including schizophrenia or Gilles de la Tureure syndrome; disorders of appetite regulating systems, bulimia, Zol 1 iriger-EI 1 ison syndrome, and central células-cell hyperplasia and substance abuse treatment.

The compounds of the present invention may be used in the form of salts derived from inorganic or organic acids.

These salts include, but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentenopropionate, dodecylsulfate, 2-hydroxyethane sulfonate, lactate, maleate, maleate, maleate, maleate, maleate, maleate, maleate maleate, maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate maleate methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, pierate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Groups containing basic nitrogen may also be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates, chain halides

J 71 210

Such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl, aryl alkyl halides such as benzyl and phenethyl bromides and the like. Dispersible or water-soluble or oil-soluble products may be obtained herefrom.

The pharmaceutically acceptable salts of the present invention may be synthesized from the compounds of Formula I which contain a. basic or acidic part, by conventional means. In general the salts are prepared by reacting the free base or acid with stoichiometric or common excess amounts of organic or inorganic acid or base forming the intended salt in a suitable solvent or in various combinations of solvents. Examples of acids which may be used to form pharmaceutically acceptable acid addition salts, inorganic acids such as hydrochloric acid and phosphoric acid, and organic acids such as. oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or with alkaline earth metals such as sodium, potassium, calcium or magnesium or with organic bases.

The pharmaceutically acceptable salts of the acid of formula I are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of base, such as an alkali metal or alkaline earth metal hydroxide, e.g. sodium, potassium, lithium, calcium or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.

When a compound of Formula I is used as an antagonist of CCK or gastrin in a human patient, the total daily dose administered in a single dose or in divided doses may be in the range of, for example, 0.001 to 1000 mg per day, and more usually from 1 to 1000 mg. The dosage unit compositions may contain their submultiple quantities to make up the daily dose.

J 71 210

The amount of the active principle which can be combined with the carrier to produce a single dosage form will vary depending on the host treated, the particular treatment and the particular mode of administration.

It should be noted, however, that the specific dosage level for a given patient depends on a variety of factors including the activity of the specific compound used, age, body weight, general health, sex, diet, administration, rate of excretion, drug combination and the severity of the specific disease receiving the therapy.

The compounds of the present invention may be administered orally, parenterally, by &quot; spray &quot; by rectal or topical route in unit-dosage formulations containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants and carriers as desired. The parenteral term used herein includes Subcutaneous, Intravenous, Intramuscular, Intra-external, or Intravenous Injections. of - infusion.

Injectable preparations, e.g., aqueous or oily suspensions, Injectables, sterile, may be formulated according to the art using suitable dispersing or wetting agents and suspending agents. The sterile Injectable preparation may also be a sterile Injectable solution or suspension , in a non-toxic solvent or parenterally acceptable solvent, e.g., a solution in 1,3-butanediol. Among the acceptable carriers and solvents which may be used are water, Rhenger's solution, Isotonic solution of sodium chloride. In addition, stable, sterile oils, such as solvent or suspension honey, are conventionally used. For this purpose any stable, stable oil may be used Including synthetic mono- or dl-glycerides. Also fatty acids, such as oleic acid, have application in the preparation of Injections.

Suppositories for rectal administration of the drug may be prepared by mixing the drug with a suitable exponent, not

Irritant, such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the temperature

J 71210

And thus melt in the rectum and release the drug.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent such as sucrose lactose or starch. These dosage forms may also comprise, as is customary practice, additional substances in addition to inert diluents, eg, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may further comprise buffering agents. The tablets and pills may further be prepared with enteric coatings.

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

These agents may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other pictorial substances. The liposomes are formed by hydrated, mono- or multilamellar liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable metabolizable lipid capable of forming liposomes may be used. The present compositions in the form of liposomes may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic.

Methods for preparing liposomes are known in the art. See, e.g., Schott, Ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N, Y, 1976, p. Et seq.

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Case 4714.ΡΘ.01

The foregoing disclosure is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to the person skilled in the art are intended to be within the scope and nature of the invention as defined in the appended claims.

Claims (7)

J 71 210 Case 4714.P8.01 Ί06 R ...... E ....... I_V ....... I ....... ND I ....... C ..... A ... A process for the preparation of a compound of formula wherein R6 is (2) R8 is CD (2) (3) (4) wherein R6 is hydrogen or C1-4 alkyl, (1) hydrogen (2) lower alkyl (3) functionalized alkyl (4) cycloalkyl (5) aryl (6) aryl (6) aryl (6) alkyl substituted with carboxy or alkyl substituted with carboxyester, functionalized oxyalkyl or (7) a heterocyclic group with the proviso that D is other than indolinyl, indoxymethyl or oxindolylmethyl or R 1 taken together with D, is (1) C 1-6 alkylene (-) CH2) qV- (CH2) r- where q is 1 to 3, r is 1 to 3 and V is (CH2) n -O- (iv) â € ƒâ € ƒâ € ƒwherein R25 is hydrogen, lower alkyl, haloalkyl, alkoxyalkyl, arylalkyl, aryl or a protecting group of N, or Rg taken together with D, 2), where p is 1 to 3, t is 1 to 3 and V a defined as above, 2 is (1) -C (O) - (2) -C (S) -or (3) -S (O) 2-B is absent (2) alkylene (3) (4) substituted alkenylene (5) wherein R26 is absent or is CH2 and R27 is -O-, -S-, -NH- or - &quot; N (lower alkyl) ) Wherein R 27 is defined as above, and Ar is (1) aryl or (2) a heterocyclic group, characterized in that it comprises coupling an amine of formula where P-j is hydrogen with a compound of formula Wherein Zf is an activator group; or B-2-2 'taken together represents -N =: C = O, -N = C = S, -, or CH2 = &numsp; = C = S. J 71 210 Case 4714.P3.01 -108- A process according to claim 1 wherein D is (1) aryl (2) arylalkyl (3) a heterocyclic (4) heterocycloalkyl group (5) functionalized oxyalkyl (6) lower alkyl substituted by - . where it is lower alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or (7) lower alkyl substituted by -S-lower alkyl, -S (O) -lower alkyl, -S (O) 1-lower alkyl, -S-aryl, -S (O) -aryl or -S (O) j-aryl and Ar is a heterocyclic group. A process as claimed in claim 1, wherein Ar is a heterocyclic group; B is absent; 2 is -C (Q) -; Rg and Rz are hydrogen; D is lower alkyl, functionalized oxyalkyl, aryl or a heterocyclic group; and Θ is amino substituted. A process according to claim 3, characterized in that Ar is quinolyl, hydroxyquinolyl or dihydroxy quinolyl; D is phenyl, a heterocyclic, hydroxyalkyl or alkoxy alkyl group; and Θ is dialkylamino. 5. A compound according to claim 1 for preparing a compound of the group consisting of: N- (3 '' - carbonyl) carbonyl (2R, 3S) - (O-methyl) threonine-di-n-pen (2R, 3S) -1-oxadiazol-1-one-1-en-1-amide dihydrochloride (3'-quinolinecarbonyl) -R-phenylglycine-di-n-pentylamide and N - (4 ', 8'-dihydroxy- 21-quinolinecarbonyl) -R-phenylglycine di-n-pentylamide. 6. A process for the preparation of a pharmaceutical composition for antagonizing CCQ characterized in that it comprises associating a pharmaceutical carrier with a therapeutically effective amount of a compound of claim 1. 7. A process for the preparation of a pharmaceutical composition for the treatment or prevention of hyperinsulinemia or gastrointestinal disorders of the central nervous system, appetite regulator or pain regulator, characterized in that it comprises associating a pharmaceutical carrier with a therapeutically effective amount of a compound of claim 1, wherein: 3HL 1790 By ABBOTT LABORATORIES - 0 OFFICIAL AGENT -