Inhibitors prenyltransferase

 

The invention relates to the compounds of formula I or formula II, where R1denotes N(R10)(R11); R2means thio-lower alkyl; each of R3and R5independently represents CH2or C(O); R4denotes a substituted or unsubstituted dionissia alkyl, where the Deputy is CH2NHC(O)R13and he added to the specified tighrope; R6denotes the residue synthetic heteroaromatic-amino acids; R7denotes a residue of natural or synthetic-amino acids; R8IT denotes or lower alkoxy, or together with R7forms homoserine; R9denotes H; each of R10and R11, independently, is H; R12denotes a substituted or unsubstituted fragment selected from aryl, allyssia of alkyl, where the substituents are one or more lower Akilov or halogen; R13denotes lower alkyl; R18denotes H; provided that if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2and R4can form disulfide bonds; or its pharmaceutically acceptable salts. Connection to izopet is to make these connections, as well as the method of inhibiting the activity prenyltransferase. 4 C. and 18 h.p. f-crystals.

The background to the invention the Ras Family of proteins is important in modulating cell growth path signal transduction. The protein is produced in the ribosome is released into the cytosol and excision modified. The first stage in a series of post-translational modifications is the alkylation of Cys168farnesyl or geranylgeranylpyrophosphate in reactions catalyzed by enzymes prenyltransferase, such as farnesyltransferase and geranylgeranyltransferase (Hancock, JF, et al., Cell 57:1167-1177 (1989)). Subsequently, the three C-terminal amino acids otscheplaut (Gutierrez, L., et al., EMBO J. 8:1093-1098 (1989)) and the terminal Cys is transformed into methyl ester (Clark, S., et al., Proc. Nat'1 Acad. Sci. (USA) 85:4643-4647 (1988)). Some forms of Ras are also reversible palmitoylated on cysteine residues immediately N-terminal to Cys168(Buss, JE, et al. , Mol. Cell. Biol. 6:116-122 (1986)). It is assumed that these modifications increase the hydrophobic C-terminal region of Ras, causing it to be localized on the surface of the cell membrane. Localization of Ras to the cell membrane is necessary for signaline cancer, including over 50 percent of cancer of the colon and over 90 percent of pancreatic cancers (Bos JL, Cancer Research, 49:4682-4689 (1989)). These observations suggest that interfering with the function mediated by the Ras signal transduction may be useful in the treatment of cancer.

It was previously shown that the C-terminal of tetrapeptide Ras is the motive "SHAH" (where C denotes cysteine, And represents aliphatic amino acid and X represents any amino acid). It was shown that tetrapeptide having this structure, are inhibitors prenyltransferase (Reiss, et al., Cell 62: 81-88 (1990)). Weak potency of these inhibitors still farnesyltransferase encouraged to find new inhibitors with more favorable pharmacokinetic character (James, GL, et al., Science 260:1937-1942 (1993); Kohl, NE, et al., Proc. Nat'1 Acad. Sci. USA 91:9141-9145 (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. NAT'l Acad. Sci. USA 93:4454 (1996)).

It was recently revealed that the inhibitor prenyltransferase can block the growth of Ras-dependent tumors in Nude mice (Kohl, NE, et al., Proc. Nat'1 Acad. Sci. USA 91:9141-9145 (1994)). In addition, it was found that more than 70 percent of large numbers obrazrovanii epithelial cells (Sepp-Lorenzino, I, et al., Cancer Research 55:5302-5309 (1995)).

Brief description of the invention In one aspect the invention relates to a compound of formula I or formula IIwhere R1denotes N(R10)(R11); R2means dionissia alkyl; each of R3and R5independently represents CH2or C(O); R4denotes a substituted or unsubstituted dionissia alkyl, where specified by the Deputy is CH2NHC(O)R13and this Deputy is attached to the specified tighrope;
R6denotes the residue of a natural or synthetic-amino acids;
R7denotes the residue of a natural or synthetic-amino acids;
R8IT denotes or lower alkoxy, or together with R7forms homoserine;
each of R9, R10and R11independently, represents H or lower alkyl;
R12denotes a substituted or unsubstituted cycloalkyl, cycloalkenyl alkyl, aryl, arlinski alkyl, heterocycle or heterozyklisches alkyl, where the Deputy is lower alkyl, aryl, halogen, lower alkoxy or C(O)-R7-R8;
R13indicates the lowest Ala is the condition, if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2free tigraphy of R4can form disulfide bonds; or its pharmaceutically acceptable salt.

In one embodiment the compound is a compound of formula I, where R6represents-N(R14)CH(R15)C(O)-, where R14denotes H or lower alkyl; and R15denotes a substituted or unsubstituted lower alkyl, aryl, arlinski alkyl, heterocycle or heterozyklisches alkyl, where specified by the Deputy is lower alkyl, halogen or lower alkoxygroup, or where R15together with the adjacent NR14C form a heterocycle; and R7represents-N(R16)CH(R17)C(O)-, where R16denotes H or lower alkyl; and R17means (CH2)mS(O)nCH3or substituted or unsubstituted lower alkyl, dionissia alkyl, where specified by the Deputy is C(O)N(R10)(R11), m is 1-6, n is 0-2 and R8IT denotes or lower alkoxygroup. In this embodiment R2maybe CH2SH; R4can be(CH3)2S or CH2SH, where free tighrope of R2and free tighrope of R4the image is 16 can be H; and R17can be (CH2)2S(O)nCH3; in addition, R1maybe NH2; R3maybe CH2; R5can be C(O); and R8maybe HE or och3. In the same embodiment R2can be (CH2)S; R4may be C(CH2)2SCH2NHCOCH3or CH2S2MNSON3; R15together with the adjacent NR14C can form a heterocycle; R16can be H; and R17can be (CH2)2S(O)nCH3; in addition, R1denotes NH2; R3denotes CH2; R5denotes C(O); and R8indicates HE or och3.

In another embodiment the compound is a compound of formula II, where R2denotes CH2SH; R4denotes C(CH3)2S or CH2SH, where free tighrope of R2and free tighrope of R4form a disulfide bond; R12denotes a substituted or unsubstituted aryl or arlinski alkyl, and R18denotes N. In this embodiment R1maybe NH2; R3maybe CH2; R5can be C(O); R9can be H; and R12may be substituted or nezameshchenny R2means (CH2)S; R4denotes C(CH2)2S2The N3or CH2S2The N3; and R12denotes a substituted or unsubstituted aryl or arlinski alkyl. In this embodiment R1maybe NH2; R3maybe CH2; R5may be; R9can be H; and R12may be substituted or unsubstituted phenyl or benzyl, where the specified Deputy is lower alkyl or halogen.

Examples of the present invention include compounds 1-24 (see the end of the description).

The compounds of this invention can have asymmetric centers and can exist as racemates, racemic mixtures and individual diastereomers, with all possible isomers, including optical isomers are included in this invention. For simplicity, where not indicated the specific configuration in the structural formula, it should be understood that presents all enantiomeric forms and mixtures thereof.

As used here, a "lower alkyl" denotes a saturated aliphatic hydrocarbon group having 1-6 carbon atoms. Examples of the lower altergroup include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and so on is include methoxy, ethoxy, propoxy, isopropoxy and the like. All alkyl and alkoxygroup can be branched or linear, but not cyclic. The term "cycloalkyl" denotes the ring of 3-7 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "halogen" denotes chlorine, bromine, iodine or fluorine. The terms "heterozyklisches alkyl", "dionissia alkyl", "cycloalkenyl alkyl" and "arlinski alkyl" refers to these radicals, substituted respectively with one to three groups: a heterocycle, thio, cycloalkyl and aryl.

As is used herein, "aryl" refers to any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, where at least one ring is aromatic. Examples of airgroup include phenyl, naphthyl, anthracene, biphenyl, tetrahydronaphthyl, indanyl, phenanthrene and the like.

The term "heterocycle", as used here, refers to a stable 5 - or 7-membered monocyclic or stable 8-or 11-membered bicyclic or stable 11 - or 15-membered tricyclic heterocyclic ring which is saturated or unsaturated, and which consists of atomo the Bo bicyclic group, in which any of the above heterocyclic rings condensed with the benzene ring. Heterocyclic ring may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepine, benzimidazolyl, benzisoxazole, benzofurazanyl, benzopyranyl, benzothiophene, benzofuran, benzothiazole, benzothiazyl, benzoxazolyl, bromanil, cinnoline, dihydrobenzofuran, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, furyl, imidazolidinyl, imidazolyl, imidazolyl, indolinyl, indolyl, isopropanol, isoindolines, ethenolysis isothiazolinones, isothiazolin, morpholinyl, naphthyridine, oxadiazole, 2-oxazinyl, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, piperidyl, piperazinil, pyridyl, pyridyl-N-oxide, honokalani, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydroquinoline, thiomorpholine, themorphological, thiazolyl, thiazolyl, diazolidinyl, cyanophoric, theNational, thienyl and the like.

When the group is substituted, it can be substituted one to four times. Various sketsa here the term "residue-amino acids" is set for the remainder of-an amino acid which is either natural-an amino acid that occurs in nature (e.g., cysteinyl, methionyl, phenylalanine, Latini and so on), or synthetic-amino acid that does not occur in nature (for example, norlaili or the remainder of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or penicillamine, and so on).

The compounds of this invention can be represented in the form of pharmaceutically acceptable salts. Acceptable salts include, but are not limited to, acid additive salts of inorganic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluensulfonate, pamoate, salicylate, oxalate, and stearate. Within the scope of the present invention, where applicable, include salts formed from bases such as sodium hydroxide or potassium. Additional examples of pharmaceutically acceptable salts, see "Pharmaceutical Salts," J. Pharm. Sci. 66:1 (1977).

In another aspect, the invention relates to a method of inhibiting prenyltransferase (for example, farnesyltransferase or geranylgeranyltransferase) objective number of the compounds of formula I or formula II. Specifically, the invention also covers a method of treating restenosis or proliferative diseases of the tissues (i.e., tumor) in a subject by introducing to the subject a therapeutically effective amount of the compound or its salts. Examples of proliferative tissue diseases include those associated with benign (i.e. non-cancerous) cell proliferation, such as fibrosis, benign prostatic hyperplasia, atherosclerosis and restenosis, and those associated with malignant proliferation of cells, such as cancer (i.e., rs-mutant tumors). Examples of treatable tumors include cancers of the breast, colon, pancreas, prostate, lung, ovarian, epidermal and hematopoietic cancer (Sepp-Lorenzio, I, efc al. , Cancer Research 55:5302 1995)).

A therapeutically effective amount of a compound of the invention and the substance pharmaceutically acceptable carrier (e.g., magnesium carbonate, lactose, or a phospholipid with which therapeutic compound can form a micelle) together form a pharmaceutical product (e.g., pill, tablet, capsule, or liquid) for administration (e.g. oral, intravenous, dermal or subcutaneous) to the subject, well the drug from stomach acid and intestinal enzymes in the stomach of a subject over a period of time, sufficient to ensure that the drug has passed undigested in the small intestine of the subject.

The dose of a compound of the present invention for the treatment of the above diseases or disorders varies depending on the method of administration, age and body weight of the subject and the condition of the subject being treated, and ultimately will be determined by the regular physician or veterinarian. This number of connections, which is determined by the physician or veterinarian, called here "therapeutically effective amount".

Also considered within the scope of the invention is a method of obtaining compounds of formula I or formula II and new chemical intermediate compounds used in these syntheses as described here.

Other characteristic features and advantages of the present invention will be ascertained from the detailed description of the invention and claims.

Detailed description of the invention
It is assumed that the expert in this area may be based on the descriptions given here to use this invention in its fullest extent. Therefore, the following specific embodiment is reproduced as merely illustrative and not limiting ostalog is implemented here have the same value, which usually means an expert in this field to which this invention belongs. In addition, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.

The following is a description of the synthesis of compounds 1, 4 and 9. Other compounds of the invention can be obtained in a similar way an expert in this field.

The compounds of this invention will be received, using standard methodology solvent phase, for example, as described 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 condensation reaction is carried out in an inert organic solvent, for example dimethylformamide, dichloromethane, tetrahydrofuran, benzene or acetonitrile, using a suitable soft condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-Hcl (EDC), hexaflurophosphate 0-benzotriazol-1-yl-N,N, N', N'-tetramethyluronium (HBTU), and, optionally, a catalyst such as 1-hydroxybenzotriazole (NOVT). The reaction temperature kept lower than room temperature (-15oC to room temperature), in order to minimize side reactions. The formation of cyclic disulfide is carried out in the HF), acetic acid, water and so on). Century Kamber, et al. , Helv. Chim. Acta, 63(96):899 (1980). The intermediate and final products are isolated and purified by standard methods, such as column chromatography or HPLC. Compounds where R8together with R9form CH2CH2can be obtained according to the methods of Williams et al., J. Med. Chem. 39(7):1346 (1996), for example, starting with the protected cysteine.

Example 1
Cyclic disulfide complex methyl ester N-[2-(R)-amino-3-mercaptopropyl] -L-penicillamine-1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (compound 1)
a) N-tert-butoxycarbonyl-S-trityl-L-cysteinyl-N,O-dimethylamide
It chilled with ice to a solution of N-tert-butoxycarbonyl-L-cysteine (8.0 g) and the hydrochloride of N, O-dimethylhydroxylamine (7,1 g) in 80 ml of dimethylformamide add to 4.2 ml diethylthiophosphate and 14.7 ml of diisopropylethylamine and after stirring at 0oC for 1 h the reaction mixture was kept at room temperature during the night. Volatiles are removed in vacuo to dryness and the residue distributed between ethyl acetate and water. The ethyl acetate layer was washed with aqueous NaHCO3, water and dried (MgS4). The solvent is evaporated in vacuum to dryness and the residue is subjected to chromatography on silica in vacuum to dryness. White foam 8,08 g TLC (silica gel; l3/acetone 9:1; Rf= 0,58).

b) 2(R)-tert-butoxycarbonylamino-3-triphenylmethylchloride
It chilled with ice to a solution of N-tert-butoxycarbonyl-S-trityl-L-cysteinyl-N, O-dimethylamide of 0.85 g) in 20 ml of tetrahydrofuran (THF) is added dropwise 3 ml of 1.0 M LiAlH4in THF under nitrogen atmosphere. The mixture is then stirred for 30 min at 0oC, slowly add 1 M KHSO4and the resulting emulsion is filtered through a layer of celite and then washed with ethyl acetate. After drying over anhydrous MgSO4the solvent is removed in vacuum to dryness, resulting in the 0.7 g specified in the connection header. TLC (silica gel; l3/acetone = 4:1; Rf=0,88).

C) methyl ester of N-tert-butoxycarbonyl-S-acetamidobenzenesulfonyl-1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl
It chilled with ice to a solution of N-tert-butoxycarbonyl-L-1,2,3,4-tetrahydro-3(S)-isoquinoline (2,77 g) and hydrochloride difficult methyl ester of L-methionine (2.0 g), 1-hydroxybenzotriazole (NOVT) (1,37 g) and hexaphosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU) (a 3.87 g) in 30 ml of dimethylformamide added to 4.9 ml of diisopropylethylamine (DIEA). After stirring at 0oWith over 30 mi is e to dryness and the residue partitioned between EtOAc and water. The EtOAc layer was washed with water Panso3, water and dried (MgSO4). The solvent is evaporated in vacuum to dryness. The residue is treated with 50% solution triperoxonane acid in chloroform (40 ml) containing 4.8 ml of triethylsilane, within 1 hour and the volatiles removed in vacuum to dryness. Traces triperoxonane acid (TFA) in addition evaporated with toluene. To this TFA salt complex methyl ester L-1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (2.2 g) in dichloromethane (20 ml), cooled to 0oTo add 1.2 ml of DIEA, and then the solution NOWT (0.7 g), N-tert-butoxycarbonyl-S-acetamidomethyl (1.6 g) in DMF (3 ml) and EDC (1.2 g). The mixture was stirred at 0oC for 30 min and then incubated at room temperature overnight. Volatiles are removed in vacuo to dryness. The residue is partitioned between EtOAc and water. The ethyl acetate layer was washed with water Panso3, water and then dried (MgSO4). The solvent is evaporated in vacuum to dryness to obtain 3,3 g of orange solid.

d) methyl ester of L-[S-acetamidobenzenesulfonyl-1,2,3,4-tetrahydro-3[S]-ethynodiolthinyl and its salt with TFA
Methyl ester of N-tert-butoxycarbonyl-S-acetamidobenzenesulfonyl-1,2,3,4-Tetra the current 1 ml of triethylsilane, within 30 minutes Volatiles removed in vacuum to dryness. Traces of TFA remove joint evaporation with toluene several times. The TFA salt was dissolved in l3(30 ml), treated with excess triethylamine, washed with water, dried (MgS4) and the solvent evaporated in vacuo to obtain the free base.

e) methyl ester of N-[2-(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylchloride]-L-[S-acetamidobenzenesulfonyl]-1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl
To a solution of 2(R)-tert-butoxycarbonylamino-3-triphenylmethylchloride (0.7 g) and compound methyl ester of L-[S-acetamidobenzenesulfonyl] -1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (0,43 g) in CH2Cl2(20 ml) containing 1% acetic acid, add triacetoxyborohydride sodium PA(SLA)3NR (360 mg) in one portion. After stirring for 2 hours the mixture was washed with water, 5% aqueous solution Panso3, water and then dried (MgSO4). The solvent is evaporated in vacuum to dryness and the residue is subjected to chromatography on silica gel (50 g), using l3/acetone (19:1 to 9:1) as solvents for elution. The appropriate fractions are combined and the solvents removed in vacuo to dryness, the floorf=0,4).

f) a Cyclic disulfide complex methyl ester N-[2-(R)-(tert-butoxycarbonyl)amino-3-mercaptopropyl] -L-penicillamine] -1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl
To a solution of complex methyl ester N-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylchloride] -L-[S-acetamidobenzenesulfonyl] -1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (500 mg) in 50 ml of 90% aqueous solution Meon is added dropwise a solution of iodine (250 mg) in methanol (Meon) (10 ml). After stirring for 1 hour the greater part of the methanol is removed in vacuo to obtain a small volume, diluted with water and extracted with ethyl acetate. The extract in ethyl acetate washed with water, aqueous Na2S2About3, water and then dried (MgSO4). The solvent is evaporated in vacuum to dryness, receiving 400 mg specified in the connection header.

g) a Cyclic disulfide complex methyl ester N-[2-(R)-amino-3-mercaptopropyl] -L-penicillamine-1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl
The crude cyclic disulfide complex methyl ester N-[2(R)-tert-butoxycarbonyl)amino-3-mercaptopropyl] -L-penicillamine]-1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (400 mg) is treated with 90% R is the cosmology vacuum to dryness and the traces of TFA is evaporated with toluene several times and the residue triturated with hexane, decanted and then dried. The crude product is subjected to preparative high performance liquid chromatography (HPLC) using a column C18and 0.1% TFA and CH3The JV as the mobile phase. Appropriate fractions merge together and the solvents removed, getting mentioned in the title compound as a white solid (78 mg). M/e=541,1.

Example 2
N-[2-(R)-amino-3-mercaptopropyl] -L-[S-acetamidobenzenesulfonyl] -1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (compound 4)
To a solution of complex methyl ester N-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylchloride] -L-[S-acetamidobenzenesulfonyl] -1,2,3,4-tetrahydro-3(S)-ethynodiolthinyl (example 1(e)) (500 mg) in 10% water-Meon (50 ml) add 2 ml of 2 N NaOH. After 30 min the greater part of the Meon removed in vacuo to obtain a small volume, diluted with water, acidified with 5% aqueous citric acid solution and extracted with ethyl acetate. The extract in ethyl acetate then dried (MgSO4). The solvent is evaporated in vacuum to dryness. The residue is treated with 50% TFA solution in CH2Cl2containing triethylsilane (E3Si)(0.5 ml) over 40 minutes Volatiles removed to dryness and the traces of TFA is evaporated with toluene and then the g) as a white solid. M/e=600,2.

Example 3
Cyclic disulfide of N-[2-(R)-amino-3-mercaptopropyl]-L-penicillamine] -2,3-dimethylaniline (compound 9)
a) [N-tert-butoxycarbonyl-S-atsetamidometil] -penicillamine-2,3-dimethylaniline
It chilled with ice to a solution of N-[tert-butoxycarbonyl)-S-acetaminophenaffeineyrilamine (Bachem California, Torrance, CA) (0.64 g), 2,3-dimethylaniline (0.25 g), hydroxybenzotriazole (0,41 g) in dimethylformamide (DMF)/CH2Cl2(1: 1, 20 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0,57 g). The mixture is stirred at 0-5oC for 30 min and then the temperature is slowly increased to room temperature over night. After evaporation of the solvents the residue is distributed between ethyl acetate (EtOAc) and water. Extract into EtOAc washed with water Panso3, water and then dried (MgSO4). The solvent is evaporated in vacuum to dryness. The residue is subjected to chromatography on silica gel (40 g), using l3/acetone = 19:1 as the solvent for elution, the appropriate fractions are combined and the solvents removed in vacuo to dryness, receiving 350 mg specified in the connection header. TLC (silica gel; SNS3/acetone = 4:1; Rf=0,77).

b) TFA Salt of L-[3-acetamidobenzenesulfonyl]-2,3-dimethylaniline
[N-tert-butok the (20 ml) for 30 minutes Volatiles removed in vacuum to dryness. Traces of TFA remove joint evaporation with toluene several times. The TFA salt was dissolved in l2(30 ml), treated with excess triethylamine, washed with water, dried (MgSO4) and the solvent evaporated in vacuo to obtain the free base.

c) N-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylchloride]-L-[S-acetamidobenzenesulfonyl-2,3-dimethylaniline
To a stirred solution of 2(R)-tert-butoxycarbonylamino-3-triphenylmethylchloride (0.5 g, example 1b) and the TFA salt of L-[S-acetamidobenzenesulfonyl] -2,3-dimethylaniline (0.3 g) in Meon containing 1% acetic acid (SPLA) (10 ml) is added by portions NN3(100 mg). The mixture is stirred at room temperature overnight. A large part of the solvent is evaporated in vacuo to a small volume, which is partitioned between EtOAc and water. The EtOAc layer is washed then water Panso3, water and then dried (MgSO4). After evaporation of the solvent the residue is subjected to chromatography on silica gel (30 g) using l3/acetone (19:1 to 9:1) as eluents. The appropriate fractions are combined and the solvents evaporated in vacuum to dryness, getting 360 mg specified in sialometaplasia]-L-penicillamine]-2,3-dimethylaniline
To a stirred solution of N-[2(R)-(tert-butoxycarbonyl)amino-3-triphenylmethylchloride] -L-[S-acetamidobenzenesulfonyl] -2,3-dimethylaniline (350 mg) in 50 ml of 90% aqueous solution Meon in water, add a solution of iodine (250 mg) in Meon (5 ml). After 1 hour, the greater part of the solvent is evaporated in vacuum to small volume, diluted with water and extracted with EtOAc. The EtOAc layer was washed with aqueous Na2S2About3, water, then dried (MgS4). The solvent is removed in vacuum to dryness (220 mg), the residue is treated with 90% aqueous TFA solution (ml) for 30 min and the volatiles removed in vacuum to dryness. The crude product is purified preparative HPLC, receiving 62 mg specified in the title compounds as white solids. M/e=340,2.

Other embodiments
It should be understood that although the invention is described together with details of the above description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the attached claims. Other aspects, advantages, and modifications are covered by the claims.


Claims

1. The compound of formula I or formula II

-amino acids;
R7denotes a residue of natural or synthetic-amino acids;
R8IT denotes or lower alkoxy, or together with R7forms homoserine;
R9denotes H;
each of R10and R11independently, represents H;
R12denotes a substituted or unsubstituted fragment selected from aryl, allyssia of alkyl, where the substituents are one or more lower Akilov or halogen;
R13denotes lower alkyl;
R18denotes H; provided that if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2and R4can form disulfide bonds;
or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which the above-mentioned compound represented by formula I, or its pharmaceutically acceptable salt.

3. Connection on p. 1, in which Obedinenie under item 2, in which R6represents-N(R14)CH(R15)C(O)-, where R14denotes H or lower alkyl; and R15denotes a substituted or unsubstituted fragment selected from lower alkyl, aryl, allyssia of alkyl, heterocycle or heterozyklisches of alkyl, which is specified by the Deputy is lower alkyl, halogen or lower alkoxygroup, or R15together with attached group N(R14)C form a heterocycle;
R7represents-N(R16)CH(R17)C(O)-where R16denotes H or lower alkyl; and R17means (CH2)mS(O)nCH3where m is 1-6 and n is 0-2, or substituted or unsubstituted fragment selected from lower alkyl, finissage of alkyl, where specified by the Deputy is C(O)N(R10)(R11), and R8IT denotes or lower alkoxygroup, or its pharmaceutically acceptable salt.

5. Connection on p. 4, where R2denotes CH2SH; and R4denotes C(CH3)2SH or CH2SH, where available tigraphy of R2and R4form a disulfide bond, or its pharmaceutically acceptable salt.

6. Connection on p. 5, where R15together with attached group N(R14C form hetesi acceptable salt.

7. Connection on p. 6, where R1denotes NH2; R3denotes CH2; R5denotes C(O); and R8indicates HE or och3or its pharmaceutically acceptable salt.

8. Connection on p. 4, where R2denotes CH2SH; and R4denotes C(CH3)2SCH2NHC(O)CH3or CH2SCH2NHC(O)CH3or its pharmaceutically acceptable salt.

9. Connection on p. 8, where R15together with attached group N(R14)C form a heterocycle; R16denotes H; and R17means (CH2)2S(O)nCH3or its pharmaceutically acceptable salt.

10. Connection on p. 9, where R1denotes NH2; R3denotes CH2; R5denotes C(O); and R8indicates HE or och3or its pharmaceutically acceptable salt.

11. Connection on p. 3, where R2denotes CH2SH; and R4denotes C(CH3)2SH or CH2SH, where available tigraphy of R2and R4form a disulfide bond, or its pharmaceutically acceptable salt.

12. Connection on p. 11, where R12denotes a substituted or unsubstituted aryl or substituted or unsubstituted arlinski alkyl, and RNH2; R3denotes CH2; R5denotes C(O); and R9denotes H; and R12represents substituted benzyl, wherein said Deputy represents lower alkyl, or its pharmaceutically acceptable salt.

14. Connection on p. 3, where R2means (CH2)SH; and R4denotes C(CH3)2SCH2NHC(O)CH3or CH2SCH2NHC(O)CH3or its pharmaceutically acceptable salt.

15. Connection on p. 14, where R12denotes a substituted or unsubstituted aryl or arlinski alkyl, or its pharmaceutically acceptable salt.

16. Connection on p. 15, where R1denotes NH2; R3denotes CH2; R5denotes C(O); and R9denotes H; and R12represents substituted benzyl, wherein said Deputy represents lower alkyl, or its pharmaceutically acceptable salt.

17. Connection on p. 1 represented by the formula (see the graphical part)
18. The compound of formula I under item 1 (see graphic part).

or its pharmaceutically acceptable salt.

19. A method of inhibiting the activity prenyltransferase the subject, in need thereof, introducing a specified subject a therapeutically effective the new under item 17.

21. Pharmaceutical composition having the ability to inhibit prenyltransferase containing compound under item 1.

22. Pharmaceutical composition having the ability to inhibit prenyltransferase containing compound under item 18 and a pharmaceutically acceptable carrier.

 

Same patents:

The invention relates to new compounds of General formula 1: R1- SO2- B - X - Z - C(O) - Y, where R1represents a (1-12C)alkyl, which optionally may be substituted CF3, (7-15C)aralkyl or Campari; represents a bond, an amino acid of formula-NH-CH[(CH2)pC(O)OH]-C(O)-, where R = 1, 2, or 3, D-3-Tiq, or L - or D-amino acid containing a hydrophobic or neutral side chain; X represents an amino acid with a hydrophobic side chain, glutamine, cyclic amino, -NR2-CH2-C(O) -, or a group:

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where n = 2, 3 or 4, W represents CH; R3represents H, (1-6C)alkyl; Z represents a lysine or 4-aminocyclohexanol; Y represents-NH-(1-6C)alkylene-C6H5, -OR4where R4represents H, (2-6C)alkyl, or NR5R6and R5and R6independently represent H, (1-6C)alkoxy or (1-6C)alkyl, optionally substituted with halogen, or R5and R6together represent a (3-6C)alkylene, or R5and R6together with the nitrogen atom to which they are attached, represent< / BR>
where V carts is naphthyl-SO2-Asp-Pro-Lys[COCO]-OH,having anticoagulant activity; and the pharmaceutical composition having inhibitory by combinationally

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC

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The invention relates to sterylsulfonate compounds of formula I, where n represents zero or one; R1selected from the group comprising chlorine, fluorine or bromine; and R2selected from the group comprising chlorine, fluorine and bromine; R3selected from the group comprising hydrogen and fluorine; each radical R1and R2may not be chlorine when R3represents hydrogen; and R1may not be chlorine when R2represents fluorine, and R3is hydrogen in the same connection
The invention relates to medicine, namely to Oncology, and can be used for the treatment of intracerebral tumors
The invention relates to medicine and relates to a means and method for the treatment of skin diseases

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The invention relates to new compounds of General formula I

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where R is chosen from the group comprising R2, R2NH - or R3R4N-R5-, where R2selected from the group including9-C12-alkyl,

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and

< / BR>
where each R6independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m = integer 0-8; x = 1-8 integer; n = 0-8 integer; z is chosen from the group comprising phenyl, heterocycle, cycloalkyl and naphthalene, and M is chosen from the group comprising hydrogen, C1-C4-alkyl,

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and

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where each R6' are independently selected from the group including hydrogen, C3-C8-cycloalkyl,1-C4-alkyl and (CH2)m-phenyl, where m' = integer 0-8; n' = integer 0-8; x' = 1-8 integer; Q is hydrogen or C1-C4-alkyl, and Z' is chosen from the group comprising phenyl, heterozygote selected from the group including D, E,

< / BR>
and

< / BR>
where each D is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E is independently selected from the group including Hal, HE and1-C8-alkyl; Z is chosen from the group comprising phenyl, cycloalkyl and naphthalene; each R6"is hydrogen, n = integer 0-8; x" = 1-8 integer, and M' is hydrogen, Z' may be optionally substituted by groups D', E', each D' is independently selected from the group comprising trifluoromethyl, triptoreline and C1-C4-alkoxy; each E' is independently selected from the group including Hal, HE and1-C8-alkyl; R3and R4selected from the group including hydrogen, C1-C4-alkyl and (CH2)y-phenyl, where y = 0-8 integer, provided that R3and R4both denote hydrogen; R5- C1-C8-alkylene and R1selected from the group including cyclopentyl, cyclopentenyl and isopropyl, and their pharmaceutically acceptable salts, optical isomers and hydrates, provided that when R2refers to a group

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and

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where D, b, R6", x", n", M' and Z" accept above values

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or their tautomeric forms, where the join pyridine in position 2, 3 or 4; R1denotes hydrogen; Q represents C1-C9is a divalent saturated hydrocarbon radical; X denotes methylene or oxygen; R represents hydrogen, halogen, nitro, methylenedioxy, alkyl or alkoxy containing from 1 to 4 carbon atoms, or their pharmaceutically acceptable non-toxic smolem and N-oxides

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< / BR>
where R4represents N or CH3, R5is CHR, benzyl or ortho - or para-substituted benzyl, R represents H, CH3CH2CH3CH2CH2-CH3or CH(CH3)2, R' represents the residue of phosphoric acid, salt of phosphoric acid or-S-S-R" group, R" is CH2CH2OTHER6CH2CH2HE, CH2COOR7, ortho - or para-substituted C1-C3alkylphenyl or ortho - or para-substituted nitrophenyl, R6represents H, C1-C4acyl group, trifluoracetyl, benzoyloxy or substituted benzoyloxy group, R7represents H, C1-C4alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl

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