MXPA98010693A - Inhibitors of the prenyl-transfer - Google Patents

Abstract

The present invention relates to: A family of compounds capable of inhibiting the activity of transferases. The compounds are covered by any of the two formulas (I, II). Each of the R groups is defined in the following description

Description

INHIBITORS OF THE PRENYL- TRANSFERASES BACKGROUND OF THE INVENTION The Ras protein family is important in the signal transduction pathway that modulates cell growth. The protein is produced in the ribosome, released into the cytosol, and post-modified transductionally. The first step in the series of post-transductional modifications is the ratio Cys168 with farnesyl pyrophosphate or geranylgeranil in a reaction catalyzed by prenyltransferase enzymes such as farnesyltransferase and geranylgeranyltransferase (Hancock, JF, et al., Cell. 57: 1167-1177 (1989)). Subsequently, the three C-terminal amino acids are cleaved (Gutiérrez, L., et al., EMBO J. 8: 1093-1098 (1989)), and the terminal Cys is converted to the methyl ester (Clark, S., et al. Proc. Nat'l Acad. Sci, (USA) 85: 4643-4647 (1988)). Some forms of Ras are also reversibly palmitoylated in cysteine residues immediately at the N-terminus to Cys168 (Buss, JE, et al., Mol Cell. Biol. 6: 116-122 (1986)). It is believed that these modifications increase the hydrophobicity of the C-terminal region of Ras, causing it to locate the surface of the cell membrane. The localization of Ras to the cell membrane is necessary for signal transduction (illumsen, BM, et al., Science 310: 583-586 (1984)). Oncogenic forms of Ras are observed in a relatively large number of cancers including more than 50% of colon cancers and more than 90% of pancreatic cancers (Bos, JL, Cancer Research 49: 4682-4689 (1989)). These observations suggest that intervention in the function of signal transduction mediated by Ras may be useful in the treatment of cancer. Previously, it has been shown that the tetrapeptide C-terminal Ras is a "CAAX" portion (where C is cysteine, A is an aliphatic amino acid, and X is any amino acid). It has been shown that tetrapeptides having such structure are inhibitors of prenyl transferases (Reiss, et al., Cell 62: 81-88 (1990)). The poor potency of these farnesyl transferase inhibitors has promoted the search for new inhibitors with more favorable pharmacokinetic behavior (James, GL, et al., Science 260: 1937-1942 (1993); Kohl, NE, et al., Proc. Nat'l Acad. Sci. USA 91: 9141-9145 (1994), de Solms, SJ, et al., J. Med. Chem. 38: 3967-3971 (1995), Nagasu, T. et al., Cancer Research 55: 5310-5314 (1995); Lerner, EC, et al., J. Biol. Chem. 270: 26802-26806 (1995); Lerner and James, et al., Proc. Natl. Acad. Sci. USA 93: 4454 (1996 )). Recently, it has been shown that an inhibitor of prenyl transferases can block the growth of Ras-dependent tumors in nude mice (Kohl, NE, et al., Proc. Nat'l Acad. Sci. USA 91: 9141-9145 (1994)). In addition, it has been shown that more than 70% of a sampling of tumor cell lines are inhibited by prenyltransferase inhibitors with selectivity over non-transformed epithelial cells (Sepp-Lorenzino, I, et al., Cancer Research, 55 : 5302- 5309 (1995)).

SUMMARY OF THE INVENTION In one aspect, the invention features a compound of formula I or formula II Formula I Formula II wherein Rx is H or NR20R21; R2 is (CH2) mSR22, (CH2) mSSR22, substituted or unsubstituted heterocycle, or substituted or unsubstituted heterocycle-lower alkyl, wherein m is 1-6 and the substituent is lower alkyl, lower alkenyl, aryl, or aryl-lower alkyl; each of R3 and R7, independently, is CH2 or C (0); each of R4 and R15, independently, is H or lower alkyl; each of R5 and R16, independently is H or a substituted or unsubstituted portion selected from lower alkyl, thio-lower alkyl, lower alkenyl, thio-lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, aryl and aryl-lower alkyl, where the substituent is lower alkyl, hydroxy, halo, C (0) NR23R24, or COOH; each of R6, R8, R9, R1X, R12, R13 and R17, independently, is H or a substituted or unsubstituted portion selected from lower alkyl, lower alkenyl, thio-lower alkyl, cycloalkyl, aryl and aryl-lower alkyl , wherein the substituent is lower alkyl, halo, hydroxy, C (0) NR25R26; or COOH; R10 is S, SO, or S02; R18 IS COOR27 or C (0) NR28R29, or together with R16, form -C00CH2CH2-. R19 is a substituted (with one or more substituents, same as later) or unsubstituted portion selected from lower alkyl, lower alkenyl, aryl, and aryl-lower alkyl, wherein the substituent is lower alkyl (eg, an alkyl group also can be considered as a substituent), halo, or alkoxy; and each of R20 / R21 'R22' R23 R24 • / R25 * R26 'R27' R²ß 'and R 29' independently, is H or lower alkyl; with the proviso that if R2 is (CH2) mSH and R5 is thio-lower alkyl, the free thio groups of R2 and R5 can form a disulfide bond; or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is of the formula I wherein R2 is (CH2) mSR22, heterocycle, or heterocyl-lower alkyl, each of R4 and R15, independently, is H; R5 is lower alkyl; R6 is H; each of R8, R9, R11 # and R12, independently, is H or lower alkyl; R10 is S; R13 is H; R16 is lower alkyl or thio-lower alkyl, substituted, wherein the substituent is lower alkyl; and R17 is H. In this embodiment, R1 may be NR20R21 (e.g., NH2); R2 can be (CH2) mSR22 (e.g., CH2SH); R3 can be CH2; each of R8 and R9, independently, can be H; and R18 can be C00R27; In addition, R5 can be CH (CH3) (CH2CH3), (CH2) 3CH3, CH (CH3) 2, or C (CH3) 3; each of R? t and R12, independently, may be CH3; R16 can be (CH2) 2SCH3 or CH2CH (CH3) 2; and R18 can be COOH or COOCH3. In the same modality, RL can be H; R 2 can be heterocycle or heterocycle-lower alkyl; R3 can be CH2; each of R8 and R9, independently, can be H; and R18 can be COOR27, where R27 is H or lower alkyl, furthermore, R2 can be imidazolyl-lower alkyl; R5 can be CH (CH3) (CH2CH3), CH (CH3) 2, or C (CH3) 3; each of R1X and R12, independently, may be CH3; R16 can be (CH2) 2SCH3, (CH2) 3CH3, or CH2CH (CH3) 2; and R18 can be COOH or COOCH3. In another embodiment, the compound of formula II wherein R2 is (CH2) mSR20, heterocycle, or heterocycle-lower alkyl; each of R8, R9, Rll t and R12, independently, is H or lower alkyl; R10 is S; R13 is H; and R15 is H. In this embodiment, Rx may be NR20R21; R2 can be (CH2) mSR22; R3 can be CH2; each of R8 and R9, independently, can be H; and R19 can be aryl-substituted or unsubstituted lower alkyl, wherein the substituent is halo or lower alkyl; Also, R? it can be NH2; R2 can be CH2SH; each of Rn and R12, independently, may be CH3; and R19 is 2,3-dichlorobenzyl or l-naphthylmethyl. In the same modality, Rx can be H; R 2 can be heterocycle or heterocycle-lower alkyl; R3 can be CH2; each of R8 and R9, independently, can be H; and R19 can be aryl-substituted or unsubstituted lower alkyl, wherein the substituent is halo or lower alkyl; in addition, R2 is imidazolyl or imidazolyl-lower alkyl; each of RX1 and R12, independently, may be CH3; and R19 can be 2,3-dichlorobenzyl or 1-naphthylmethyl. The examples of the present invention include the following: Compound 1; Compound 2; Compound 3; Compound 4; Compound 5; Compound 6; Compound 7; Compound 8; Compound 9; Compound 10; Compound 11; Compound 12; Compound 13; Compound 14; Compound 15; Compound 16; Compound 17; Compound 18; Compound 19; Compound 20; Compound 21; In another aspect, the invention provides a numerical compound consisting of a first portion and a second portion, wherein each of the first and second portions, independently, is of Formula I or II shown above, except that each R2 of the first portion and R2 of the second portion, independently, are - (CH2) raS-, and form a disulfide bond; or a pharmaceutically acceptable salt thereof. The first and second portions may be identical or different. In reality, R2 of the first portion and R2 of the second portion may also be identical or different. An example of this dimeric compound is shown below.

Compound 22; The compounds of the present invention can have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, which are included in the present invention. For simplicity, where the specific configuration in the structural formulas is not represented, it is understood that all the enantiometric forms and mixtures thereof are represented. As used herein "lower alkyl" is proposed to include saturated aliphatic hydrocarbon groups having from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and the like. The "lower alkenyl" groups include those groups having 2-6 carbon atoms and having one or more double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, and the like. The "lower alkoxy" groups include those groups having 1-6 carbon atoms. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, ispropoxy, and the like. All the alkyl, alkenyl and alkoxy groups can be branched or straight chain, but are not cyclic. The term "cycloalkyl" means a ring of 3-7 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "halo" means chlorine, bromine, iodine or fluoro. The terms "heterocycle-lower alkyl", "thio-lower alkyl", "thio-lower alkenyl", "aryl-lower alkyl", and,? hydroxy-lower alkyl ", are substituted, respectively, with one to three heterocycle, thio, thio, aryl, and hydroxy groups. As used herein," aryl "is intended to include any monocyclic, bicyclic, or tricyclic, stable, up to 7 members in each ring, wherein at least one ring is aromatic Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like. present, represents a 5- to 7-membered monocyclic ring, or 8 to 11 membered bicyclic, stable, or tricyclic ring of 11 to 15 members, stable, which is either saturated or unsaturated, and which consists of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, 0, and S, and including any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. Ociclo can be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of these heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromatyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopdirrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolyl, thiazolidinyl, thienofuryl, thienothienyl, thienyl, and the like. When a group is replaced, it can be replaced one or four times. The various substituents can be linked through the heteroatoms (for example, S, N, or 0). The compounds of this invention can be provided in the form of pharmaceutically acceptable salts. Acceptable salts include, but are not limited to, acid addition salts of inorganic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate. Also within the scope of the present invention, where applicable, salts are formed from bases such as sodium or potassium hydroxide. For additional examples of pharmaceutically acceptable salts see, "Pharmaceutical Salts," J. Pharm. Sci. 66: 1 (1977). In a still further aspect, the invention provides a method of inhibiting prenyl transferases (e.g., farnesyl transferase or geranylgeranyl transferase) in a subject, eg a mammal such as a human, by administering to the subject a therapeutically effective of a compound of Formula I or II. In particular, the present invention also covers a method for treating restenosis or tissue proliferative diseases (eg, tumor) in a subject, by administering to the subject a therapeutically effective amount of a compound or its salt. Examples of proliferative disease tissue include those associated with the proliferation of benign cells (e.g., non-malignant) as fibrosis, hyperplasia Benign prostatic, atherosclerosis, and restenosis, and those associated with malignant cell proliferation, such as cancer (for example, Ras mutant tumors). Examples of treatable tumors include breast, colon, pancreas, prostate, lung, ovarian, epidermal, and hematopoietic cancers (Sepp-Lorenzino, I, et al., Cancer Research 55: 5302 (1995)). A therapeutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier substance (e.g., magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle) together form a pharmaceutical composition (e.g., a pill, tablet, capsule or liquid) for administration (eg, orally, intravenously, transdermally or subcutaneously (to a subject in need of the compound) The pill, tablet or capsule may be coated with a substance capable of protecting the composition of gastric acid or intestinal enzymes in the subject's stomach for a period of time sufficient to allow the composition to pass undigested to the small intestine of the subject.The dose of a compound of the present invention to treat the diseases mentioned above or disorders, varies depending on the way of administration , the age and body weight of the subject, and the condition of the subject to be treated, and finally will be dictated by the attending physician or veterinarian. This amount of compound as determined by the attending physician or veterinarian is referred to herein as "a therapeutically effective amount". Also contemplated within the scope of the invention are pharmaceutical preparations and compounds of Formula I and II, methods for preparing the compounds of Formula I or II and the new intermediate chemical compounds used in this synthesis as described herein. Other features and advantages of the present invention will become apparent from the detailed description of the invention and from the claims.

DETAILED DESCRIPTION OF THE INVENTION It is believed that one skilled in the art can use, based on the description herein, the present invention to its fullest extent. The present specific modalities will therefore be considered as illustrative only, and not limitative of the rest of the description in any way whatsoever. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as are commonly understood by one skilled in the art to which this invention pertains. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. The following is a description of the synthesis of the compounds from 1 to 12. Other compounds of the invention can be prepared in an analogous manner by a person skilled in the art. The compounds of this invention were prepared by using peptide synthesis methodologies in a normal solution phase as well as other normal manipulations such as hydrolysis with esters and reductive alkylation of an amine by an aldehyde, for example, as described in Greenstein, and collaborators, chemistry of the Amino Acids, Vols. 1-3 (J. Wiley, New York (1961)); and M. Bodanszky, et al., The Practice of Peptide Synthesis (Springer-Verlag, 1984)). For amide formation reactions, EDC / HBOt or HBTU / DIEA / DMF was used as the coupling agent. Deprotection of the protecting groups was made by using TFA / DCM. The reducing agent used in the reductive alkylation of an amine was sodium cyanohydride. The final products were purified by using preparative HPLC and analyzed by XH NMR or mass spectroscopy.

Example 1: N- [N '- [2 (S) - (2 (R) -amino-3-mercaptopropylamine) -3 (S) -methylpentyl] -L-5,5-dimethylthiazolidine-4-carboxyl] -methionine (Compound 1) (a) Na- (tert-butoxycarbonyl) -L-5, 5- dimethylthiazolidine-4-carboxylic acid: A solution of L-5,5-dimethylthiazolidine-4-carboxylic acid (2.5 g, 15.5 mmol) in water (10 mL), dioxane (20 mL), and 2N NaOH (7.8 mL) was stirred and cooled in an ice-water bath. Di-tert-butyl dicarbonate (3.72 g, 17.1 mmol) was added and stirring was continued at room temperature overnight. The solution was concentrated in vacuo to approximately 25 ml and ethyl acetate (EtOAc) was added.; 30 mL). The pH of the solution was adjusted to 2 at 0 ° C by the addition of 2N HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (20 mL). The organic layers were combined, washed with water (2 times), dried over anhydrous MgSO 4, filtered and evaporated in vacuo. The title compound as a white solid (3.60 g, yield: 89%) was obtained, used in the next reaction without further purification. H-NMR (300 MHz, CDC13) d 4.68 (m, 2H), 4.39 (s, 1H), 4.23 (S, 1H) 1.60-1.40 (m, 15H). (b) Methyl ester of N- [(tert-butoxycarbonyl) -L-5, 5- dimethylthiazolidine-4-carboxylic acid] -L-methionine A solution of N- (tert-butoxycarbonyl-L-5, 5-dimethylthiazolidine- 4-carboxylic acid (1.00 g, 3.83 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 0.734 g, 3.83 mmol), 1-hydroxybenzotriazole (HOBt, 0.517 g, 3.83 mmol), and diisopropylethylamine ( DIEA, 0.495 g, 3.83 mmol) in dichloromethane (DCM, 20 mL) was stirred at 0 ° C for 10 minutes, to this solution was added methionine methyl ester hydrochloride (0.765 g, 3.83 mmol). The solvent was removed in vacuo, the residue was dissolved in EtOAc, washed with 5% citric acid (2 times), 5% Na2CO3 (2 times), and brine (2 times). ), dried over anhydrous MgSO 4, and filtered The residue obtained after the concentration was further purified by column chromatography on silica, eluting with hexanes / EtO Ac (2: 1) The title compound, as a white solid (1.09 g; performance; 70%), was obtained. NMR * H (300 MHz, CHC13) d 6.67 (d, ÍH), 4.78-4.60 (m, 3H), 4.11 (s, ÍH), 3.75 (s, 3H), 2.55 (m, 2H), 2.24-2.00 (m, 5H), 1.56-1.40 (m, 15H). (c) Na- (tert-butoxycarbonyl) -N-methoxy-N-methyl-L-isoleucinamide A solution of Na- (tert-butoxycarbonyl) -isoleucine (8.00 g, 33.3 mmol), 0-benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate (HBTU, 12.63 g, 33.3 mmol), DIEA (17.21 g, 133.2 mmol) in dimethylformamide (DMF, 35 ml) was stirred at room temperature for 2 minutes. To this solution was added N, 0-dimethylhydroxylamine hydrochloride (3.25 g, 33.3 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc and washed with 5% citric acid (2 times), 5% Na 2 CO 3 (2 times and brine (2 times), dried over MgSO 4, and The residue obtained after the concentration was further purified by chromatography on a silica column, eluting with EtOAc / hexanes (1: 1). (yield: 90%) the title compound was obtained. NMR XH (300 MHz, CHC13) d 5.12 (d, HH), 4.62 (m, HH), 3.79 (s, 3H), 3.23 (s, 3H), 1.72 (m, HH), 1.58 (m, HH) , 1.45 (s, 9H), 1.30-1.05 (m, ÍH), 1.00-0.85 (m, 6H). (d) N-α- (tert-butoxycarbonyl) -L-isoleucinal LiAlH 4 (0.20 g, 5.25 mmol) was stirred in 20 mL of anhydrous ether at room temperature for 30 minutes. The suspension was cooled to -45 ° C, and a solution of Na- (er-butoxycarbonyl) -N-methoxy-N-met il -L-isoleucinamide (1.10 g, 3.89 mmol) in 6 mL of tetrahydrofuran (THF) was added. ) drop by drop to the suspension. The mixture was heated to 0 ° C and stirred for 2 hours. The mixture was then cooled to -45 ° V. To this solution was slowly added a solution of KHS04 (1.17 g) in H20 (10 mL). The resulting mixture was filtered through celite. The filtrate was washed with 5% citric acid (2 times) and brine (2 meces), dried over anhydrous MgSO 4, filtered and concentrated to dryness. 0.60 g of the title compound was obtained as a colorless oil and used immediately in the next step without further purification. (e) Methyl ester of N- [N '- [2- (S- (tert-butoxycarbonylamino) -3 (S) -methylpentyl] -L-5, 5- dimethyl thiazole idine-4-carboxyl] -methionine The ester N- [(tert-butoxycarbonyl) -L-5,5-dimethylthiazolidine-4-carboxyl] -L-methionine methyl ester (1.09 g, 2. 68 mmol) was dissolved in a mixture of TFA (15 ml) and DCM (15 mL) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The resulting residue and N-a- (tert-butoxycarbonyl) -L-isoleucinal (0.70 g, 3.25 mmol) were dissolved in a mixture of methanol (MeOH, 30 mL) and acetic acid (0.6 mL). To this solution, sodium cyanoborohydride (0.204 g, 3.25 mmol) was added in portions over a period of 30 minutes. MeOH was removed in vacuo. To the rest of the solution was added EtOAc and saturated NaHCO 3. The organic layer was separated and washed with saturated NaHCO 3 (1 time), water (1 time) and brine (1 time), dried over anhydrous MgSO 4, filtered and concentrated. The obtained residue was further purified by column chromatography on silica, eluting with EtOAc hexanes (1: 2). 1.06 g (yield: 78%) of the title compound were obtained. XH NMR (300 MHz, CHC13) d 8.70 (d, ÍH), 4,687 (m, ÍH), 4.53 (s, 2H), 3.90 (m, ÍH), 3.79 (s, ÍH), 3.75. As used herein, "aryl" is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like. 3.42 (s, ÍH), 2.95 (dd, ÍH), 2.78 (dd, ÍH), 2.50-2.70 (m, 2H), 2.2 (m, 2H), 2.13 (s, 3H), 1.60-1.40 (m, 12H), 1.36 (m, 2H), 1.38 (m, 2H), 0.92 (m, 9H); mass spectroscopy (electron spray) ((MS (ES)): 505.4 Calculated molecular weight (MW Cal.) -505.7. (f) Na- (tert-butoxycarbonyl) -S- (triphenylmethyl) - L-cysteine The compound The title was synthesized by initiating with Na- (tert-butoxycarbonyl) -S- (triphenylmethyl) -L-cysteine using the same procedure described in the synthesis of Na- (tert-butoxycarbonyl) -L-isoleucinal. (g) Ester N- [N '- [2 - (S) - (2 (R) - (tert-Butoxycarbonylamino) -3-triphenylmethyl-mercaptopropylamine-3 - (S) -met-pentyl] -L-5, 5- methyl ester dimethyl thiazole idine-4-carboxyl] -methionine N- [N '- (2 (s) - (tert-butoxycarbonylamino) -3 (S) -methylpentyl] -L-5,5-dimethylthiazolidine methyl ester -4-carboxy) -met ionin (1.06 g, 2.10 mmol) was dissolved in a mixture of trifluoroacetic acid (TFA, 15 mL) and DCM (15 mL) and stirred for 30 minutes at room temperature. The residue obtained and the La- (tert-butoxycarbonyl) -S- (triphenyl) ethyl) -L-cysteine (1.10 g, 2.46 mmol) were dissolved in a mixture of MeOH (15 mL) and HOAc (0.3 mL). To this was added in portions sodium cyanoborohydride (0.158 g, 2.52 mmol) over a period of 30 minutes. The mixture was stirred at room temperature overnight. 5 ml of saturated NaHCO 3 was added, and MeOH was removed in vacuo. To the rest of the solution was added EtOAc and saturated NaHCO 3. The organic layer was separated and washed by saturated NaHCO 3 (1 time) and brine (2 times, dried over anhydrous MgSO 4 and filtered.The concentration in vacuo gave the title compound, which was used directly the next step without further purification. MS (ES): 836.5, MW.Calc-836.8. (H) N- [N '- (2, (S) - (2 (R) -amino-3-mercaptopropylamine) -3- (S) -met ilpent il] -L- 5, 5-dimethylthiazolidin-4-carboxy] -methionine N- [N '- [2 (S) - (2 (R) - (tert-butoxycarbonylamino) -3-triphenylmethylmercaptopropylamine) methyl ester) -3- (S) -methylpentyl) -L-5,5-dimethylthiazolidine-4-carboxyl) -methionine (0.50 g, 0.42 mmol) was dissolved in a mixture of MeOH (16 mL) and 5 N NaOH (4 mL) at 0 ° C and stirred for 3 hours. The solution was neutralized to pH 7 by the addition of 2N HCL. The MeOH was removed in vacuo and EtOAc was added. The mixture was cooled to 0 ° C, and the aqueous layer was acidified to pH 2 by using 2N HCl. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The organic layers were mixed, washed with brine (1 time), dried over anhydrous MgSO 4, filtered. The residue obtained after concentration in vacuo was dissolved in a mixture of trifluoroacetic acid (TFA; 6 mL), DCM (6 mL), and triethylsilane (0.6 mL). The solution was stirred at room temperature for 40 minutes. The residue after concentration in vacuo was divided between ether and aqueous 0.1% TFA solution. The aqueous layer was separated, purified on preparative high performance liquid chromatography (HPLC) eluting with 0.1% TFA in H20 / CH3CN buffer, and lyophilized to give the title compound. MS (ES): 480.3, MW Cale. -4880.8.

Example 2: N- [N '- [2 (S) - (2 (R) -amino-3-mercaptopropylamine) -3 (S) -methylpentyl] -L-5, 5-dimethylthiazolidine-4-carboxyl methyl ester ] -methionine (Compound 2) The methyl ester of N- [N '- [2 (S) - (2 (R) - (tert-butoxycarbonylamino) -3-triphenylmethylmercaptopropylamine) -3 (S) -methylpentyl] -L- 5, 5-dimethylthiazolidine-4-carboxyl] -methionine (0.60 g, 0.718 mmol; Example 1 (g) was dissolved in a mixture of TFA (10 mL), DCM (10 mL), and triethylsilane (1 mL). The reaction mixture was stirred at room temperature for 30 minutes The solution was concentrated in vacuo The residue was partitioned between aqueous solution of 1% TFA and ether The organic layer was separated, lyophilized to give the title compound. (ES): 494.3, PM, Cale.-494.8.

Example 3: N- [N '- N "- (2 (R) -amino-3-mercaptopropyl) -tele-leucine] -L-5, 5-dimethylthiazolidine-4-carboxyl] -methionine (Compound 3) ( a) N- [N '[(tert-butoxycarbonyl) -tetraleral) methyl ester -L-5, 5-dimethylthiazolidine-4-carboxyl] -methionine N- [(tert-butoxycarbonyl) -L methyl ester 5,5-dimethylthiazolidine-4-carboxyl] -methionine (1.63 g, 4.01 mmol); Example 1 (b)) was dissolved in a mixture of TFA (5 mL) and DCM (5 mL) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The residue was dissolved in toluene, and the solution was condensed in vacuo. This procedure was repeated three times and a white foam was obtained. A solution of N-α- (tert-butoxycarbonyl) -tele-leucine (1.0 g, 4.01 mmol), EDC (0.769 g, 4.01 mmol), HBOt (0.650 g, 4.81 mmol), and DIEA (0.570 g, 4.41 mmol) in DCM (15 mL) was stirred at room temperature for 10 minutes.

To this the previous white foam was added. The mixture was stirred overnight. The solution was diluted with DCM (15 mL) and washed with 5% NaHCO 3 (2 times), 5% citric acid (2 times), and brine (2 times) 1, dried over anhydrous MgSO 4, filtered and it was concentrated in vacuo. The residue was purified by column chromatography, eluting with hexanes: EtOAc (2: 1) and hexanes: EtOAc (1: 1). 0.63 g of the title compound were obtained (yield: 30%). NMR H H (300 MHz, CHC13) δ 6.48 (d, HH), 5.25 (d, HH), 5.12 (d, HH), 4.95-4.62 (m, 2H), 4.43-4.30 (m, 2H), 3.77 (s, 3H), 2.58 (m, 2H), 2.21, (m, ÍH), 2.11 (s, 3H), 2.04 (m, ÍH), 1.55-1.33 (m, 12H), 1.12-0.94 (m, 12H). (b) Methyl ester N- [N '- [N "- (2 (R) - (tert-butocarbonylamino) -3-triphenylmethyl-mercaptopropyl) -tele-leucine] -L-5, 5- dimethylthiazolidine-4- carboxyl] -methionine 0.6 g (1.15 mmol) of N- [N '- (tedr-butoxycarbonyl) -tele-leucine] -L-5,5-dimethylthiazolidine-4-carboxyl] -methionine methyl ester was dissolved in a mixture of TFA (5 mL), DCM (5 mL) and triethylsilane (Et3SiH) (1 mL) and stirred at room temperature for 30 minutes. The solution was concentrated in vacuo. The residue was dissolved in toluene, the solution condensed to dryness. This procedure was repeated until a white foam was obtained (4 times). This foam and 0.5 g (1.12 mmol) of Na- (tert-butoxycarbonyl) -S- (triphenylmethyl) -L-cysteine (Example 1 (f)) were dissolved in 4 mL of methanol, 0.2 mL of acetic acid. NaBH3CN (72 mg 1.15 mg) was added and stirred for 30 minutes, 0.5 g (1.12 mmol) of Na- (tert-butoxycarbonyl) -S- (triphenylmethyl) -L-cysteine and 72 mg (1.15 mmol) of NaBH3CN were added. The reaction mixture was stirred for 30 minutes, then 0.5 g (1.12 mmol) of Na- (tert-butoxycarbonyl) -S- (triphenylmethyl) -L-cysteine and 72 mg (1.15 mL of NaBH3CN followed by addition of 0.1 mL of acetic acid The solution was stirred overnight and concentrated in vacuo The residue was dissolved in EtOAc and washed with saturated NaHCO 3 (2 times) and brine (2 times), dried over Anhydrous MgSO 4 was filtered and condensed in vacuo. The residue was purified by using column chromatography (silica), eluting with EtOAc: hexanes (1: 2) and EtOAC: hexanes (1: 1). 930 mg (yield: 95%) of the title compound were obtained, as a white solid. MS (IS): 850.5 PM. Cale. = 850.8. (c) N- [N '- [N "(2 (R) -amino-3-mercaptopropyl) -terleucine] -L-5, 5-dimethylthiazolidine-4-carboxyl] -methionine 230 mg (0.27 mmol ) of N- [N '- [N "- (2 (R) - (tert-butoxycarbonylamino) -3-triphenylmethyl-mercaptopropyl) -tele-leucine] -L-5,5-dimethylthiazolidine-4-methyl ester carboxyl] -methionine were dissolved 2 mL of methanol at 0 ° C. To these were added 0.4 mL of IN KOH solution. The white precipitator was dissolved by the addition of 0.8 mL of THF. The mixture was warmed to room temperature and stirred for 1.5 hours. To the solution 2N HCl was added at 0 ° C until the pH was approximately 2. The solution was diluted to 25 mL by the addition of EtOAc and then 10 mL of brine was added. The organic layer was separated, dried over anhydrous MgSO 4, filtered, and concentrated in vacuo to give a white solid (220 mg). The white solid was dissolved in a mixture of 5 mL of DCM and 1 mL of triethylsaline (Et3SiH). To this, 5 mL of TFA was added, and the solution was stirred for 40 minutes. The solution was concentrated in vacuo. The white solid was triturated with hexanes and then dissolved in aqueous 0.1% TFA solution. Purified on a preparative HPLC and lyophilization gave the title compound (47 mg; yield: 36%). NMR XH (300 MHz, CHC13) d 8.28 (d, HH), 5.02 (d, HH), 4.74 (d, HH), 4.66 (m, HH), 4.53 (s, HH), 4.47 (m, HH) , 3.30 (m, 2H), 2.77 (m, 2H), 2.58 (m, ÍH), 2.51 (m, 4H), 2.03 (m, 4H), 1.82 (m, ÍH), 1.54 (s, 2H), 1.38 (s, 3H), 1.03 -0.8 (m, 12H); MS (ES): 494.2, PM. Cale. = 494.7.

Example 4: N- [N '- [N "- (2 (R) -amino-3-mercaptopropyl) -ter-leuucin] -L-5, 5-dimethylthiazolidine-carboxy] -methionine methyl ester 660 mg (0.776 mmol of N- [N '- [N7' - (2 (R) - (tert-butoxycarbonyl-amino) -3-triphenylmethyl-mercaptopropyl) -terleucine] -L-5, 5-methyl ester -dimethylthiazolidine-4-carboxyl] -methionine (Example 3 (b)) a mixture of DCM (5 mL) and Et3SiH (1 mL) was dissolved in. To these were added 5 mL of TFA.The mixture was stirred at room temperature during 0.5 hours The solution was concentrated in vacuo.The residue was triturated with hexanes and then dissolved in aqueous 0.1% TFA solution, purified by preparative HPLC, eluting with a gradient (buffer A: 0.1% in H2O, buffer B: 0.1 TFA in CH3CN) The lyophilization gave the title compound as a white solid (310 mg, yield: 78%) MS (ES): 508.3, MW Cale = 508.8.

Example 5: N- [N '- [N "- (2 (R) -amino-3-mercaptopropyl) -terleucine] -L-5,5-dimethylthiazolidine-4-carboxyl] -leucine (Compound 5) . The title compound was synthesized by using an analogous procedure described in the synthesis of Example 3. MS (ES) 476.2, PM Cale. = 476.3.

Example 6: N- [N '- (N "- (2 (R) -amino-3-mercaptopropyl) -tele-leucine] -L-5, 5-dimethylthiazolidine-4-carboxyl] -leucine methyl ester compound of the title was synthesized by using an analogous procedure described in the synthesis of Example 4. MS (ES): 490.3, MW Cale. = 490.7.

Example 7: N- [N '- [N "- (2 (R) -amino-3-mercaptopropyl) -valin] -L-5, 5-dimethylthiazolidine-4-carboxyl] -leucine (Compound 7) The compound of the title was synthesized by using an analogous procedure described in the synthesis of Example 3. MS (ES): 462.4, MW Cale. = 462.7.

Example 8: Methyl ester of N '- [N "- (2 (R) -amino-3-mercaptopropi) -valine] L-5, 5-dimethylthiazolidine-4-carboxyl] -leucine (Compound 8) The compound of The title was synthesized by using an analogous procedure described in the synthesis of Example 4. MS (ES): 476.3, MW Cale. = 476.7.

Example 9: N- [N '- [N "- (2 (R) -amino-3-meraptopropyl) -valine] -L-5,5-dimethylthiazolidine-4-carboxyl] -methionine (Compound 9) The compound of the title was synthesized by using an analogous procedure described in the synthesis of Example 3. MS (ES): 480.3, MW Cale. = 480.7.

Example 10: N- [N '- [N "- (2 (R) -amino-3-mercaptopropyl) -valine] -L-5,5-dimethylthiazolidine-4-carboxy] -methionine methyl ester (Compound 10) ) The title compound was synthesized by using an analogous procedure described in the synthesis of Example 4. MS (ES): 494.3, MW Cale. = 494.8.

Example 11: [N- (2 (R) -amino-3-mercaptopropyl) -L-5, 5-dimethylthiazolidine-4-carboxyl] -2,3-dichlorobenzamide (Compound 11) (a) [(tert-butoxycarbonyl) -L-5, 5-dimethylthiazolidine-4-carboxyl] -2,3-dichlorobenzamide A solution of Na- (tert-butoxycarbonyl) -L-5,5-dimethylthiazolidine-4-carboxylic acid (0.65 g, 2.50 mmol, Example 1 (a), HBTU (0.948 g, 2.50 mmol), and DIEA (1.3 g, 10 mmol) in DMF (25 mL) was stirred at room temperature for 3 minutes, and 2,3-dichlorobenzylamine (0.44 g) was added thereto. 2.50 mmol) The mixture was stirred overnight, the solvent was removed in vacuo, the residue was dissolved in EtOAc, washed with 5% NaHC03 (2 times), 5% citric acid (2 times), and Brine (2 times), dried over anhydrous MgSO 4, filtered and concentrated in vacuo The title compound (0.83 g, yield: 79%) was obtained after chromatography (silica) with EtOAc: hexanes (1: 2). NMR * H (300 MHz, CHC13) d 7.40 (m, 2H), 7.18 (m, ÍH), 6.55 (bs, H), 4.65 (m, 3H), 4.52 (m, IH), 4.07 (s, IH), 1.58 (s, 3H), 1.20 (m, 12H). (b) [N- (2 (R) -amino-3-mercaptopropyl) -L-5,5-dimethylthiazolidine-4-carboxyl] -2,3-dichlorobenzamide [(tert-butoxycarbonyl) -L-5 was dissolved , 5-dimethylthiazolidine-4-carboxy] -2, 3-disclorobenzamide (0.419 g, 1 mmol) in 10 mL of 50% TFA in DCM. The mixture was stirred at room temperature for 0.5 hours. The TFA and the solvent were removed in vacuo. The residue of N-a- (tert-butoxycarbonyl) -S- (triphenylmethyl) -L-cysteine (2 mmol; Example 1 (f)) were dissolved in MeOH (10 mL) and HOAc (0.2 mL). To this, sodium cyanoborohydride (94 mg, 1.5 mmol) was added in portions. The mixture was stirred at room temperature overnight. The solvents were removed in vacuo, the residue was dissolved in EtOAc. The solution was washed with 5% NaHC03 (2 times), 5% citric acid (2 times), and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 15 mL of DCM and 2 mL of triisopropylsilane. To the solution, 10 mL of TFA were added. The reaction mixture was stirred at room temperature for 0.5 hours. The solution was condensed in vacuo, and the resulting residue was partitioned between aqueous 0.1% TFA solution and EtOAc. The organic layer was concentrated in vacuo. The residue was triturated with hexanes and then purified by HPLC. Lyophilization gave the title compound (339 mg, yield: 83%). MS (IS): 407.0 PM Cale. = 407.4 XH NMR (300 MHz, CHC13) d 8.21 (bs, 2H), 7.61 (t, ÍH), 7.41 (dd, ÍH), 7.27 (dd, ÍH), 7.19 (dd, ÍH), 4.55 d24.43 (d, ÍH), 3.8, (d, ÍH), 3.28 (s, ÍH), 3.22 (m, ÍH), 3.10 (m, 2H), 2.79 (m, 2H), 1.73 (bs, ÍH), 1.57 (s, 3H), 1.38 (s, 3H).

Example 12: [N- (2 (R) -amino-3-mercaptopropyl) -L-5, 5-dimethylthiazolidin-4-carboxyl] -naphthylmethylamide (Compound 12) The title compound was synthesized using an analogous procedure of Example 11. MS (ES): 389.1, PM Cale. = 389.6. NMR XH (300 MHz, CHC13) d 8.15 (d, ÍH), 7.90 (m, ÍH), 7.82 (d, ÍH), 7.61-7.41 (m, 5H), 5.22 (dd, ÍH), 4.63 (dd, ÍH), 4.39 (d, ÍH), 3.78 (d, ÍH), 3.24 (s, ÍH), 2.97 (m, 2H), 2.76 (m, ÍH), 2.48 (m, 2H), 1.57 (s, 3H ), 1.40 (s, 3H), 1.28 (m, ÍH).

Other embodiments It will be understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the claims annexes. Other aspects advantages and modifications are within the claims.

Claims (19)

CLAIMS;

1. A compound of Formula I or II Formula I wherein Rx is H or NR20R21; R2 is (CH2) mSR22, (CH2) mSSR22, substituted or unsubstituted heterocycle, or substituted or unsubstituted heterocycle-lower alkyl, wherein m is 1-6 and the substituent is lower alkyl, lower alkenyl, aryl, or aryl-lower alkyl; each of R3 and R7, independently, is CH2 or (C); each of R4 and R15, independently, is H or lower alkyl; each of Rs and R16, independently is H or a substituted or unsubstituted portion selected from lower alkyl, thio-lower alkyl, lower alkenyl, thio-lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl, aryl and aryl-lower alkyl, wherein the substituent is lower alkyl, hydroxy, halo, C (0) NR23R24, or COOH; each of R6, R8, Rg, Rl ?; R12M, R13 and R17, independently, is H or a substituted or unsubstituted portion selected from lower alkyl, lower alkenyl, thio-lower alkyl, cycloalkyl, aryl and aryl-lower alkyl, where the substituent is lower alkyl, halo, hydroxy , C (0) NR25R26, or COOH; R10 is S, SO, or S02; R18 is coor27 or C (0) NR28R29, or together with R16, forms -COOCH2CH2-. R19 is a substituted (with one or more substituents, same as later) or unsubstituted portion selected from lower alkyl, lower alkenyl, aryl, and aryl-lower alkyl, wherein the substituent is lower alkyl (eg, an alkyl group also can be considered as a substituent), halo, or alkoxy; and each of 20 '21 * ^ 22' ^ 23 '^ 4 * f ^ 25 • R26' ^ 271 R²ß 'Y "R 29' independently is H or lower alkyl, with the proviso that if R 2 is (CH 2) mSH and R 5 is thio-lower alkyl, the free thio groups of R 2 and R 5 can form a disulfide bond; pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the compound has Formula I; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein the compound has the Formula II; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2, wherein R2 is (CH2) mSR22, heterocycle, or heterocycle-lower alkyl; each of R4 and R15, independently, is H; R5 is lower alkyl; R6 is H; each R8, R9, R and R12, independently is H or lower alkyl; R10 is S; R13 is H; R16 is lower alkyl or thio-substituted lower alkyl, wherein the substituent is lower alkyl; and R17 is H; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4, wherein Rx is NR20R21 and R2 is (CH2) mSR22; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5, wherein R3 is CH2; each of R8 and R9, independently, is H; and R18 is COOR27; or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6, wherein R is NH2; R2 is CH2SH; R5 is CH (CH3) (CH2CH3), CH (CH3) 2, or C (CH3) 3; each of R and R12, independently is CH3; R16 (CH2) 2SCH3 / (CH2) 3CH3, or CH2CH (CH) 2; and R18 is COOH or COOCH3; or a pharmaceutically acceptable salt thereof

8. A compound according to claim 4, wherein R1 is H; and R2 is heterocycle or heterocycle-lower alkyl; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8, wherein R3 is CH2; each of R8 and R9, independently, is H; and R18 is COOR27; or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 9, wherein R2 is imidazolyl or imidazolyl-lower alkyl; R5 is CH (CH3) (CH2CH3), CH (CH3) 2, or C (CH3) 3; each of Rn and R12, independently, is CH3; R16 is (CH2) 2SCH3, (CH12) 3CH3, or CH2CH (CH3) 2; and R18 is COOH or C00CH3; or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 3, wherein R2 is (CH2) mSR20, heterocycle, or heterocycle-lower alkyl; each of R8, R9, R11 (and R12, independently is H or lower alkyl; R10 is S; R13 is H; and R15 is H; or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11, wherein Rx is NR20R21; and R2 is (CH2) mSR22; or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 12, wherein R3 is CH2; R8 and R9 are H; and R19 is aryl-substituted or unsubstituted lower alkyl, wherein the substituent is halo or lower alkyl; or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 13, wherein Rt is NH2; R2 is CH2SH; each of RX1 and R12 independently, is CH3; R19 is 2, 3-dichlorobenzyl or 1-naphthylmethyl; or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 11, wherein Rx is H and R2 is heterocycle or heterocycle-lower alkyl; or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 15, wherein R3 is CH2, each of R8 and R9, independently, is H; and R19 is aryl-substituted or unsubstituted lower alkyl wherein the substituent is halo or lower alkyl; or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 16, wherein R2 is imidazolyl or imidazolyl-lower alkyl; each of Ru and R12, independently is CH3; and R19 is 2,3-dichlorobenzyl or l-naphthylmethyl; or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1, the compound that is of the Formula: 10 fifteen 19. A compound consisting of a first portion and a second portion, wherein each of the first and second portions, independently, is of Formula I or Formula II of claim 1 except that each R 2 of the first portion and R 2 of the second portion, independently are - (CH2) mS-, and form a disulfide bond; or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 19, wherein the first and second portions are identical; or a pharmaceutically acceptable salt thereof. 21. A method for treating tumors or restenosis in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of the compound or salt of claim 1. 22. A method according to claim 21, wherein the compound or salt is that of claim

18. 23. A method according to claim 22, wherein the compound or salt is that of the claim

19.