MXPA93007574A - Tetrapeptides that include modified fenethylamids to inhibit you - Google Patents

Abstract

The new tetrapeptides including the modified phenethylamides are explained and synthesized to find that they exhibit inhibitory effects on the tumor when measured against the NCI test for the six major types of human cancer and against the murine P388 lymphocyte cell line. The new modified phenethylamide tetrapeptides are 6 (a-

Description

* TETRAPEPTIDES THAT INCLUDE THE MODIFIED FENTILYLAMIDS TO INHIBIT THE TUMOR INVENTORS: GEORGE R. PETTIT and J0ZSEF BARK0CZY American and Hungarian domiciled at 6232 Bret Hills Drive, Paradise Valley, Arizona 85253 and at Szirom Utca 4-6 / B Budapest Hungary, cede all their rights to ARIZONA B0ARD OF REGENTS duly organized and incorporated company in accordance with the Laws of the State of Arizona, United States of America, with address at Arizona State University Tempe, Arizona, United States of America, for the invention that is described below.

SUMMARY OF THE INVENTION The new tetrapeptides that include the modified phenethylamides are explained and synthesized to find that they exhibit inhibitory effects on the tumor when measured against the NCI test for the six major types of human cancer and against the P388 lymphocyte cell line of the urine. The new modified phenethylamide tetrapeptides are 6 (a-k).

INTRODUCTION This invention relates generally to the field of antineoplastic compounds, and more particularly to the design and synthesis of the selected tetrapeptides which include the modified phenethylamides, which exhibit tumor inhibitory effects. Financial assistance for this project will be provided by the Government of the United States with Permit Number 0IG-CA44344-01 1 -2. The Government of the United States may have certain rights to this invention.

BACKGROUND OF THE INVENTION The ancient marine invertebrate species of Phyla Bryozoa, Molluska and Porifera have settled well in the oceans for a billion years. These organisms have suffered millions of biosynthetic reactions from their evolutionary chemistry to achieve their present level of cellular organization, regulation and defense. For example, marine sponges have minimally changed the physical appearance for approximately 500 million years. This suggests a resistance • Chemical chemistry is very effective at evolving in response to changing environmental conditions during this period of time. The recognition of the potential for the use of this biologically potent marine animal for medical purposes was recorded in Egypt approximately 2,700 years BC. and 200 years A.C. Sea hare or marine extracts were used in Greece for their healing effect. This consideration together with the observation of these marine animals, for example invertebrates and sharks, hardly develop cancer, leads to the systematic investigation of anticancer compounds in marine plants and animals. In 1968, ample evidence was obtained based on the experimental cancer study systems of the U.S. National Cancer Institute (NCI), that certain marine organisms could provide new and structurally novel cytotoxic and / or antineoplastic agents which would be effective in the control and / or eradication of viral diseases. In addition, these marine organisms are believed to possess potential potentially useful drug-free structures that can be discovered by other methods of medical chemistry. Fortunately, these expectations have been realized, for example the discovery of briostatins, dolastatins and § Cephalostinas, many of which are now in preclinical development or in human clinical trials. Those researchers who are currently involved in medical chemistry know well the time between the isolation of a new compound and its introduction to the market. Often this procedure takes several years and can take decades. As a result, the industry, in partnership with the Government of the United States, has developed a test criteria system which serves two purposes. One is to eliminate those substances that show through tests that are economically unproductive. The second purpose, the most important is to identify those compounds that show a high probability of success and also guarantee a greater study and qualification, and together with the expenses, the need to satisfy the strict registration requirements which control the last place in the market . The current costs to develop the necessary data approximates ten million dollars per compound. The economy dictates that a high investment would be only when there is a reasonable opportunity to recover it. In the absence of this opportunity, there would be no investment and the investigation that involves ¿. the discovery of these potentially life-saving compounds. Only two hundred years ago many diseases plagued the human being. Many of these have now been controlled or eradicated. During the advance of the means for the treatment or elimination of these diseases, work with the appropriate animals was of critical importance. Current research in cancer control in the United States is coordinated by the National Cancer Institute (NCI). To determine if a substance has anticancer properties, the NCI has established a systematic protocol. This protocol, which involves testing a substance against a list of standard cell lines containing 60 human tumor cell lines, has been verified and accepted in scientific circles. The protocol, and the statistical means established to analyze the results obtained in the standardized tests, have been fully described in the literature. See: Body, Dr. Michael R., Principies & Practice of Oncology. PPO Updates, Volume 3, Number 10, October 1989, for a thorough description of the test protocol; and Paull, K. D., "Display and Analysis of Patterns of Differential Activity of Drugs Against Human Tumor Cell Lines; Development of Mean Graph and COMPARE • Algorithm, "Journal of the National Cancer Institute Reports, Vol. 81, No. 14, Page '1088, July 14, 1989 for a description of statistical analysis methods, both references are incorporated herein for reference. Substances have been discovered which demonstrate significant antineoplastic or tumor-inhibiting characteristics As previously stated, many of these compounds have been extracted, albeit with great difficulty, from marine animals such as the sponge and the sea or marine free. Once the isolation and testing of these compounds has been carried out, a practical question remains, namely how to produce commercially significant quantities of the desired substances: Quinine, which is available in practical quantities from the bark of The cinchona plant differs from the compounds that are extracted from marine beings that possess antineoplastic qualities. The processing of these last compounds from their natural sources goes from the impractical to the really impossible. Without taking into account the ecological impact, the population of these creatures and the cost of selection and extraction makes the process a little - i functional. The artificial synthesis of the active compounds is the only possible solution. In addition, the elucidation of the structure of these antineoplastic compounds is essential. After the structure has been determined, then the synthesis form must be completed. This is often a long and difficult procedure due to the particular complexity of these compounds that appear naturally, modified in evolution. In addition, research is necessary to determine if any portion of the compound that appears naturally is important for the desired properties, such that the approach can be on a simpler structure having the known properties. The Constitution of the United States (Article 1, Section 8) authorizes Congress to establish the United States Patent and Trademark Office (USPTO) to promote scientific progress. In order to obtain patent rights, one must show the utility of the invention. The growth of cancer cells in humans often causes pain, suffering, and premature death. The deterioration in the growth of the human cancer tumor is useful in that it alleviates these conditions, it also allows the human being to # Affected to have a longer and more productive life. Little could be more utilitarian than this result. The only right that is obtained from the permission of a Patent is to prevent others from exploiting the subject matter of the patent. In this way the inventor is protected for a suitable period to allow the investment to be recovered. This in turn provides * incentives for further investigation. The recognition of antineoplastic activity and tumor inhibition as demonstrated by the NCI criterion accepted as "useful" may favor research efforts in the United States and is undoubtedly essential if these efforts are to obtain a modest success.

BRIEF DESCRIPTION OF THE INVENTION The different species of sponges and sea or sea hares produce cyclic and linear peptides that contain amino acids which have been shown to be effective in the treatment and / or control of cancer in humans. For example, Dolastatin 10 (US Patent No. 4,816,444), which has recently been synthesized, has proven to be a potent antineoplastic substance. This finding, in turn, promotes research into other compounds related to Dolastatin 10. Accordingly, a primary objective of this invention is to provide a new agent useful in the delay or remission of one or more types of cancer. Another objective of the present invention is to provide the methods and methods for designating and synthesizing the selected tetrapeptides including the modified phenethylamides for the treatment of neoplastic diseases and the inhibition of growth in the tumor. These and other objects, as may be presented hereinafter, are readily realized in the present invention in a remarkably unexpected manner as will readily be discovered from the following detailed description of an exemplary embodiment thereof.

DETAILED DESCRIPTION OF THE INVENTION The discovery of new types of potentially antineoplastic peptides presents a more essential and hopeful approach for a synthesis of the new anti-cancer drugs and immunosuppressants. Dolastatins, an unprecedented series of antineoplastic peptides and / or linear and cyclic cytostatics isolated from the Dolabella auricularia sea hare or marine of the Indian Ocean (See: Pettit et al., J. Am. Chem. Soc., 1976, 98, 4677) have demonstrated excellent antineoplastic activity . The productive sea hare or marine D. auricularia has produced many peptides of different structures. Currently Dolastatin 10, a linear pentapeptide, represents the most important member with profiles of antineoplastic activity potentially useful against different cancer tests currently known (See: Pettit et al., J. Am. Chem. Soc., 1987, 109, 6883). The total synthesis and absolute configuration of this biologically active peptide and unique structure have now been reported (See: Pettit et al., J. Am. Chem. Soc. 1989, 111, 5463). After this report, this compound attracted considerable interest in the research community (See, for example, Hamada et al., Tetrahedron Lett., 1991, 32, 931, Hayashi et al., Peptide Chemistr. 1989, 291 and Tomioka et al., Tetrahedron Lett .. 1991, 32 (21), 2395-2398). A series of chiral isomers of Dolastatin 10 have been documented (See: Pettit et al., J. Med. Chem. 1990, 33, 3132). Currently these experiments have been extended to the synthesis of R-Doe-isodolastatin 10. We have found that the substitution ip # of R-dolafenin (Doe) has no significant difference in its activity in the human cancer cell line when compared to Dolastatin 10. This fact suggests that the 2-thiazolyl unit can be replaced with a simple amide. The molecular length of the amide has been examined, starting with benzylamine, phenethylamine and 3-phenyl-1-propylamine. I also know # has studied the systematic series of modifications in the dilaphenin position introducing a substituted nitrogen instead of the phenyl ring. Then, fixing the length of the side chain at n = 2 shows the importance of replacing the phenyl ring and the aliphatic side chain in the amide part. The role of placing the substituents on the phenyl ring was then investigated using protruding electrons (4-nitro, 4-chloro, 4-fluoro, 4-bromo, 3-chloro, 2-chloro) and the groups that release the electron (3 4- dimethoxy). The corresponding amine (2a-s) is allowed to react with dolaproin (_). The synthesis of amides 3a-s uses diethyl phosphorocyanidate (FCDE) for condensation and leads to an excellent product. There is no racemization during this reaction. Below are the syntheses that follow it and the amides (3a-s): F # # The protecting groups of amides 3a-s are removed with trifluoroacetic acid to produce the trifuoroacetate salt 4a-s as shown in the following: Sal trifluoroacetate 4a-s Diethyl phosphorocyanidate (FCDE) has again been used with excellent results to couple the tripeptide 5 with each of the trifluoroacetate salts 4a-s to produce the structural modification of Dolastatin 10 6a-s according to the following reaction: Synthesis of Peptides 6a-s The effect of substituting an aliphatic chain and the nitrogen amide at the modified dolafenin position using the unsubstituted phenyl ring was then investigated. The methyl and hydroxyl substituents were then applied starting with (1R, 2R) -2-methylamino-1-phenylpropanol (2h), (1S, 2R) -norephedrine (2i), D (+) - (1S, 2S) -norephedrine (21) and (1R, 2S) -norephedrine (2k). The synthesis of the tetrapeptide phenethylamides modified 6h-k was carried out by means of the methods developed for the 6a-s amides according to the reactions shown in the following: 2h (R = CH3, R = H, R = CH3, 2H (R4 = CH3, R5 = H, R6 = CH3, R7 = H, RS = OH) R7 = H, R8 = OH) 2Í (R = H, R5 = H, R6 = CH3, 2i (R4 = H, R5 = K, RS = CH3, R7 = OH, R8 = H) R7 = OH, R8 = K) 2i (R4 = H, R5 = CH3, R6 = H, 2i (R4 ^ H, R5 = CH3l R6 = H, R7 = OH, R8 = H) R7 = OH, R8 = H) 2Ji (R = H, R5 = CH3, R6 = H, 2k (R4 = H R5 = CK3, R6 = H, R7 = H, R8 = OH) R7 = H, R8 = OK) 1 (R4 = CH3, R5 = H, R5 = CK3, R7 = H, R8 = OH) _Ü (R = H.R5 = K, Rd = CH3, R7 = OH, RS = H) i (R = H. R5 = CH3, Rβ = H, R7 = OH, R8 = H) (R4 = H, RS = CH3, R6 = K, R7 = H, RS = OH) áh (R = CH;, R5 = H, R6 = CH3, R7 = H, R8 = OK) £ I (R = K, R5 = [- Í, R5 = CH3, R7 = OH, RS = H) = i (R4 = H, R5 = CH3, R6 = K, R7 = OH, RS = K)? K (R4 = H, RI = CH3, Rd = H, R7 = H, R3 = OH) In a preferred embodiment of the present invention, the synthesis of the intermediate structures of the constituent is carried out in advance by means of the following steps.

Synthesis of Amides 3a-k (shown in the above). General Procedure A To a solution of acid [2S- [2R * (aS *, β *)]] -1 - [(1,1-dimethylethoxy) carbonyl] -B-methoxy-methyl-2-pyrro-lidinpropanoic acid (t-Boc) -Dolaproin, JL, 0.144 g, 0.5 mmol) in dichloromethane (3 ml, distilled from CaH ^) is added the respective amine (2a-k 0.5mmol) followed by triethylamine (0.77ml, 0.55mmol) and phosphorus cyanide. diethyl (FCDE, 0.09 ml, 93%, 0.55 mmol, in an ice bath) and the solution is stirred with argon for two hours. The solvent is removed (under vacuum and at room temperature) and chromatography of the residue is carried out (column of silica gel using hexane-acetone 3: 1 as eluent). After evaporation of the solvent from the fractions (selected from TLC) 2 ml of dry dichloromethane are added and the evaporation is repeated. The residue is dried in a vacuum dehydrator during f the night to produce the amide (3a-k) as a viscous oil.

Acid [2S- [2R * [1 S *, 2S *]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[2- (3, 4-dimethoxy-phenyl) -ethyl) ] amino] ropil] -1-pyrrolidincarboxylic acid, 1,1-dimethylethyl ester (3a) P Compound 3a is synthesized from t-Boc-Dolaproin (1) and 3,4-dimethoxyphenethylamine (2a) according to General Procedure A.

Yield of 3a: 0.189 g (84%) Analysis Calculated for C24Í? 3gN2? G, P. m. : 450,566 Acid [2S- [2R * [1S *, 2S *]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[2- (4-nitro-phenyl) -ethyl] amino] propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3b) Compound 3b is synthesized from t-Boc-Dolaproin (1_) and 4-nitrophenethylamine (2b) according to General Procedure A.

Performance of 3b: 0.176 g (81%) [] D25 = -54 (c = 0.29 in CHCI3) * Analysis Calculated for C22H33N3 ° 6 'p- «: 435.505 Acid [2S- [2R * [1S *, 2S *]]] - 2- [1-methoxy-2-methyl-3-oxo-3- [[2- (4-chloro-phenyl) -ethyl] amino] ropil] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3c) Compound 3c is synthesized from t-Boc-Dolaproin (1) and 2- (4-chloro-phenyl) -ethylamine (2c) according to General Procedure A.

Yield of 3c: 0.183 g (85.5%) [] D25 = -38 (c = 1.52 in CHC13) Analysis Calculated for C22? I33N2O CI, P. m. : 424.953 Acid [2S- [2R * [1S *, 2S *]]] - 2- [1-methoxy-2-ethyl-3-oxo-3- [[2- (4-fluoro-phenyl) -ethyl] amino] propyl] -1-pyrrolidinecarboxylic acid, 1,1-di-ethylethylester (3d) The 3d compound is synthesized from t-Boc-Dolaproin (1) and 2- (4-fluoro-phenyl) -ethylamine (2d) according to General Procedure A.

Performance of 3d: 0.192 g (94.3%) Calculated Analysis for C22H33N2O4F # Acid [2S- [2R * [1S *, 2S *]]] - 2- [1-methoxy-2-methyl-3-oxo-3- [[2- (4-bromo-phenyl) -ethyl] amino ] propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3e) Compound 3e is synthesized from t-Boc-Dolaproin (1) and 2- (4-bromo-phenyl) -ethylamine (2e) according to General Procedure A.

Performance of 3e: 0.193 g (82.1%) P. m. : 469.49 C22H33N2? Br Acid [2S- [2R * [1S *, 2S *]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[2- (3-chloro-phenyl) -ethyl] amino] propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3f) Compound 3f is synthesized from t-Boc-Dolaproin (1) and 2- (3-chloro-phenyl) -ethylamine (2f) according to General Procedure A.

Yield of 3f: 0.202 g (95.3%) P. m. : 424.953 C22H33N204C1 Acid [2S- [2R * [1 S *, 2S *]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[2- (2-chloro-phenyl) -ethyl] amino] ] ropil] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3s) Compound 3g is synthesized from t-Boc-Dplaproin (1) and 2- (2-chloro-phenyl) -ethylamine (2a) according to General Procedure A.

Performance of 3s: 0.194 g (91.7%) P. m. : 424.953 C ^ H ^ N ^ Cl Acid [2S- [2R * [1S *, 2S *, 3 (1S *, 2S *)]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl-1] -hydroxy-2-propyl] methylamino] -propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3h) F The compound 3h is synthesized from t-Boc-Dolaproin (1) and (1R, 2R) - ( -) -2-methylamino-1-phenyl-propan-1-ol (2h) according to General Procedure A.

Yield of 3h: 0.14 g (64%) [] D25 = -184.7 (c = 0.17 in CHC13) Analysis Calculated for C ^ H ^ g ^ Or;, P. m. : 434.56 • Acid [2S- [2R * [1S *, 2S *, 3 (1R *, 2S *)]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl- 1-hydroxy-2-propyl] amino] propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3i) Compound 3i is synthesized from t-Boc-Dolaproin (1) and (1S, 2R) -norephedrine (2i) according to General Procedure A. In this case, in the final drying, colorless crystals are obtained.

Yield of 3i: 0.145 g (69%) P. f. : 55-57 ° C Analysis Calculated for C23H36N205, P. m. : 420.54 Acid [2S- [2R * [1S *, 2S *, 3 (1R *, 2R *)]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl-1] -hydroxy-2-propyl] amino] propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3) Compound 3j is synthesized from t-Boc-Dolaproin (1) and D (+) - (1S, 2S) -norephedrine (2 ±) according to General Procedure A. In this case in the final drying are obtained colorless crystals.

Yield of 3: 0.204 g (97.6%) P. f. : 65-67 ° C * P. m. : 420.54 C23H36N2 ° 5 Acid [2S- [2R * [1S *, 2S *, 3 (1S *, 2R *)]]] -2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl-1] -hydroxy-2-propyl] amino] propyl] -1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (3k) F Compound 3k is synthesized from t-Boc-Dolaproin (1) and (1R, 2S) -norephedrine (2k) according to General Procedure A. In this case, in the final drying, colorless crystals are obtained.

Yield of 3k: 0.201 g (96.0%) P. f. : 53-55 ° C P. m. : 420.54 C23H36N205 Synthesis of Peptides 6a-k (shown in the above). General Procedure B.

A solution of amide 3a-k (0.2 mmol) in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) is stirred (in an ice bath with an argon atmosphere) for two hours. The solvent is removed under reduced pressure and the residue is dissolved in toluene. Sun- • Vente is once again eliminated under vacuum and this operation is repeated. The residue is dried in a dehydrator (vacuum overnight) to produce the trifluoroacetate salt 4a-k as a viscous oil. To a solution of the trifluoroacetate salt 4a-k (0.2 mmol) in dichloromethane (2 ml, distilled from CaH 4) is added the trifluoroacetate salt * of the tripeptide (the previously reported synthesis) F (5. 0.109 g, 0.2 mmol) followed by triethylamine (0.088 ml, 0.63 mmol) and diethyl phosphorocyanidate (FCDE, 0.036 ml, 93%, 0.22 mmol, in an ice bath) . The solution is stirred with argon for two hours. The solvent is removed (under vacuum and at room temperature) and chromatography of the residue is carried out (column of silica gel using 3: 2 acetone-hexane as eluent). After the evaporation of the solvent from the F fractions (selected by the behavior in TLC) add 2 ml of dry dichloromethane. The residue is dried in a vacuum dehydrator overnight to produce a white, solid solid. [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2 - [1-methoxy-2-methyl-3-oxo-3- [[2- (3, 4-dimethoxy-phenyl) -ethyl] amino] propyl] -1-pyrrolidinyl-1- (methylpropyl) -4-oxobutyl ] -N-methyl-L-valinamide (6a) • Compound 6a is synthesized from the trifluoroacetate salt of 4a (from amide 3a) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6a: 128 mg (84%) P. f. : 145-147 ° C Calculated Analysis: C4- | E - | N ^ Og, P. m. 762,018 [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2 - [1-methoxy-2-methyl-3-oxo-3- [[2- (4-nitro-phenyl) -ethyl] amino] ropil] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] - N-methyl-L-valinamide (6b) F Compound 6b is synthesized from the trifluoroacetate salt of 4e (from amide 3b) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6b: 129 mg (87%) P. f. : 73-76 ° C Calculated Analysis: C39H66N6 ° 8 'p * m "746.965 [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2 - [1-methoxy-2-methyl-3-oxo-3- [[2- (4-chlorophenyl) -ethyl] amino] propyl] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] - N-methyl-L-valinamide (6c) Compound 6a is synthesized from the trifluoroacetate salt of 4c (from amide 3c) and the trifluoroacetate salt of tripeptide j3 by General Procedure B.

Yield of 6c: 125 mg (85%) P. f. : 75-78 ° C [a] D25 = -47.9 (c = 0.19 in CDC13) Calculated Analysis t: C39H66N5 ° 6C1 'p- ra' 736.411 [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L- # valyl-N- [2-methoxy-4- [ 2- [1-methoxy-2-methyl-3-oxo-3- [[2- (4-chlorophenyl) -ethyl] amino] ropil] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] -N-methyl-L-valinamide (6d) Compound 6d is synthesized from the trifluoroacetate salt of 4d (from amide _3d) and the trifluoroacetate salt of tripeptide 5 by General Procedure B. • 6d yield: 0.105 g (72.8%) P. f. : 76-78 ° C Calculated Analysis: C39H66N5 ° 6F 'p * m' 719.958 [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2 - [1-methoxy-2-methyl-3-oxo-3- [[2- (4-bromo-phenyl) -ethyl] amino] propyl] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] -N-methyl-L-valinamide (6e) Compound 6e is synthesized from the trifluoroacetate salt of 4e (from amide _3e) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

F Yield of 6e: 0.113 g (72.7%) P. f. : 107-109 ° C [a] D25 = -41.76 (c = 0.17 in CDC13) Calculated Analysis: C39H66N506Br, P. m. 780,867 [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2 - [1-methoxy-2-methyl-3-oxo-3- [[2- (3-chlorophenyl) -ethyl] amino] ropil] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] - N-methyl-L-valinamide (6f) ^ Compound 6f is synthesized from the trifluoroacetate salt of 4f (from amide 3f) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6f: 0.103 g (69.7%) w P. f. : 79-81 ° C [] D25 = -41.79 (c = 0.28 in CDC13) Calculated Analysis: , P. m. 736,411 [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2 - [1-methoxy-2-methyl-3-oxo-3- [[2- (2-chlorophenyl) -ethyl] amino] ropil] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] - N-methyl-L-valinamide (6s) Compound 6g is synthesized from the trifluoroacetate salt of 4g (from amide 3s) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6s: 0.105 g (71.3%) P. f. : 145-147 ° C [] D25 = -44.17 (c = 0.36 in CDC13) Calculated Analysis: 3gHggN50gCl, P. m. 736,411 • [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *, 3 (1S *, 2S *)]]] - N, N-dimethyl-L-valyl-N - [2-methoxy-4- [2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl-1-hydroxy-2-propyl] methylamino] propyl] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] -N-methyl-L-valinamide (6h) The compound 6h is synthesized from the trifluoroacetate salt of 4o; (from the amide _3h) and the trifluoroacetate salt of the tripeptide 5 by General Procedure B.

Yield of 6h: 92 mg (62%) P. f. : 108-110 ° C Calculated Analysis: C4-lH71N507, P. m. 746,018 '[2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *, 3 (1R *, 2S *)]]] - N, N-dimethyl-L-valyl-N - [2-methoxy-4- [2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl-1-hydroxy-2-propyl] amino] propyl] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] -N-methyl-L-valinamide (6i) Compound 6i is synthesized from the trifluoroacetate salt of 4i (from amide _3i) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6i: 0.101 g (69%) P. f. : 92-94 ° C [] D25 = -20 (c = 0.12 in CDC13) Calculated Analysis: H69N507, P. m. : 731,992 • [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *, 3 (1R *, 2R *)]]] - N, N-dimethyl-L-valyl-N- [2-methoxy-4- [2- [1-methoxy-2-methyl-3-oxo-3- [[1-phenyl-1-hydroxy-2-propyl] amino] ropil] -1-pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] -N-methyl-L-valinamide (6) Compound 6j is synthesized from the trifluoroacetate salt of 4j. (from amide 3) and the trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6i: 0.110 g (75.4%) P. f. : 108-110 ° C Calculated Analysis: C4oH69N5 ° 7 'P. m. 731,992 • [2S- [1 [1R * (R *), 2S *], 2R * [1S *, 2S *, 3 (1S *, 2R *)]]] -N, N- dimethyl-L-valil -N- [2-methoxy-4- [2- [1-methoxy-2-methyl-3-oxo-3- [[1-f-enyl-1-hydroxy-2-propyl] amino] propyl] -1- pyrrolidinyl-1 - (methylpropyl) -4-oxobutyl] -N-methyl-L-valinamide (6k) The compound 6k is synthesized from the 4k trifluoroacetate salt (from amide _3k) and trifluoroacetate salt of tripeptide 5 by General Procedure B.

Yield of 6k: 0.098 g (67%) P. f. : 100-102 ° C [] D25 = -39.26 (c = 0.27 in CDC13) Calculated Analysis: C40H69N5 ° 7 'p * m *: 731.992 • The extraordinary inhibition of cell growth shown by tetrapeptides 6a-k against the six main types of human cancer and against the murine P388 lymphocytic leukemia cell line are presented in Table 1-2, below.

* Table 1. Biological activity of Peptides 6a-g Line Type 6a Si £ s £ d Sa ß f £ 3 Cell Cell ~ Mouse leukemia cells DE-SO (μg / ml) P-3B8 0.003500 0.045900 0.005330 0.00372 0.00515 0.00225 0.000289 Ovary OVCAfl-3 0.000007 0.00024 < 0.000001 0.000016 0.00015 «0.000001 < 0.000001 SNC Sr-295 0.000029 0.00035 0.000010 0.000046 0.00043 0.000023 «0.000001 Renal cancer cell A498 0.00O016 0.00064 0.00062 0.000059 0.0Q046« 0.000001 «0.000001 human lung-IC-50 (μg / ml) NSC NCi-460 0.000031 0.00028 «0.000001 0.000025 0.00027« 0.000001 «O.0C00O1 Colon KM20L2 0.00002 = 0.00030« O.000C01 0.C0033 0.CQ032 0.0000007 «0.030001 Melanoma SKI / IEL.-3 0.000013 0.CO012 «0.000OO1 0.000044 0.00C3S« 0.000001 «O.OC0001 Ovarlo OVCAR-3 0.000061 0.00065« 0.000001 0.000030 0.00050 «0.000001« 0.0X001 SNC Sr-295 O.0COO83> 0.01 0.0019> 0.01 > 0.01? OI> C01 Renal A498> 0.0001> 0.01 0.0023> 0.01 0.0017 0.002 Cclu of cancer Lung- 0.000094 0.0012 0.0011 0.00014 0.0012 0.00010 0.00011 human NSC NC1'46D CIT (μg ml) Colon KM20L2 O O00S1 0.0013 0.C011 0.0029 0.0041 0.0017 0.00028 V? Elanoma SK-MB.-3 O.0OO0SS 0.0013> 0.01? 01> 0.01> 0Ü1 a .01 Ova ™ OVCAR-3> o.ooo? > oo?> ao? ooooo96 0.0094 0.00073> ao? SNC SF-295> sooooo? oo?> ooooo? oo? # Renal M ° s > 0.0001 > O01 > O01 > O.C001 > 0.01 > 0-! 1 saoi Cancer Cell Pu] mon- ^ ^ 50.0031 s? .01 > 0.01 > 0.000l? 0_ > 1 > 0.01 50.01 human NSC CL-50 (μg / ml) Colon 20 > o.ooo? ? O.oi > o.o? > o.ooo? > S? I > O.OI s oi Melanoma SK-ME? .- 3 > 0.0001 > 0J) 1 > 0O1 »0.0001 > 0.01 > 0.01 s? .01 - Table 1. Activity? Biological Peptide 6h-k Line Type gh lí 11 Si- Cell Cell Mouse Leukemia Cells DE-50 < μ g / ml) P "388 0- °° 1710 ° -000503 OR" 0003 * 1 ° - °°° «4 Ovari ,, OVCAR-3 O.OOOOS 0.000021 0.0000097 0.00017 SNC SF-295 0.00031 0.000016 0.00034 0.00060 Cell Cancer Rcnal A498 0.00099 0.0000027 0.000096 0.00075 human Lung NSC CI-SO (μg / ml) NCI-460 0.00006 0.000025 0.000026 0.00030 Colon KM20L2 0.00023 0.00011 0.000022 0.00029 Melanoma S - EL-3 0.00030 0.000 = 3 0.000044 0.00053 Ovary OVCAR-3 0.0009 0.000042 0.000046 0.00053 SNC SF-295 > 0.01 0.00024 0.01 > 0.01 Renal Cancer Cell A498 50.01 0.:C00086 0.0097 > 0.01 Human Lung CIT < μg / ml) NSC NCI-460 0.0014 > 0.Q1 0.00011 0.001 Colon KM20L2 0.0033 0.0070 0.00052 0.0013 Melanoma Si < - EL-3 50.01 > 0.01 > 0.01 50.01 f 0.0C0038 50.01 s? .01 SNC SF-295 > 0.01 > 0.01 s? .01 50.01 Renal A g3 j? .01 0.00029 50.01 50.01 Human cancer cell Lung- NSC NCI-460 > 0.01 > 0.01 50.01 50.01 CL-50 (μg / ml) Colon KM20L2 s? .01 0.01 50.01 50.01 Melanoma SK-EL-3 s? .01 50.01 s? .01 50.01

Claims (8)

* From the foregoing, it is very clear that a useful embodiment of the present invention has been described herein and illustrated which covers all the objectives set forth above in a remarkably unexpected manner. Of course it is understood that the modifications, alterations and adaptations that can easily occur to the technicians examining this invention are proposed within the spirit of this invention in which it is limited only to the scope of the appended claims. NOVELTY OF THE INVENTION * Having described the invention as above, property is claimed as contained in the following: CLAIMS

1. A compound that has the following structural formula: characterized in that R1 is selected from # group consisting of OCH3, N02, S, Cl, CF, and H; R2 is selected from the group consisting of OCH3, H, and Cl; and R3 is selected from the group consisting of H and Cl, with the proviso that if R 'is N02, Cl, S, or Br, R2 = R3 = H; that if R = C1 then R1 = R3 = H; that if R3 = C1 then R2 = R3 = H and that if R ^ DCH ^, then R2 = R1 and R3 = H. í *

2. The compound that has the following structural formula: ,--4*. # characterized in that R is selected from the group consisting of H and CH3, R ^ is selected from the group consisting of H and CH3, R6 is selected from the group consisting of CH3 and H, R7 is selected from from the group consisting of H and OH, and R ° is selected from the group consisting of H and OH; with the proviso that if R 7 or that at least one of R4, R5 and and that at least two of R4, R5, R6, R7 and R8 = H.

3. The method for inhibiting the growth of cancer cells selected from the group of cell lines consisting of P388, OVCAR-3, SF295, A498, NCI-460, KM20L2 and SK-MEL-3, characterized in that it comprises the use of these cells selected with an inhibitory amount of the cell growth of the compound having the structural formula # following: wherein R 'is selected from the group consisting of OCH3, N02, F, Cl, Br, and H; R2 is selected from the group consisting of OCH3, H, and Cl; and R3 is selected from the group consisting of H and Cl, with the proviso that if R 'is N02, Cl, F or Br, R ^ = RJ = H; that if R2 = C1 then R1 = R3 = H; that if R3 = C1 then R = R2 = H and that if R1 = 0CH3, then R = R1 and R3 = H.

4. A method for inhibiting the growth of cancer cells selected from the group of cell lines consisting of P388, OVCAR-3, SF295, A498, NCI-460, KM20L2 and S-MEL-3, characterized in that it comprises the use of these cell lines with an inhibitory amount of cell growth of the compound having the following structural formula: wherein R is selected from the group consisting of H and CH3, R5 is selected from the group consisting of H and CH3, R ° is selected from the group consisting of CH3 and H, R is selected from the group which consists of H and OH, and R8 is selected from the group consisting of H and OH; with the condition of • if R7 or R8 = OH, that at least one of R4, R5 and R6 = CH3 and that at least two of R, R, R, R7 and R8 = H.

5. The compound according to claim 1, characterized in that or Cl, or Cl and R3 = C1 or H.

6. The method according to claim 3 characterized in that R '= H or Cl, R2 = H or Cl and R3 = C1 or H.

7. The compound in accordance with Claim 2, characterized in that R7 = OH or H, R8 = OH or H and R7 = R

8. 8. The method according to claim 4, characterized in that or H, R8 = OH or H and R7 = R8. In testimony of which, I have signed the previous description and novelty of the invention as representative of ARIZONA BOARD OF REGENTS, in Mexico City, Federal District, today, December 1, 1993.