KR20050019004A - Prenyl trnasferase inhibitors - Google Patents

Abstract

The present invention relates to a line of compounds capable of inhibiting prenyl activity. This compound is defined by one of the following formulas (I) and (II).

(I) (II)

(Definitions for each R group are the same as detailed description)

Description

Prenyl transferase inhibitors {PRENYL TRNASFERASE INHIBITORS}

Ras-based proteins are important in the signal transduction pathway that regulates cell growth. The protein is produced in liposomes, secreted into the cytosol and post-translationally modified. The first stage of post-translation modification is panesyl or gera in a reaction catalyzed by prenyl transferases such as farnesyl transferase and geranylgeranyl transferase. Alkylation of Cys ¹⁶⁸ with nigeranyl pyrophosphate (Hancock, JF, et al., Cell 57: 1167-1177 (1989)). As a result, the three C-terminal amino acids are split (Gutierrez, L., et al., EMBO J. 8: 1093-1098 (1989)) and the terminal Cys are converted to methyl esters (Clark, S. et al , Proc. Nat'l Acad.Sci. (USA) 85: 4643-4647 (1988)). The form of Ras is also reversily palmitoylated to Cys ¹⁶⁸ directly at the N-terminus (Buss, JE, et al., Mol. Cell. Biol. 6: 116-122 (1986)). . This modification increases the hydrophobicity of the C-terminal region of Ras, which is located on the surface of the cell membrane. Localization of Ras to the cell membrane is essential for signaling (Willumsen, BM, et al., Science 310: 583-586 (1984)).

Carcinogenic forms of Ras have been observed in a large number of cancers, including at least 50% of colon cancer and at least 90% of pancreatic cancer (Bos, JL, Cancer Research 49: 4682-4689 (1989)). In these studies, the intervention of Ras in regulating signaling would be useful in the treatment of cancer.

It has already been found that the C terminal tetrapeptide of Ras is a "CAAX" modif (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). Tetrapeptides with this structure were found to be inhibitors of prenyl transferase (Reiss, et al., Cell 62: 81-88 (1990)). Because of the poor potency of these early farnesyl transferase inhibitors, they have facilitated the study of novel inhibitors with more desirable pharmacokinetic action (James, GL, et al., Science 260: 1937-1942 (1993); Kohl, NE , et al., Proc. Nat'l Acad. Sci. USA 91: 9142-9145 (1994); deSolms, 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, EC, et al., J. Biol Chem. 270: 26770 (1995); and James, et al., Proc. Natl. Acad. Sci. USA 93: 4454 (1996)).

Recently, prenyl transferase inhibitors have been shown to prevent 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, over 70% of large-scale sampling of tumor cell species was inhibited by selective prenyl transferase inhibitors against untransformed epithelial cells (Sepp-Lorenzino, I, et al., Cancer Research, 55: 5302-). 5309 (1995)).

One aspect of the invention is characterized by a compound of formula I or formula II or a pharmaceutically acceptable salt thereof.

Equation I

R ₁ is N (R ₁₀ ) (R ₁₁ );

R ₂ is thio lower alkyl;

Each R ₃ and R ₅ is, independently, CH ₂ or C (0);

R ₄ is substituted or unsubstituted thio lower alkyl, wherein the substitution is CH ₂ NHC (O) R ₁₃ and the substitution is attached to the thio group;

R ₆ is a residue of a natural or synthetic α-amino acid;

R ₇ is a residue of a natural or synthetic α-amino acid;

R _{8 together} with OH or lower alkoxy, or R ₇ forms a homoserine lactone;

Each R ₉ , R ₁₀ and R ₁₁ is independently H or lower alkyl;

R ₁₂ is substituted or unsubstituted cycloalkyl, cycloalkyl lower alkyl, aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl—wherein the substitution is lower alkyl, aryl, halo, lower alkoxy, or C (O) -R ₇ -R ₈ ;

R ₁₃ is lower alkyl, aryl, or aryl lower alkyl;

R ₁₈ together with H or R ₉ form —CH ₂ CH ₂ —;

Provided that if R ₄ is unsubstituted thio lower alkyl, the free thi group of R _{2 and} the free thi group of R ₄ may form a disulfide bond.

In one embodiment, the compound is a compound wherein R ₆ is -N (R ₁₄ ) CH (R ₁₅ ) C (0)-, R ₁₄ is H or lower alkyl and R ₁₅ is optionally substituted lower alkyl, aryl , Aryl lower alkyl, heterocycle, or heterocycle lower alkyl, wherein the substitution is lower alkyl, halo, or lower alkoxy- or R ₁₅ together with NR ₁₄ C attached thereto form a heterocycle; And R ₇ is N (R ₁₆ ) CH (R ₁₇ ) C (O) —, R ₁₆ is H or lower alkyl, and R ₁₇ is (CH ₂ ) mS (O) nCH ₃ or substituted or unsubstituted Lower alkyl, thio lower alkyl-wherein the substitution is C (0) N (R ₁₀ ) (R ₁₁ ), where m is 1-6, n is 0-2; And R ₈ is represented by formula I, which is OH or lower alkoxy. In this example, R ₂ can be CH ₂ SH; R ₄ is C (CH ₃ ) ₂ SH or CH ₂ SH, wherein the free thi group of R _{2 and} the free thi group of R ₄ may form a disulfide bond; R ₁₅ may form a heterocycle with NR ₁₄ C attached thereto; R ₁₆ can be H; And R ₁₇ can be (CH ₂ ) ₂ S (O) nCH ₃ ; R ₁ may also be NH ₂ ; R ₃ may be CH ₂ ; R ₅ may be C (O); And R ₈ may be OH or OCH ₃ . In the same embodiment, R ₂ can be (CH ₂ ) SH; R ₄ may be C (CH ₂ ) ₂ SCH ₂ NHCOCH ₃ or CH ₂ SCH ₂ NHCOCH ₃ ; R ₁₅ may form a heterocycle with NR ₁₄ C attached thereto; R ₁₆ may be H and R ₁₇ may be (CH ₂ ) ₂ S (O) nCH ₃ ; In addition, R ₁ is NH ₂ ; R ₃ is CH ₂ ; R ₅ is C (0); And R ₈ is OH or OCH ₃ .

In another embodiment, the compound is a compound wherein R ₂ is CH ₂ SH; R ₄ is C (CH ₃ ) ₂ SH or CH ₂ SH, wherein the free thi group of R _{2 and} the free thi group of R ₄ form a disulfide bond; R ₁₂ is substituted or unsubstituted aryl or aryl lower alkyl, and R ₁₈ is represented by Formula II wherein H is H. In this embodiment, R ₁ can be NH ₂ ; R ₃ may be CH ₂ ; R ₅ may be C (O); R ₉ may be H; And R ₁₂ may be substituted or unsubstituted phenyl or benzyl, wherein the substitution is lower alkyl or halo.

In another embodiment, R ₂ is (CH ₂ ) SH; R ₄ is C (CH ₂ ) ₂ SCH ₂ NHCOCH ₃ or CH ₂ SCH ₂ NHCOCH ₃ ; And R ₁₂ is substituted or unsubstituted aryl or aryl lower alkyl. In this embodiment, R ₁ can be NH ₂ ; R ₃ may be CH ₂ ; R ₅ may be CO; R ₉ may be H; And R ₁₂ may be substituted or unsubstituted phenyl or benzyl, wherein the substitution is lower alkyl or halo.

Embodiments of the present invention include the following compounds.

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

Compound 22

Compound 23

Compound 24

Since the compounds of the present invention may have asymmetric centers and form racemates, racemic mixtures and individual diastereomers together with all possible isomers, including optical isomers, the present invention includes them all. In summary, it is to be understood that unless a specific configuration is described in the structural formula, it is intended to be representative of all stereoisomers and mixtures thereof.

As used herein, "lower alkyl" is intended to include saturated aliphatic hydrocarbon groups having 1-6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and the like. "Lower alkoxy" groups include groups having 1-6 carbon atoms. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy and the like. All alkyl and alkoxy groups are branched or straight chain but not cyclic. The term "cycloalkyl" means a carbon ring of 3-7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloceptyl. The term "halo" means chloro, bromo, iodo or fluoro. The terms "heterocycle lower alkyl", "thio-lower alkyl", "cycloalkyl lower alkyl", and "aryl lower alkyl" are each substituted with one of three heterocycles, thio, cyclo alkyl, and aryl groups.

As used herein, "aryl" is intended to include stable 7-membered or less carbocyclic monocyclic, bicyclic or tricyclic, at least one ring being aromatic. Examples of the aryl group include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.

As used herein, the term heterocycle means a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic or stable 11 to 15-membered tricyclic heterocyclic ring. Which may be saturated or unsaturated, consist of carbon atoms, and from 1 to 4 heteroatoms selected from the group consisting of N, 0, and S, and any bi- ions in which any of the heterocyclic rings as defined above are melted in the benzene ring. It includes a cyclic group. The heterocyclic ring is attached to any hetero atom or carbon atom to form a stable structure. Examples of the heterocyclic element include azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxaza Benzoxazolyl, chromanyl, cynolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazole zidi Neil, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromenyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyl Naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl , Piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, quinoxalinyl (quinoxali nyl), tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thiazolidinyl , Thienofuryl, thienothienyl, thienyl, and the like.

When the group is substituted, it may be substituted 1 to 4 times. Various substituents may be attached to carbon atoms or heteroatoms (eg, S, N, or 0).

As used herein, the term “residue of α-amino acid” refers to naturally occurring α-amino acids (eg, cysteinyl, methionyl, phenylalyl, rucinyl, etc.) found in nature or in nature. Α-amino acid residues which are not synthetic amino acids (e.g., noilusinyl, or 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or penicylamine, etc.).

The compounds of the present invention may be provided in the form of pharmaceutically acceptable salts. Acceptable salts include acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate, salicylate, oxalate and stearate Acid addition salts of the same inorganic acid include, but are not limited to. Applicable within the scope of the present invention are salts formed from bases such as sodium hydroxide and potassium. Another example of a pharmaceutically acceptable salt is "Pharmaceutical Salts," J. Pharm. Sci. 66: 1 (1977).

In another embodiment of the invention, a pharmaceutically effective amount of a compound of Formula I or Formula II is administered to a mammal, such as, for example, a human, to provide prenyl transferase (eg, farnesyl transferase or geranyl gera). It is characterized by a method of inhibiting (nile transferase). In particular, the present invention provides a method of treating restenosis or tissue proliferative disease (ie, tumor) in a subject since a therapeutically effective amount of the compound or salt thereof is administered to the subject. Examples of tissue proliferative diseases include benign (eg non-malignant) cell proliferation such as fibrosis, benign prostatic hyperplasia, atherosclerosis and restenosis, and malignant cell proliferation (eg Ras mutant tumors) such as cancer and It includes everything related. Examples of treatable tumors include breast, colon, pancreas, prostate, lung, ovary, epithelial and hematopoietic cell carcinoma (Sepp-Lorenzino, I, et al., Cancer Research 55: 5302 (1995)).

A therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier component (eg, phospholipid, magnesium carbonate, or lactose together with a therapeutic compound capable of forming micelles) are taken together. A therapeutic composition (e.g., a pill, tablet, capsule or liquid) is formed for administration (e.g., oral, intravenous, intraperitoneal, or subcutaneous) to this required subject. The pills, tablets or capsules may be coated with ingredients that can protect the composition from gastric acid or intestinal enzymes in the small intestine of the subject for a sufficient time to allow the composition to pass through the small intestine undigested. .

The dosage of a compound of the present invention for treating the disease or condition will vary depending on the method of administration, the age and weight of the subject, and the condition of the subject to be treated, and ultimately will be determined by the attending physician or veterinarian. The content of a compound as determined by the attending physician or veterinarian is expressed herein as a "therapeutically effective amount."

Within the scope of the present invention are considered to be compounds of formulas I and II and novel compound intermediates used in the synthesis as described herein.

Other features and advantages of the invention will be apparent from the description and claims of the invention.

Example

It is believed that one skilled in the art can, to the fullest extent, utilize the present invention based on the description herein. Accordingly, the following specific embodiments are merely illustrative and are not intended to limit the invention in any way.

Unless limited otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, all publications, patent applications, patents, and other materials mentioned herein are incorporated herein by reference.

The following describes the synthesis of compounds 1, 4 and 9. Other compounds of the present invention can be prepared in a similar manner by those skilled in the art.

Compounds of the invention are described, for example, in Greenstein, et al., 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)).

The concentration reaction can be carried out, for example, in an inert organic solvent such as dimethylformide, dichloromethane, tetrahydrofuran, benzene or acetonitrile, for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-HCl ( EDC), 0-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), and conditionally catalysts such as 1-hydroxybenzo Triazole (HOBT) was performed. The reaction temperature was kept below room temperature (-15 ° C. to room temperature) to minimize side reactions. Cyclic disulfide formation was performed at high dilution conditions using iodine in various solvents (eg, methanol, tetrahydrofuran, acetic acid, water, etc.). B. Kamber, et al., Helv. Chim. See Acta, 63 (96): 899 (1980). The intermediate and the final product were separated and purified by standard methods such as column chromatography or HPLC. Compounds which form CH ₂ CH ₂ with R ₈ and R ₉ are, for example, Williams, et al., J. Med. Chem. 39 (7): 1346 (1996).

Example 1 N- [2- (R) -Amino-3-mercaptopropyl] -L-penicylaminyl-1,2,3,4-tetrahydro-3 (S) -isoquinoline carbonyl methionine Methyl Ester Cyclic Disulfide (Compound 1)

a) N-t-butoxycarbonyl-S-trityl-L-cysteinyl-N, O-dimethylamide

In ice water of 80 ml dimethylformamide of Nt-butoxycarbonyl-L-cysteine (8.0g) and N, O-dimethylhydroxylamine hydrochloride (7.1g) After isopropylethylamine was added and stirred at 0 ° C. for 1 hour, the reaction mixture was left at room temperature overnight. The volatiles were removed in vacuo and dried, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with aqueous NaHCO ₃ , water and dried (MgSO ₄ ). The solvent was evaporated in vacuo to dryness and the residue was chromatographed on silica gel (165 g) using CHCl ₃ as eluent. The appropriate fractions were pooled and the solvent was removed in vacuo and dried. White foam 8.08 g TLC (silica gel: CHCl ₃ / acetone = 9: 1 R _f = 0.58).

b) 2 (R) -t-butoxycarbonylamino-3-triphenylmethylmercapto-propanal

To an ice solution of 20 ml tetrahydrofuran (THF) of Nt-butoxycarbonyl s-trityl-L-cysteinyl-N, O-dimethylamide (0.85 g) 3 ml 1.0 M LiAH in THF under nitrogen atmosphere ₄ was added dropwise. After the mixture was stirred for 30 minutes, at 0 ° C., 1M KHSO ₄ was slowly added and the resulting suspension was filtered through a pad of celite and further washed with ethyl acetate. After drying with anhydrous MgSO ₄ , the solvent was further removed in vacuo and dried to yield 0.7 g of the title compound TLC (silica gel; CHC1 ₃ / acetone = 4: 1; Rf = 0.88).

c) N-t-butoxycarbonyl-S-acetamidomethylphenicilaminyl-1,2,3,4-tetra

Hydro-3 (S) -isoquinolinecarbonyl-methionine methyl ester

Ice solution of Nt-butoxycarbonyl-L-1,2,3,4-tetrahydro-3 (S) -isoquinoline (2.77 g) and L-methionine methylester hydrochloride (2.0 g), 1-hydro 30 ml dimethylform of oxybenzotriazole (HOBT) (1.37 g) and O-benzotriazol-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) (3.87 g) To the mead was added 4.9 mL diisopropylethylamine (DIEA). After stirring at 0 ° C. for 30 minutes, the reaction mixture was left at room temperature overnight. The volatiles were evaporated to dryness in vacuo and the residue was partitioned between EtOAc and water. EtOAc layer was washed with aqueous NaHCO ₃ , water and dried (MgSO ₄ ). The solvent was evaporated in vacuo and dried. Treated with chloroform (40 mL) containing 4.8 mL triethylsilane of 50% trifluoroacetic acid for 1 hour, the volatiles were removed in vacuo and dried. Trace amount of trifluoroacetic acid (TFA) was further evaporated to toluene. 1.2 ml DIEA was added to dichloromethane (20 ml) of the L-1,2,3,4-tetrahydro-3 (S) -isoquinolinecarbonyl methionine methylester TFA salt (2.2 g) cooled to 0 ° C. Then, a solution of HOBT (0.7 g), DMF (3 mL) of Nt-butoxycarbonyl-S-acetamidomethyl penicillin (1.6 g), and EDC (1.2 g) were added. The mixture was stirred at 0 ° C. for 30 minutes and then left at room temperature overnight. The volatiles were removed in vacuo and dried. The residue was partitioned between EtOAc and water. The ethyl acetate layer was washed with aqueous NaHCO ₃ , water and dried (MgSO ₄ ). The solvent was evaporated in vacuo and dried to give 3.3 g orange solid.

d) L- [S-acetamidomethylphenicilaminyl-1,2,3,4-tetrahydro-3 [S]-

Isoquinolinecarbonyl methionine methyl ester and its TFA salt

Nt-butoxycarbonyl-S-acetamidomethyl-penicilaminyl-1,2,3,4-tetrahydro-3 [S] -isoquinolinecarbonyl methionine methylester (3.3 g) is 50% TPA Treated with CH ₂ Cl ₂ (20 mL) containing 1 mL of triethylsilane of 30 min. The volatiles were removed in vacuo and dried. Trace amounts of TFA were removed by several co-evaporation with toluene. The TFA salt was dissolved in CHCl ₃ (30 mL), treated with excess triethylamine, washed with water and dried (MgSO ₄ ), and the solvent evaporated in vacuo to give a free base.

e) N- [2 (R)-(t-butoxycarbonyl) amino-3-triphenylmethylmercapto-

Propyl] -L- [S-acetamidomethyl-penicylaminyl] -1,2,3,4-tetrahydrate

Rho-3 (S) -isoquinolinecarbonyl methionine methyl ester

2 (R) -t-butoxycarbonylamino-3-triphenylmethyl-mercapto-propanal (0.7 g) and L- [S-acetamidomethylphenicilaminyl-1,2,3,4 Triacetoxy sodium borohydride Na (OAc) in CH ₂ Cl ₂ (20 mL) containing 1% acetic acid in a solution of tetrahydro-3 (s) -isoquinolinecarbonyl methionine methylester (0.43 g) ₃ BH (360 mg) was added. After stirring for 2 hours, the mixture was washed with water, 5% aqueous NaHCO ₃ , water and dried (MgSO ₄ ). The solvent was evaporated in vacuo and dried and the residue was chromatographed on silica gel using CHCl ₃ / acetone (19: 1 to 9: 1) as eluent. The appropriate fractions were pooled and the solvent removed in vacuo to dryness to give a white foam (390 mg) of the title compound. TLC (silica gel; CHCl ₃ / acetone = 4: 1; Rf = 0.4).

f) N- [2 (R)-(t-butoxycarbonyl) amino-3-mercaptopropyl] -L-penicilami

Nil] -1,2,3,4-tetrahydro-3 (S) -isoquinoline carbonyl methionine

Methyl Ester Cyclic Disulfide

N- [2 (R)-(t-butoxycarbonyl) amino-3-triphenylmethylmercaptopropyl] -L- [S-acetamidomethyl-penicylaminyl] -1,2,3, A 50 mL solution of 4-tetrahydro-3 (S) -isoquinoline carbonyl methionine methylester (500 mg) was added dropwise a solution of methanol (MeOH) (10 mL) of iodine (250 mg) to 90% aqueous MeOH. Was added. After stirring for 1 hour, most of the methanol was removed in vacuo, leaving a small amount, diluted with water, and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous Na ₂ S ₂ 0 ₃ , water, and dried (MgSO ₄ ). The solvent was evaporated in vacuo and dried to give 400 mg of the title compound.

g) N- [2- (R) -amino-3-mercaptopropyl] -L-penicylaminyl-1,2,3,4-tetra

Hydro-3 (S) -isoquinoline carbonyl methionine methylester cyclic

Disulfide

Starting material N- [2 (R)-(t-butoxycarbonyl) amino-3-mercaptopropyl] -L-penicylaminyl] -1,2,3,4-tetrahydro-3 (S)- Isoquinoline carbonyl methionine methylester cyclic disulfide (400 mg) was treated with 90% trifluoroacetic acid (TFA) water TFA / H ₂ 0 (9: 1) (10 mL) for 30 minutes. The volatiles were removed in vacuo and dried, the trace amount of TFA evaporated several times with toluene, triturated with hexanes, sealed in a glass jar and dried. The preliminary product was subjected to preparative high performance liquid chromatography (HPLC) with a C ₁₈ column and 0.1% TFA and CH ₃ CN on the mobile. The appropriate fraction was pooled and the solvent removed to give the title compound as a white solid (78 mg). M / e 541.1.

Example 2: N- [2- (R) -Amino-3-mercaptopropyl] -L- [s-acetamidomethyl-

Penicilaminyl] -1,2,3,4-tetrahydro-3 (S) -isoquinolinecarr

Bonyl Methionine (Compound 4)

N- [2 (R)-(t-butoxycarbonyl) amino-3-triphenylmethylmercaptopropyl] -L- [s-acetamidomethyl penicilaminyl] -1,2,3,4 2 mL 2 N-NaOH was added to 10 MeOH (50 mL) of a solution of -tetrahydro-3 (S) -isoquinolinecarbonyl methionine methylester (Example I e)) (500 mg). After 30 minutes most of the MeOH was removed under vacuum, leaving only a small amount, diluted with water, acidified with 5% aqueous citric acid and extracted with ethyl acetate. The ethyl acetate extract was then dried (MgSO ₄ ). The solvent was evaporated in vacuo and dried. The residue was treated with CH ₂ Cl ₂ containing triethylsilane (Et ₃ SiH) (0.5 mL) of 50% TFA for 40 minutes. Volatile material was removed and dried, and trace amounts of TFA were evaporated and dried to toluene. The preliminary product was preparative HPLC purified to give the title compound (100 mg) as a white solid. M / e = 600.2

Example 3: N- [2- (R) -Amino-3-mercaptopropyl] -L-phenyylaminyl] -2,3-dimethylanilide cyclic disulfide (Compound 9)

a) [N-t-butoxycarbonyl-S-acetamidomethyl] penicilaminyl-2,3-dimethyl

Anilid

N- [t-butoxycarbonyl] -S-acetamidomethyl penicillamine (Bachem California, Torrance, CA) (0.64 g), 2,3-dimethylaniline (0.25 g), hydroxybenzotriazole ( 0.41 g) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) in dimethylformamide (DMF) / CH ₂ Cl ₂ (1: 1, 20 mL) in an ice solution (0.57 g) Was added. The mixture was stirred at 0-5 ° C. for 30 minutes, slowly adjusted to room temperature and left overnight. After evaporation of the solvent, the residue was partitioned between ethyl acetate (EtOAc) and water. EtOAc extract was washed with aqueous NaHCO ₃ , water and dried (MgSO ₄ ). The solvent was evaporated in vacuo and dried. The residue was chromatographed on silica gel (40 g) using CHC1 ₃ / acetone = 19: 1 as eluent, the appropriate fractions were pooled and the solvent removed in vacuo to give 350 mg of the title compound. TLC (silica gel: CHC1 ₃ / acetone = 4: 1, Rf-0.77).

b) L- [S-acetamidomethylphenicilaminyl-2,3-dimethyl anilide TFA salt

[Nt-butoxycarbonyl-S-acetamidomethyl] -phenylaminyl-2,3-dimethylanilide was treated with CH ₂ Cl ₂ (20 mL) of 50% TFA for 30 minutes. The volatiles were removed in vacuo and dried. Trace TFA was co-evaporated several times with toluene. The TFA salt was dissolved in CHC1 ₃ (30 mL), treated with excess triethylamine, washed with water, dried (MgSO4) and the solvent evaporated in vacuo to give a free base.

c) N- [2 (R)-(t-butoxycarbonyl) amino-3-triphenylmethylmercapto

Propyl] -L- [S-acetamidomethylphenicilaminyl-2,3-dimethylamid

2 (R) -t-butoxycarbonylamino-3-triphenylmethylmercaptopropanal (0.5 g; Example lb) and L- [S-acetamidomethylphenicilaminyl-2,3-dimethyl NaCNBH ₃ (100 mg) was added in portions to MeOH (HOAc) (10 mL) containing 1% acetic acid in a stirred solution of anilide TFA salt (0.3 g). The mixture was left overnight at room temperature. Most of the solvent was evaporated in vacuo to a small amount and fractionated between EtOAc and water. EtOAc layer was further washed with aqueous NaHCO ₃ , water and dried (MgSO ₄ ). After evaporation of the solvent, the residue was chromatographed on silica gel using CHCl ₃ -acetone (19: 1 to 9: 1) as eluent (30 g). The appropriate fractions were pooled and the solvent was evaporated in vacuo and dried to afford 360 mg of the title compound. TLC (silica gel: CHCl ₃ / acetone = 9: 1, Rf = 0.13.

d) N- [2- (R) -amino-3-mercaptopropyl] -L-penicylaminyl-2,3-dimethyl

Amyl cyclic disulfide

N- [2 (R)-(t-butoxycarbonyl) amino-3-triphenylmethylmercaptopropyl] -L- [S-acetamidomethyl penicylaminyl] -2,3-dimethylamide To a stirred aqueous solution of (350 mg) of 50 mL 90% MeOH was added iodine (250 mg) of MeOH (5 mL). After 1 hour, most of the solvent was evaporated in vacuo to a small amount, diluted with water and extracted with EtOAc. EtOAc layer was washed with aqueous Na ₂ S ₂ 0 ₃ , water and dried. (MgSO ₄ ). The solvent was removed in vacuo and dried (220 mg), treated with 90% aqueous TFA (ml) for 30 minutes, and the volatiles were removed in vacuo and dried. The preliminary product was purified by preparative HPLC to give 62 mg of the title compound as a white solid. M / e = 340.2.

Other Example

While the invention has been described in connection with the detailed description thereof, the foregoing description is intended to be illustrative and not intended to limit the scope of the invention, the scope of which is defined by the appended claims. Other aspects, advantages and modifications are within the scope of the claims.

The present invention relates to a line of compounds capable of inhibiting prenyl activity.

Claims (12)

Compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof: Equation I R ₁ is N (R ₁₀ ) (R ₁₁ ); R ₂ is thio (C ₁ -C ₆ ) alkyl; Each R ₃ and R ₅ is, independently, CH ₂ or C (0); R ₄ is substituted or unsubstituted thio (C ₁ -C ₆ ) alkyl, wherein the substitution is CH ₂ NHC (O) R ₁₃ and the substitution is attached to the thio group; R ₆ is —N (R ₁₄ ) CH (R ₁₅ ) C (0)-, R ₁₄ is H or (C ₁ -C ₆ ) alkyl, or R ₁₅ is substituted or unsubstituted (C ₁ -C ₆ ) Alkyl; Phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl; Phenyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, anthracenyl (C ₁ -C ₆ ) alkyl, biphenyl (C ₁ -C ₆ ) alkyl, tetrahydronaphthyl (C ₁ -C ₆ ) alkyl, indanyl (C ₁ -C ₆ ) alkyl, phenanthrenyl (C ₁ -C ₆ ) alkyl; Azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl ), Clinolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imida Zolyl, indolinyl, indolyl, isochromenyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadizolyl (oxadiazolyl), 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, Pyridyl, pyridyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahigh Rooisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thiazolidinyl, thienofuryl, thienothienyl , Thienyl; And azepinyl (C ₁ -C ₆ ) alkyl, benzimidazolyl (C ₁ -C ₆ ) alkyl, benzisoxazolyl (C ₁ -C ₆ ) alkyl, benzofurazanyl (C ₁ -C ₆ ) alkyl, Benzopyranyl (C ₁ -C ₆ ) alkyl, benzothiopyranyl (C ₁ -C ₆ ) alkyl, benzofuryl (C ₁ -C ₆ ) alkyl, benzothiazolyl (C ₁ -C ₆ ) alkyl, benzothier Neyl (C ₁ -C ₆ ) alkyl, benzoxazolyl (C ₁ -C ₆ ) alkyl, chromanyl (C ₁ -C ₆ ) alkyl, cynolinyl (C ₁ -C ₆ ) alkyl, dihydrobenzofuryl ( C ₁ -C ₆ ) alkyl, dihydrobenzothienyl (C ₁ -C ₆ ) alkyl, dihydrobenzothiopyranyl (C ₁ -C ₆ ) alkyl, dihydrobenzothio-pyranyl sulfone (C ₁ -C ₆ ) alkyl, furyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, imidazolinyl (C ₁ -C ₆ ) alkyl, imidazolyl (C ₁ -C ₆ ) alkyl, indolinyl (C ₁ -C ₆₎ alkyl, indolyl (C ₁ -C ₆₎ alkyl, iso-chromanyl (C ₁ -C ₆₎ alkyl, isoindolinone carbonyl (C ₁ -C ₆₎ alkyl, iso quinolinyl (C ₁ -C ₆₎ alkyl, isobutyl thiazolidinyl (C ₁ -C ₆₎ alkyl, isobutyl T Thiazolyl (C ₁ -C ₆₎ alkyl, isobutyl thiazolidinyl (C ₁ -C ₆₎ alkyl, morpholinyl (C ₁ -C ₆₎ alkyl, naphthyridine piperidinyl (C ₁ -C ₆₎ alkyl, oxadiazolyl (C ₁ -C ₆₎ alkyl, 2-oxide in children Jaffe carbonyl (C ₁ -C ₆₎ alkyl, 2-oxide Sophie piperazinyl (C ₁ -C ₆₎ alkyl, 2-oxo-piperidinyl (C ₁ -C ₆ ) alkyl, 2-oxopyrrolidinyl (C ₁ -C ₆ ) alkyl, piperidyl (C ₁ -C ₆ ) alkyl, piperazinyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyridyl N-oxide (C ₁ -C ₆ ) alkyl, quinoxalinyl (C ₁ -C ₆ ) alkyl, tetrahydrofuryl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, tetrahydro-quinolinyl (C ₁ -C ₆ ) alkyl, thiamopolynyl (C ₁ -C ₆ ) alkyl, thiamopolynyl sulfoxide (C ₁ -C ₆ ) alkyl, Thiazolyl (C ₁ -C ₆ ) alkyl, thiazolinyl (C ₁ -C ₆ ) alkyl, thiazolidinyl (C ₁ -C ₆ ) alkyl, thienofuryl (C ₁ -C ₆ ) alkyl, thienothier A group selected from the group consisting of niyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl Wherein the substitution is (C ₁ -C ₆ ) alkyl, halo, or (C ₁ -C ₆ ) alkoxy; R ₇ is a residue of a natural or synthetic α-amino acid; R _{8 together} with OH or (C ₁ -C ₆ ) alkoxy, or R ₇ forms a homoserine lactone; Each R ₉ , R ₁₀ and R ₁₁ is independently H or (C ₁ -C ₆ ) alkyl; R ₁₂ is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; Cyclopropyl (C ₁ -C ₆ ) alkyl, cyclobutyl (C ₁ -C ₆ ) alkyl, cyclopentyl (C ₁ -C ₆ ) alkyl, cyclohexyl (C ₁ -C ₆ ) alkyl, cycloheptyl (C _1- C ₆ ) alkyl; Phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl; Phenyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, anthracenyl (C ₁ -C ₆ ) alkyl, biphenyl (C ₁ -C ₆ ) alkyl, tetrahydronaphthyl (C ₁ -C ₆ ) alkyl, indanyl (C ₁ -C ₆ ) alkyl, phenanthrenyl (C ₁ -C ₆ ) alkyl; Azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl ), Clinolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imida Zolyl, indolinyl, indolyl, isochromenyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadizolyl (oxadiazolyl), 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, Pyridyl, pyridyl N-oxide, quinoxalinyl, tetrahydrofuryl, tetrahigh Rooisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thiazolidinyl, thienofuryl, thienothienyl , Thienyl; And azepinyl (C ₁ -C ₆ ) alkyl, benzimidazolyl (C ₁ -C ₆ ) alkyl, benzisoxazolyl (C ₁ -C ₆ ) alkyl, benzofurazanyl (C ₁ -C ₆ ) alkyl, Benzopyranyl (C ₁ -C ₆ ) alkyl, benzothiopyranyl (C ₁ -C ₆ ) alkyl, benzofuryl (C ₁ -C ₆ ) alkyl, benzothiazolyl (C ₁ -C ₆ ) alkyl, benzothier Neyl (C ₁ -C ₆ ) alkyl, benzoxazolyl (C ₁ -C ₆ ) alkyl, chromanyl (C ₁ -C ₆ ) alkyl, cynolinyl (C ₁ -C ₆ ) alkyl, dihydrobenzofuryl ( C ₁ -C ₆ ) alkyl, dihydrobenzothienyl (C ₁ -C ₆ ) alkyl, dihydrobenzothiopyranyl (C ₁ -C ₆ ) alkyl, dihydrobenzothio-pyranyl sulfone (C ₁ -C ₆ ) alkyl, furyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, imidazolinyl (C ₁ -C ₆ ) alkyl, imidazolyl (C ₁ -C ₆ ) alkyl, indolinyl (C ₁ -C ₆₎ alkyl, indolyl (C ₁ -C ₆₎ alkyl, iso-chromanyl (C ₁ -C ₆₎ alkyl, isoindolinone carbonyl (C ₁ -C ₆₎ alkyl, iso quinolinyl (C ₁ -C ₆₎ alkyl, isobutyl thiazolidinyl (C ₁ -C ₆₎ alkyl, isobutyl T Thiazolyl (C ₁ -C ₆₎ alkyl, isobutyl thiazolidinyl (C ₁ -C ₆₎ alkyl, morpholinyl (C ₁ -C ₆₎ alkyl, naphthyridine piperidinyl (C ₁ -C ₆₎ alkyl, oxadiazolyl (C ₁ -C ₆₎ alkyl, 2-oxide in children Jaffe carbonyl (C ₁ -C ₆₎ alkyl, 2-oxide Sophie piperazinyl (C ₁ -C ₆₎ alkyl, 2-oxo-piperidinyl (C ₁ -C ₆ ) alkyl, 2-oxopyrrolidinyl (C ₁ -C ₆ ) alkyl, piperidyl (C ₁ -C ₆ ) alkyl, piperazinyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyridyl N-oxide (C ₁ -C ₆ ) alkyl, quinoxalinyl (C ₁ -C ₆ ) alkyl, tetrahydrofuryl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, tetrahydro-quinolinyl (C ₁ -C ₆ ) alkyl, thiamopolynyl (C ₁ -C ₆ ) alkyl, thiamopolynyl sulfoxide (C ₁ -C ₆ ) alkyl, Thiazolyl (C ₁ -C ₆ ) alkyl, thiazolinyl (C ₁ -C ₆ ) alkyl, thiazolidinyl (C ₁ -C ₆ ) alkyl, thienofuryl (C ₁ -C ₆ ) alkyl, thienothier A group selected from the group consisting of niyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl In the above, the substitution is a (C ₁ -C ₆ ) alkyl; Phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl; Halo, (C ₁ -C ₆ ) alkoxy, and C (O) —R ₇ -R ₈ ; R ₁₃ is (C ₁ -C ₆ ) alkyl; Phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl; Or phenyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, anthracenyl (C ₁ -C ₆ ) alkyl, biphenyl (C ₁ -C ₆ ) alkyl, tetrahydronaphthyl ( C ₁ -C ₆ ) alkyl, indanyl (C ₁ -C ₆ ) alkyl, or phenanthrenyl (C ₁ -C ₆ ) alkyl; R ₁₈ together with H or R ₉ form CH ₂ CH ₂ ; Provided that the free thio groups of R ₂ and R ₄ do not form a disulfide bond, and R ₁₅ does not form a heterocycle with N (R ₁₄ ) C attached thereto. The method of claim 1, A compound or a pharmaceutically acceptable salt thereof, wherein said compound is represented by formula (I). The method of claim 1, A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula II. The method of claim 2, R ₇ is N (R ₁₆ ) CH (R ₁₇ ) C (O) —, R ₁₆ is H or (C ₁ -C ₆ ) alkyl, and R ₁₇ is (CH ₂ ) mS (O) nCH _3- Wherein m is 1-6, n is 0-2, or substituted or unsubstituted (C ₁ -C ₆ ) alkyl, thio (C ₁ -C ₆ ) alkyl, wherein the substitution is C (0) N (R ₁₀ ) (R ₁₁ )-; And R ₈ is OH or (C ₁ -C ₆ ) alkoxy or a pharmaceutically acceptable salt thereof. The method of claim 4, wherein R ₂ is CH ₂ SH; And R ₄ is C (CH ₃ ) ₂ SCH ₂ NHC (O) CH ₃ or CH ₂ SCH ₂ NHC (O) CH ₃ or a pharmaceutically acceptable salt thereof. The method of claim 3, R ₂ is (CH ₂ ) SH; And R ₄ is C (CH ₃ ) ₂ SCH ₂ NHCOCH ₃ or CH ₂ SCH ₂ NHCOCH ₃ or a pharmaceutically acceptable salt thereof. The method of claim 6, R ₁₂ is substituted or unsubstituted phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, or phenanthrenyl; Or substituted or unsubstituted phenyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, anthracenyl (C ₁ -C ₆ ) alkyl, biphenyl (C ₁ -C ₆ ) alkyl, A compound or a pharmaceutically acceptable salt thereof, which is tetrahydronaphthyl (C ₁ -C ₆ ) alkyl, indanyl (C ₁ -C ₆ ) alkyl, or phenanthrenyl (C ₁ -C ₆ ) alkyl. The method of claim 7, wherein R ₁ is NH ₂ ; R ₃ is CH ₂ ; R ₅ is C (O); R ₉ is H; And R ₁₂ is substituted or unsubstituted phenyl or benzyl, wherein said substitution is (C ₁ -C ₆ ) alkyl or halo- or a pharmaceutically acceptable salt thereof. The method of claim 1, The compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from compounds of the formula A composition for treating tumors or restenosis comprising a therapeutically effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof. The method of claim 10, A composition or a pharmaceutically acceptable salt thereof, wherein said compound or salt thereof is as defined in claim 9. A pharmaceutical composition for treating tumor or restenosis comprising the compound of claim 1 and a pharmaceutically acceptable carrier.