JPH09500105A - N-alkylthiopolyamine derivatives as radioprotectors - Google Patents

Abstract

  (57) [Summary] The present invention relates to certain polyamine tyrools that are useful as radioprotectants.

Description

Detailed Description of the Invention Title of invention N-alkylthiopolyamine derivatives as radioprotectors                          Background of the Invention   Radiation protectants, also known as radiation protectors, protect against exposure to ionizing radiation. It is defined as a reagent that protects a cell or organism from adverse effects on the cell. The adverse effects on these cells include damage to cellular DNA such as breakage of DNA strands and fine damage to cells. Cell function disruption, cell death, tumor induction, etc. are included. The mechanism of this protective effect is At least in part because of the radical scavenging properties of radioprotectors.   To be exposed to radiation in the environment and radiation during cancer radiation therapy The possibility of using these reagents for the protection provided by them has long been recognized. these Reagents are administered before or during exposure to nuclear explosions, radioactive material spills, By exposure to ionizing radiation in the environment that occurs when a person approaches a radioactive substance It will eliminate or reduce the severity of the resulting adverse effects on the cells.   In addition, these reagents are not normal cells but cancer cells during radiotherapy of cancer. Believed to selectively protect cells. For example, these reagents may Is given to normal non-cancerous cells when administered to cancer patients during radiation therapy. Is absorbed and gives a protective effect. However, radioprotectors do not affect the blood vessels associated with tumors. Therefore, it will not be absorbed to the same extent by tumor cells. Thus radiating The line protector provides a selective protective effect on normal cells compared to tumor cells, To eliminate or reduce the adverse effects of radiotherapy on cells There will be. In addition, certain radioprotective agents may not completely act in cancer cells. It can act as a prodrug that needs to be activated by elementary treatment. These reagents are supposed to be absorbed at the same concentration in normal cells and cancer cells. Is activated by enzyme treatment in normal cells but not in cancer cells. this These prodrug radioprotectors are activated only in normal cells and have a selective protective effect. Or remove the adverse effects of radiotherapy on normal cells on the cells or Reduce its awfulness.   In addition, certain radioprotectors are found in normal cells to contain cisplatin, cyclophosphamide. De, diethyl nitrosamine, benzo (a) pyrene, carboplatin, doxorubi Cells generated by certain DNA-reactive reagents such as syn and mitomitin-C Provide selective protection against adverse effects on. These DNA-reactive reagents Most of them are chemotherapeutic agents useful in treating cancer. Radioprotectors are DNA-reactive By exposure to these DNA-reactive agents, such as during cancer therapy with chemotherapeutic agents. Normal cells It is useful in eliminating the adverse effects in or reducing its severity.   In addition, certain radioprotective agents have been shown to Provides selective protection [Gardina et al., Pharmac. Ther.39, 21 (1988)]. radiation Radiation therapy and chemotherapy provide effective treatments for various neoplastic disease symptoms. Unfortunate Fortunately, these treatments themselves are often mutagenic and / or carcinogenic. Results in secondary tumor induction induced by treatment. For example, in Hodgkin's disease In contrast, patients treated had treatment-induced acute myeloid leukemia and non-Hodgkin's disease. Appears to have a relatively high risk for lymphoma. Radiation protector is radiation Tumor induction caused by chemotherapy or chemotherapy with DNA-reactive chemotherapeutic agents Provides selective protection against adverse effects on cells. Therefore, radioprotectors Eliminates the risk of secondary tumor induction posed by radiation or chemotherapy Or it is useful to reduce.   As such, radioprotectors are exposed to the environment against ionizing radiation, cancer radiation. Normal cells resulting from radiation therapy and treatment with DNA-reactive chemotherapeutic agents Useful for eliminating or reducing the severity of adverse effects on cells in . Commonly Wyeth and Simic Pharmac. Ther.39, 1 (1988).   Walter Reed Army In Stay Tu Anti-radiation drug at Walter Reed Army Institute Research The prototype radioprotector developed by the Agent Development Program is WR-2721, or Is S-2 (3-aminopropylamino) ethyl phosphorothioic acid, This is a structural formula have.   Other known radioprotectors are believed to be metabolites of WR-2721 and their structure formula Having WR-1065 and structural formula It has WR-151,327.                           Summary of the Invention   The present invention provides a novel radioprotective agent of formula (I) and of its pharmaceutically acceptable addition salts. Provide a protective agent. In the ceremony   m is an integer from 2 to 4,   n is an integer from 3 to 10,   R is C₂~ C₆Alkyl,   B₁, B₂, B_Three, B_FourAre each independently H, -CH₂CH₂SH or -CH₂CH₂SPO_ThreeH₂Is But,   However, B₁, B₂, B_ThreeOr B_FourAt least one of them is not H I have.   The present invention further provides a novel radiation of formula (II) and of its pharmaceutically acceptable addition salts. Provides line protection agents. In the ceremony   m is an integer from 2 to 4,   n is an integer from 3 to 10,   R is C₂~ C₆Alkyl,   B₁, B₂, B_ThreeAre each independently H, -CH₂CH₂SH or -CH₂CH₂SPO_ThreeH₂In Although, However, B₁, B₂, B_ThreeAt least one of them is other than H.   The invention further comprises contacting a mammalian cell with a protective amount of a compound of formula (I) or formula (II). To cells produced by exposure to ionizing radiation or DNA reactive agents A method of protecting mammalian cells from the adverse effects of   The present invention also comprises administering to a person a protective amount of a compound of formula (I) or formula (II). Cells caused by exposure to ionizing radiation or DNA reactive agents A method of protecting a human non-cancerous cell from the adverse effects thereof.   The present invention further provides a protective dose of a compound of formula (I) or formula (II) for radiotherapy or DNA reaction. Radiation consisting of administering to patients in need of chemotherapy with a chemotherapeutic agent Ray therapy Or a method of treating a patient in need of chemotherapy with a DNA-responsive chemotherapeutic agent provide.                       Detailed description of the invention   As used herein, the following terms have the meanings set forth below. (1) `` C₂-C₆The term "alkyl" refers to 1 to 6 {2 to 6 typos? ｝ Refers to a saturated linear or molecular chain hydrocarbyl group of carbon atoms. Scope of this term Included in the enclosure are ethyl, n-propyl, isopropyl, n-butyl, isobutyrate. , Secondary butyl, tertiary butyl, n-pentyl, n-hexyl, 1,1-dimethylpropyl , 3,3-dimethylpropyl, 1-methylbutyl, 2-methylbutyl and the like. (2) The term "Ts" is a formula (3) The term "Et" has the formula -CH₂-CH_Three It refers to the ethyl functional group of. (4) The term "Pr" has the formula -CH₂-CH₂-CH_ThreeThe propyl functional group You. (5) The term “Bu” refers to the formula —CH₂-CH₂-CH₂-CH_ThreeButyl functional group I have. (6) The term "halogen" or "halo" refers to chlorine, bromine, or an element atom. ing. (7) The term "pharmaceutically acceptable addition salt" is represented by formula (I) or (II) It is intended to be applied to any non-toxic organic or inorganic acid addition salts of the basic compounds mentioned. Illustrated. Examples of suitable salt forming inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid and phosphorus. Acids and acid metal salts include, for example, sodium monohydrogen orthosulfate and potassium hydrogen sulfate. I will. Examples of suitable salt forming organic acids include mono-, di- and tricarboxylic acids. I will. Examples of such acids are eg acetic acid, glycolic acid, sulfuric acid, pyruvic acid, Malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, Scorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoate Aromatic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluene Sulfonic acids and sulfonic acids such as methanesulfonic acid and 2-hydroxyethane Rufonic acid is included. Such salts exist in either hydrated or substantially anhydrous form. Can be present. In general, the acid addition salts of these compounds are water-soluble and have various hydrophilic properties. Soluble in organic solvents and generally have a higher melting point when compared to their free base forms Indicates   The formula (I) polyamine derivative can be prepared using techniques well known in the art. You. The choice of any particular manufacturing route depends on various factors. For example a general reaction The availability and price of the body, and certain generalized reactions can be tailored to specific compounds. Whether or not it depends on the person skilled in the art. The preparation of any particular compound which is a factor to be understood and is encompassed by formula (I) Can all contribute to the selection of synthetic methods in.   The following reaction pathways describe the pathways that can make compounds of formula (I) . All substituents are as previously defined unless otherwise indicated. Reagent and dispense Sources are readily available to those of ordinary skill in the art. Preparation of starting materials used in reaction pathway II Are described in Reaction Path I.   In reaction pathway I, step A, the primary amine (1) was treated with a European-specific compound, published March 1, 1990. Under conditions well known in the art, as described in license publication number 0 349 224. , Protected as a tosylate derivative as described in structure (2).   For example, mixing a primary amine (1) with dichloromethane and 10% sodium hydroxide. Dissolve in material and cool to 0 ° C. Add excess p-toluene chloride to the stirred solution. Lefonil Is added dropwise. After about 1 hour, warm the reaction to room temperature and stir for about 2 days. The reaction is 0. Neutralize with 5N hydrochloric acid and extract with a suitable organic solvent such as methylene chloride. Organic phase with water Rinse with brine, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to This gives a protected secondary amine (2).   In step B, the appropriately substituted diol (2a) was utilized to provide a protected secondary amine. (2) is subjected to Mitsunobu reaction to produce the primary alcohol described in structure (3). You.   For example, the protected secondary amine (2) can be treated with a suitable amine such as tetrahydrofuran. Dissolve in organic solvent and treat with 1 equivalent of triphenylphosphine. Then this one Treated with an equivalent of the appropriately substituted diol (2a), followed by 1 equivalent of diethylazodiene. Treat with carboxylate. Following this, stir at about 25 ° C for 4 to about 18 hours . The product was isolated by extraction methods well known in the art, such as methylene chloride extraction. Rinse with water, brine, dry over anhydrous sodium sulfate, filter and concentrate under vacuum . Mix the residue with silica gel and a suitable eluent such as methanol / methylene chloride. Purification by flash chromatography using Make a call (3).   In Step C, March, “Advanced Organic Chemistry” -reactions, mechanisms, and structures Zou- (Maguro Hill Book Company, 2nd Edition, 1977, pp. 1107-1108) As is generally stated, there are well-known recognitions in the chemical arts. Oxidation of the primary alcohol (3) under controlled conditions results in the carbohydrate described by structure (4). Provide acid.   For example, dissolve the primary alcohol (3) in acetone at 0 ° C and use a slight excess of jaws. Reagents [Bowden, K. et al., J. Chem. Soc. 39 Vol. 1946] Add dropwise. Stir the reaction for 1-4 hours at 0 ° C. Next, add isopropanol and add The reaction product was filtered through diatomaceous earth and rinsed with several portions of acetone and methyl chloride. It is. Concentrate the filtrate in vacuo and use silica gel, like methanol / methylene chloride. This technique, such as flash chromatography, can be used with an appropriate eluent mixture. Purification of the residue by techniques well known in the art yields the carboxylic acid (4).   Instead, starting from the protected secondary amine (2), the carboxylic acid is reacted. It can be prepared according to steps D and E of route I.   In step D, the protected secondary amine (2) was appropriately substituted with ethylhalocarbo When N-alkylated with xylate (2a '), X is a chloride or bromide atom Yields the N-alkylated protected amine described by structure (3a)   For example, the protected secondary amine (2) is dissolved in a suitable solvent such as tetrahydrofuran. Dissolve in medium and treat with 1 equivalent of a suitable base such as sodium hydride. reaction Stir for about 30 minutes, suitable as 1 equivalent of ethyl 4-bromobutyrate The ethyl halocarboxylate substituted in is added. Next, bring the reaction to about 30-67 ° C. Heat for about 1-24 hours. The N-alkylated protected amine (3a) is then applied by this technique. Isolate from the reaction medium by well known techniques.   In step E, the N-alkylated protected amine (3a) was prepared under conditions well known in the art. Hydrolysis of the ester functionality yields the carboxylic acid (4).   For example, the N-alkylated protected amine (3a) is treated with a suitable solvent such as methanol / water. Dissolve in solvent mixture and treat with 1 equivalent of a suitable base such as sodium hydroxide . Stir the reaction at room temperature for about 1-24 hours. The reaction is then neutralized with 1N hydrochloric acid and chlorinated. Extract with a suitable solvent such as methylene. Combine the organic extracts with anhydrous sodium sulfate. Dry over triumnium, filter and concentrate under vacuum to give the carboxylic acid (4).   B₁And B_FourIs H, B₂And B_ThreeBut -CH₂CH₂SH or -CH₂CH₂SPO_ThreeH₂Compounds of formula (I) when Can be prepared as described in Reaction Pathway II. Unless otherwise instructed All substituents are as previously defined. Reagents and starting materials readily available to one of ordinary skill in the art Available at.   In Reaction Route II, Step A, diamine (5) was added to 2 equivalents of acid (under conditions well known in the art). The amidation reaction in 4) yields the diamine (6).   For example, 2 equivalents of acid (4) are dissolved in a suitable organic solvent such as tetrahydrofuran. Dissolve and add 1 equivalent of the appropriate diamine. Next, 2.2 equivalents of N-ethoxycarboni Ru-2-ethoxy-1,2-dihydroquinone (EEDQ) is added. Reaction at room temperature for 2-24 hours Stir. Then it is concentrated under vacuum. Shrink. Residues are well known in the art, such as flash chromatography. Purification by the method gives the diamide (6).   Alternatively, the diamide (6) can be prepared by the following method. 2 equivalents of acid (4) Dissolve in a suitable organic solvent such as lahydrofuran, and add 2 equivalents of N-methylmorpholine. Process. The reaction was cooled to -20 ° C and 2 equivalents of isobutyl chloroformate were added. Process. Stir the reaction for about 30 minutes and dissolve in dimethylformamide. 1 equivalent of the appropriately substituted diamine (5) is added. Stir the reaction at -20 ° C for several hours Then warm to room temperature and dilute with ether and water. The layers are separated and the organic layer is washed with magnesium sulfate. Dry with um, filter and concentrate under vacuum. Flash chromatography The residue is purified by techniques well known in the art to yield the diamide (6). Cheat.   In step B, diamide (6) was reduced under conditions well known in the art to give structure (7). Yields the tetraamine described.   For example, Borch, Tetrahedron Lett. Volume 1 Page 61 (1968) According to the general rule, 2.2 equivalents of triethyloxonium tetrafluoroborate are salted. Dissolve in a suitable organic solvent such as methylene chloride and add 2 equivalents of diamide (6). The reaction is stirred at room temperature for about 24 hours, then the solvent is removed in vacuo. Eta the residue Dissolved in knoll Then add 4.5 equivalents of sodium borohydride little by little to the stirred solution at 0 ° C. You. After the addition is complete, warm the reaction to room temperature and stir for about 18-24 hours. Product this Isolate by extraction methods well known in the art. Flash chromatography of the residue Purify with to give the tetraamine (7).   Alternatively, tetraamine (7) can be prepared by the following method. Diamide (6) Dissolve in a suitable solvent such as trahydrofuran and add 2 equivalents of borane (tetrahydrofuran at 0 ° C). (1M solution in hydrofuran) and stir under reflux for 18 hours, then use this technique to After isolation and purification by known techniques, the tetraamine (7) is produced.   In step C, the tetraamine was di-N-alkylated with ethylene sulfide to give the structure (8) This yields the appropriately substituted di-N-alkylated amine described.   For example, dissolve tetraamine (7) in a suitable organic solvent such as tetrahydrofuran. Dissolve and treat with about 2.2 equivalents of ethylene sulfide at room temperature to reflux temperature for 2-10 hours. solvent Was removed in vacuo and the product isolated and purified by techniques well known in the art This produces a -N-alkylated amine (8).   In step D, the di-N-alkylated amine (8) was deprotected by techniques well known in the art. This produces the deprotected tetraamine (9).   For example, di-N-alkylated amine (8) can be treated with 1,2-dinotoxy Dissolve it in a suitable organic solvent such as ethane, with a slight excess of aluminum hydride. Treat with thium. The reaction is then heated to reflux for about 18 hours. Excess hydrogenation after cooling Stop lithium aluminum and isolate the product according to techniques well known in the art This produces the deprotected tetraamine (9).   Instead, di-N-alkylated amines (8) were used in the European Union published March 1, 1990. Deprotection can be done generally according to the procedure described in patent application No. 349 224. The-N- The alkylated amine (8) was dissolved in dry tetrahydrofuran, cooled to -78 ° C, Treat with concentrated ammonia. Excess sodium was added slowly at -78 ° C and the reaction mass was Stir for about 4 hours. Then it is warmed to room temperature overnight and the ammonia is evaporated. Diethyl ether was added, followed by careful addition of ethanol, and finally the reaction was stopped. Carefully add water to stop. The solvent was removed under vacuum and the residue was washed with diethyl ether. Extract with ether and chloroform. Combined extracts are anhydrous sodium sulfate Dry at rt, filter and concentrate under vacuum. Flash chromatography of the residue Purification by techniques well known in the art, such as, gives the deprotected amine (9).   In step E, which may optionally be performed, the thiol functional group of (9) is paired with the structure (10). It can be converted to the corresponding phosphorothioate.   For example, a suitably substituted deprotected amine (9) with 4 equivalents of triethyl phosphite. Treat with 2 equivalents of bromotrichloromethane. Reactants range from room temperature to reflux temperature Stir for 1-3 hours. The corresponding intermediate bis (diethyl phosphorothioate) is Removal of volatiles under vacuum and purification by flash chromatography Recovered from the response. Then the intermediate bis (diethyl phosphorothioate) was It is cleaved by treatment with trimethylsilyl bromide. Reactant is methylene chloride Contact in a suitable organic solvent in the range of -20 ° C to reflux temperature for about 2-24 hours. Next Volatiles were removed under vacuum and the residue was purified by techniques well known in the art. , Yields the phosphorothioate of structure (10).   B₁, B_Three, And B_FourIs H, B₂But -CH₂CH₂SH or CH₂CH₂SPO_ThreeH₂(I) when Compounds can be prepared as described in Reaction Pathway III. Unless otherwise instructed All substituents are as previously defined. Reactants and starting materials are well within the skill of those in the art. It is easily available.   In reaction pathway III, step A, the diamide (6) prepared in step A of reaction pathway II was Reduction using one equivalent of a suitable reducing agent under conditions well known in the art of structure (11) To give the mono-amide described in.   For example, diamide (6) is dissolved in a suitable organic solvent such as tetrahydrofuran. And treated with 1 equivalent of borane (1M solution in tetrahydrofuran) at 0 ° C, then under reflux. Stir for 6-8 hours, isolate and purify by methods well known in the art, and then Gives rise to (11).   In step B, the monoamide was mono-N-alkane with ethylene sulfide. Upon killing, the appropriately substituted mono-N-alkylated amine described in structure (12). Cause   For example, monoamide (11) is dissolved in a suitable organic solvent such as benzene and Treat with 1 equivalent of ethylene sulfide for 2-10 hours at reflux temperature. Solvent true Upon removal in air and isolation and purification of the product by techniques well known in the art, mono-N Yields the alkylated amide (12).   In step C, the mono-N-alkylated amide (12) was deprotected and at the same time treated with a suitable reducing agent. Reduction by treatment with a mono-N-alkylated tere described by structure (13). This produces traamine.   For example, a mono-N-alkylated amide (12) can be converted into a suitable compound such as 1,2-dimethoxyethane. A suitable reduction such as 4 equivalents of lithium aluminum hydride Treat with agent. The reaction is heated to reflux for about 18 hours. Next, the reaction product was mixed in a volume ratio of 1.0: 1.5: Stop by addition of 3.0 water: 10% sodium hydroxide: water. First here Water addition equals the weight used of lithium aluminum hydride. The product is then When isolated by extraction and purification methods well known in the art, mono-N-alkylated tetraamines (13 ) Occurs.   Optionally in step D, mono-N-alkylated tetraamine (13) The thiol functional groups in step E are described in step E, which may be optional additions to reaction pathway II. The corresponding mono-phosphoroti Can be converted to Oate.   For example, an appropriately substituted monoalkylated tetraamine (13) is added with 2 equivalents of phosphorous Treat with triethyl acid and 1 equivalent of bromotrichloromethane. Reaction from room temperature Stir for 1-3 hours in the temperature range up to the reflux temperature. Corresponding intermediate diethyl phospho The rothioate was recovered from the reaction by removing the volatiles under vacuum and flashing Purified by chromatography. The intermediate diethyl phosphorothioate is then It is cleaved by treatment with excess trimethylsilyl bromide. Methyl chloride reactants Approximately 2-24 hours in a suitable organic solvent such as ren at a temperature between -20 ℃ and reflux temperature. Touch it. The volatiles are then removed under vacuum and the residue is removed by techniques well known in the art. And purified to give the mono-phosphorothioate of structure (14).   B₁And B_FourBut -CH₂CH₂SH or CH₂CH₂SPO_ThreeH₂And B₂And B_ThreeWhere I is H, the formula (I) Compounds can be prepared as described in Reaction Route IV. Unless otherwise instructed All substituents are as previously defined. Reagents and starting materials readily available to one of ordinary skill in the art Available.   In reaction route IV, step A, the diamide (6) prepared in step A of reaction route II Deprotection under conditions well known in the art provides the deprotected diamide described by structure (15). Occurs.   For example, diamide (6) is described in European Patent Application No. 349 224 published on March 1, 1990. Deprotection can be done generally according to the procedure described in. Dry diamide (6) in tetra Dissolve in hydrofuran, cool to -78 ° C and treat with excess concentrated ammonia. excess Of sodium is slowly added at -78 ° C and the reaction is stirred for about 4 hours. Then this Allow to warm to room temperature overnight and evaporate the ammonia. Add diethyl ether Then add ethanol carefully and finally pour water to stop the reaction. Add it at will. The solvent was removed under vacuum and the residue was washed with diethyl ether and chloroform. Extract with rum. The combined extracts were dried over anhydrous sodium sulfate, filtered and filtered. Concentrate in the air. The residue can be removed using this technique, such as flash chromatography. Purification by well known techniques gives the deprotected diamide (15).   In step B, the deprotected diamide (15) was added to the N-alkyne previously described in step C of reaction scheme II. Di-N-alkylation by a method similar to the acetylation procedure gives the di-N-alkyl structure described in structure (16). This produces a rukylated diamide.   In step C, the di-N-alkylated diamide (16) is reduced under conditions well known in the art. This gives the tetraamine described by structure (17).   For example, di-N-alkylated diamide (16) can be converted into a suitable compound such as 1,2-dimethoxyethane. Dissolved in a suitable organic solvent and added with 2 equivalents of a suitable solvent such as lithium aluminum hydride. Treat with the base material. The reaction is heated to reflux for about 5-18 hours. Next, the reaction mixture was added at a volume ratio of 1.0: Stop by addition of 1.5: 3.0 water: 10% sodium hydroxide: water. Up here The initial water addition is equal to the weight of lithium aluminum hydride used. Then add the product Isolation by extraction and purification methods well known in the art produces the tetraamine (17).   In step D, which may optionally be performed, the tetraamine The thiol functional group of (17) may be optionally added to Reaction Path II, Step E. Conversion to the corresponding phosphorothioate of structure (18) using a procedure similar to that described in. it can.   B₁, B₂, And B_ThreeIs H, B_FourBut -CH₂CH₂SH or CH₂CH₂SPO_ThreeH₂(I) when Compounds can be prepared as described in Reaction Route V. Unless otherwise instructed, All substituents are as previously defined. Reagents and starting materials are well within the skill of those in the art. It is easily available.   Deprotection diamide prepared in Reaction Path V, Step A, Step A of Reaction Path IV (15) Mono protection of the structure (19) This produces the mono-protected diamide described.   For example, dissolve the deprotected diamide (15) in methylene chloride and 10% sodium hydroxide. And cool to 0 ° C. 1 equivalent of p-toluenesulfonyl chloride was added to the stirred solution. Add. After about 1 hour, warm the reaction to room temperature and stir for 1-48 hours. 0.5N reactant Neutralize with hydrochloric acid and extract with a suitable organic solvent such as methylene chloride. The organic phase is water, Rinse with brine, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to remove moisturizer. This gives the unprotected cyamide (19).   In step B, the mono-protected diamide (19) was added to the N- N-alkylation in a manner similar to alkylation yields the N-alkyls described in structure (20). Yields a diamide.   In Step C, the N-alkylated diamide (20) was previously described in Step C of Reaction Pathway III. When reduction and deprotection were carried out in a similar manner to the procedure described above, the N-alcohol described in structure (21) was used. This produces a killed tetraamine.   Optionally in step D, optionally in reaction pathway III N-alkylated tetraamines generally according to the procedure described in step D The thiol functional group of (21) is replaced by the corresponding phosphorothioate tetrahedron described in structure (22) Can be converted to amines.   The following example is of formula (1) described by Reaction Pathways I, II, III, IV and V Represents a typical synthesis of a compound doing. These examples are for illustration purposes only Not meant to limit the light. Reagents and starting materials are readily available to one of ordinary skill in the art . In the examples below, the following terms have the indicated meanings. "Eq" is equivalent, "g" is group Ram, "mg" milligram, "mmol" is millimol, "mL" is milliliter, "° C" is in degrees Celsius , "TLC" is thin layer chromatography, "Rf" is retention constant, and "δ" is tetramethylsilane. Points downfield ppm from the run. Example 1 2-[{8-[(2-mercapto-ethyl)-(2-butylamino-ethyl) -amino] -octyl}- Production of (2-butylamino-ethyl) -amino] -ethanethiol   Reaction Pathway I, Step A: in methylene chloride (50 mL) and 10% sodium hydroxide (50 mL) Butylamine (10 mmol) is dissolved. Cool to 0 ° C. Stirring, excess salt P-Toluenesulfonyl chloride is added. After 1 hour, warm the reaction to room temperature and stir for 2 days. Mix. The reaction is neutralized with 0.5N hydrochloric acid and the aqueous phase is extracted with methylene chloride (2 x 100 mL). . Rinse the combined organic extracts with water (100 mL), brine (100 mL), and dry with anhydrous sodium sulfate. Dried in vacuo, filtered, and concentrated in vacuo to give N-butyl-4-methyl-benzenesulfon. Yields amide.   Reaction Pathway I, Step B: N-Butyl-4-methylbenzenes Rufonamide (10 mmol) was dissolved in tetrahydrofuran (50 mL) and triphenylamine was added. Ruphosphine (10 mmol) is added. Treat this with ethylene glycol (10 mmol) Then, diethyl azodicarboxylate (10 mmol) is added. 25 ° C for reaction Stir for 18 hours. The reaction is concentrated under vacuum. Flash chroma the residue Purified by topography (silica gel, toluene / ethyl acetate) to give N-butyl This gives rise to ru-N- (2-hydroxyethyl) -4-methyl-benzenesulfonamide.   Reaction Path I, Step C: N-Butyl-N- (2-hydroxyethyl) -4-methyl-benzene The sulfonamide (10 mmol) is dissolved in acetone (50 mL) and cooled to 0 ° C. Some excess A quantity of Jones reagent is added dropwise and the reaction is stirred at 0 ° C. for 4 hours. Excess isopro Panol is added and the reaction is filtered through a plug of diatomaceous earth. Plug the plug into acetone (2 Rinse with x50 mL) and methylene chloride (3 x 50 mL). Combine the filtrates and concentrate under vacuum . The residue is flash chromatographed (silica gel, methanol / methyl chloride). Len) yields [butyl- (toluene-4-sulfonyl) -amino] -acetic acid .   [Butyl- (toluene-4-sulfonyl) -amino] -acetic acid alternative process   Reaction pathway I, step D: N-butyl-4-methylbenzenesulfonamide (10 mmol) Dissolved in tetrahydrofuran (50 mL) and treated with sodium hydride (10 mmol) You. Anti Stir the reaction for 30 minutes and add ethyl bromoacetate (10 mmol). The reaction mixture under reflux Stir for 18 hours. Next, add methylene chloride (100 mL) and add water (100 mL) and brine (1 mL). (00 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude ethyl ester. This produces ru [butyl- (toluene-4-sulfonyl) -amino] -acetate.   Reaction Pathway I, Step E: Crude ethyl [butyl- (toluene-4-sulfonyl) -amino]- Acetate (10 mmol) is dissolved in methanol (25 mL) and water (25 mL). Sodium hydroxide Thorium (10 mmol) is added and the reaction is stirred at room temperature for 5 hours. The reaction product was washed with water (10 Dilute with 0 mL) and rinse with methylene chloride. Neutralize the aqueous phase with 1N hydrochloric acid and wash with methylene chloride. Extract with (3 x 75 mL). Combine the organic extracts, water (100 mL), brine (100 mL) Rinse, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. This gives rise to ru- (toluene-4-sulfonyl) -amino] -acetic acid.   Reaction Path II, Step A: [Butyl-(- Toluene-4-sulfonyl) -amino] -acetic acid (20 mmol) was added to tetrahydrofuran (50 mL). ), And add 1,8-diaminooctane (10 mmol). N-ethoxycarbonyl 2-Ethoxy-1,2-dihydroquinoline (EEDQ) (22 mmol) is added. 6-7 hours at room temperature Stir. The reaction is concentrated under vacuum. Flash chromatography of the residue (Silica gel, methanol / methylene chloride) Purification yields the diamide.   Instead, in step A of Reaction Pathway II, [butyl- (toluene-4-sulfonyl)- Amino] -acetic acid (20 mmol) was dissolved in tetrahydrofuran (50 mL), followed by N-methyl The diamide can be made by adding rumorpholine (20 mmol). The reaction is cooled to −20 ° C. and isobutyl chloroformate (20 mmol) is added. The reaction was stirred for 30 minutes and 1,8-dia was dissolved in dimethylformamide (5 mL). Add minooctane (10 mmol). Stir the reaction for 2 hours at -20 ° C, then room temperature Warm up. Dilute the reaction with water (150 mL) and extract with diethyl ether (3 x 75 mL) I do. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and under vacuum. Concentrate to. The residue is flash chromatographed (silica gel, methanol / Methylene chloride) to give the diamide.   Reaction Path II, Step B: Triethyloxonium tetra in methylene chloride (50 mL) Fluoroborate (42 mmol) was added and the diamine prepared in Step A of Reaction Pathway II above. (20 mmol) is added. The reaction is stirred at room temperature for 24 hours and then concentrated under vacuum. The residue was dissolved in ethanol (50 mL), cooled to 0 ° C, and sodium borohydride (45 mL) was added. mmol) is added little by little. After the addition is complete, warm the reaction to room temperature and stir for 24 hours. . Dilute the reaction with methylene chloride (200 mL), rinse with water (100 mL), brine (100 mL), Anhydrous sodium sulfate Dry at rt, filter and concentrate under vacuum. Flash chromatography of the residue Purification with (silica gel, methanol / methylene chloride) yields tetraamine .   Instead, the diamide (10 mmol) prepared in step A of reaction pathway II Dissolve it in tetrahydrofuran (50 mL) to give tetraamido in Step B of Reaction Pathway II. Can be prepared. The solution was cooled to 0 ° C. and borane (20 mmol, 1M tetrahydrofuran Solution). The reaction is heated to reflux for 18 hours. After cooling, the reaction product is methyl chloride. Diluted with water (200 mL), rinsed with water (100 mL), brine (100 mL), anhydrous sodium sulfate Dry with um, filter and concentrate under vacuum. Flash chromatography of the residue Purification with fi (silica gel, methanol / methylene chloride) yields tetraamine Occurs.   Reaction Path II, Step C: Tetraamine prepared in Step B of Reaction Path II (10 mmol ) Is dissolved in tetrahydrofuran (50 mL), and ethylene sulfide (22 mmol) is added dropwise. . The reaction is heated to reflux for 4 hours. After cooling, the reaction was concentrated under vacuum and the residue was Purification by flash chromatography (silica gel, methanol / methylene chloride) When made, it produces a di-N-alkylated tetraamine.   Reaction Path II, Step D: Di-N-alkylated prepared in Reaction Path II Step C Tetraamine (10 mmol) was dissolved in 1,2-dimethoxyethane (50 mL) and hydrogenated. Luminiu Treat with mullithium (25 mmol). The reaction is heated to reflux for 18 hours. Water after cooling (1 mL), 10% sodium hydroxide (1.5 mL) and water (3 mL) were added one after another to react. Finish things. Then dilute with methylene chloride (200 mL) and add water (100 mL) and brine (10 mL). Rinse (0 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. The rest Flash chromatography of the distillate (silica gel, methanol / methylene chloride Purification with) gives the title compound.   Instead, the di-N-alkylated tetraamido prepared in Step C of Reaction Pathway II was used. Dissolved in dry tetrahydrofuran (50 mL) and the solution cooled to -78 ° C. The title compound can be prepared by Step D of Reaction Pathway II. Excess dry ammonia is added, followed by excess sodium. 4 o'clock reaction Stir, then warm to room temperature overnight. Add diethyl ether (100 mL) and continue. Carefully add ethanol (30 mL). After stirring for 30 minutes, water (5 mL) Is carefully added dropwise and the reaction is concentrated in vacuo. The residue was converted to diethyl ether ( Extract with 100 mL) and chloroform (100 mL). Combine the organic extracts and add anhydrous sulfuric acid. Dry over sodium, filter and concentrate in vacuo. Flash chroma the residue Purified by topography (silica gel, methanol / methylene chloride) to give the title compound Cause Example 2 Five, 8,17,20-Tetraaza-8,17-bis- [2- (thiophosphoryl) ethyl] -tetradodecane Manufacturing of   Reaction Pathway II, Step E, which may optionally be carried out: 2-((prepared in Example 1 2-Butylamino-ethyl)-{8-[(2-butylamino-ethyl)-(2-mercapto-ethyl) -Amino] -octyl} -amino-ethanethiol (10 mmol) with triethyl phosphite ( 40 mmol) and bromotrichloromethane (20 mmol). The reaction is brought to reflux under 2 Stir the time. The reaction was concentrated under vacuum and the intermediate bis (diethylphosphorothioate Ate) by flash chromatography (silica gel, ethyl acetate). You. Dissolve purified bis (diethyl phosphorothioate) in methylene chloride (50 mL), Treat with excess trimethylsilyl bromide. Stir the reaction for 24 hours. Reactants Concentrate under vacuum and purify to give the title compound. Example 3 2-{(2-butylamino-ethyl)-[8- (2-acetylamino-ethylamino) -octyl] -a Production of Mino} -ethanethiol   Reaction Pathway III, Step A: Triethyloxonium Teto Rafluoroborate (10 mmol) was dissolved in methylene chloride (50 mL) and treated in Example 1, Add the diamide prepared in Reaction Pathway II, Step A (10 mmol). Reaction at room temperature 2 Stir for 4 hours and concentrate under vacuum. Dissolve the residue in ethanol (50 mL), 0 ℃ Dissolve in and add sodium borohydride (45 mmol) in small portions. After the addition, Warm the reaction to room temperature and stir for 24 hours. Dilute the reaction with methylene chloride (200 mL). Dilute, rinse with water (100 mL) and brine (100 mL), dry over anhydrous sodium sulfate and filter. And concentrate in vacuo. Flash chromatograph the residue on silica gel. , Methanol / methylene chloride) to give the amide.   Instead, the diamide prepared in Example 1, Reaction Pathway II, Step A (10 mmol) Was dissolved in tetrahydrofuran (50 mL) to give a solution of reaction pathway III, step A. A mid can be prepared. The solution was cooled to 0 ° C and borane (10 mmol, 1M tetrahydrofuran) was added. Solution). The solution is heated to reflux for 18 hours. After cooling, the reaction is methylene chloride. Dilute with (200 mL), rinse with water (100 mL) and brine (100 mL), anhydrous sodium sulfate Dried, filtered and concentrated in vacuo. Flash chromatography of the residue Purification on silica gel (silica gel, methanol / methylene chloride) gives the amide.   Reaction pathway III, step B: The amide (10 mmol) prepared in step A of reaction pathway III In tetrahydrofuran (50 mL) Dissolve and add ethylene sulfide (10 mmol) dropwise. The reaction is heated to reflux for 4 hours. After cooling, the reaction was concentrated under vacuum and the residue flash chromatographed (silica). Purified with Rica gel, methanol / methylene chloride) to give N-alkylated amino acids. Cause   Reaction Path III, Step C: N-alkylated prepared in Reaction Path III Step B Dissolve the amide (10 mmol) in 1,2-dimethoxyethane (50 mL) and use aluminum hydride. Treat with mullithium (40 mmol). The reaction is heated to reflux for 18 hours. Water after cooling (1.5 mL), 10% sodium hydroxide (2.3 mL) and water (4.5 mL) were added one after another, Finish the reaction. Next, dilute with methylene chloride (200 mL) and add water (100 mL) and brine. Rinse (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. . The residue is flash chromatographed (silica gel, methanol / methyl chloride). Purification with len) yields the title compound. Example 4 Production of 5,8,17,20-tetraaza-8- [2 (thiophosphoryl) ethyl] -tetradodecane   Reaction Route III, Step D which may optionally be carried out: 2- {prepared in Example 3 (2-Butylamino-ethyl)-[8- (2-butylamino-ethylamino) -octyl] -ami No} -D Tanthiol (10 mmol) was added to triethyl phosphite (20 mmol) and bromotrichlorometa. (10 mmol). The reaction is stirred under reflux for 2 hours. Reaction under vacuum Concentrate and concentrate the intermediate diethyl phosphorothioate by flash chromatography. Purify with (silica gel, ethyl acetate). Salt with purified diethyl phosphorothioate Dissolve in methylene chloride (50 mL) and treat with excess trimethylsilyl bromide. Reactant Stir at -20 ° C for 4 hours. The reaction is concentrated under vacuum. 2-Propano residue Dissolve in water, add hydrochloric acid and collect the title compound as the hydrochloride salt by filtration. Example 5 2- {Butyl- [2- (8- {2- [butyl- (2-mercapto-ethyl) -amino] -ethylamino}- Octylamino))-ethyl] -amino} -ethanethiol production   The diamide (10 mmol) prepared in Example 1, Reaction Pathway II, Step A, was treated with dry tetra Dissolve in hydrofuran (50 mL) and cool the solution to -78 ° C. Excess dry ammoni A, followed by excess sodium. Stir the reaction for 4 hours, then Warm to room temperature overnight. Diethyl ether (100 mL) was added, followed by ethanol (30 m Add L) carefully. After stirring for 30 minutes, add water (5 mL) carefully and carefully, The reaction is concentrated under vacuum. Diethyl residue Extract with ether (100 mL) and chloroform (100 mL). Combine the organic extracts , Dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flush residue Purification by silica gel chromatography (silica gel, methanol / methylene chloride) This produces a protected diamide.   Reaction Path IV, Step B: The diamide (10 mmol) prepared in Step A of Reaction Path IV Dissolve in tetrahydrofuran (50 mL) and add ethylene sulfide (22 mmol) dropwise. Anti The reaction is heated to reflux for 4 hours. After cooling, the reaction was concentrated under vacuum and the residue was Purify by flash chromatography (silica gel, methanol / methylene chloride) This gives a di-N-alkylated diamide.   Reaction Route IV, Step C: Di-N-alkylated dia prepared in Step B of Reaction Route IV Dissolve the amide (10 mmol) in 1,2-dimethoxyethane (50 mL) and aluminum hydride Treat with lithium (40 mmol). The reaction is heated to reflux for 18 hours. After cooling, water ( 1.5 mL), 10% sodium hydroxide (2.3 mL) and water (4.5 mL) are added one after another. Next , Diluted with methylene chloride (200 mL), rinsed with water (100 mL) and brine (100 mL), Dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Flush residue ・ Refer to the table after purification by chromatography (silica gel, methanol / methylene chloride) This gives the title compound. Example 6 5,8,17,20-Tetraaza-5,20-bis [2- (thiophosphoryl) ethyl] -tetradodecane Manufacturing of   Reaction Pathway IV, optionally D, Step D: 2- {prepared in Example 5 Butyl- [2- (8- {2- [butyl- (2-mercapto-ethyl) -amino] -ethylamino} -oct Tyramino))-ethyl] -amino} -ethanethiol (10 mmol) triethyl phosphite Treat with (40 mmol) and bromotrichloromethane (20 mmol). Reactants under Ryukyu Stir for 2 hours. The reaction was concentrated under vacuum and the intermediate bis (diethylphosphoroti Oate) purified by flash chromatography (silica gel, ethyl acetate) I do. Dissolve purified bis (diethyl phosphorothioate) in methylene chloride (50 mL) Treat with excess trimethylsilyl bromide. Stir the reaction mixture at -20 ° C for 4 hours. . The reaction is concentrated under vacuum. Dissolve the residue in 2-propanol, add hydrochloric acid, The title compound is collected by filtration as the hydrochloride salt. Example 7 2- (butyl- {2- [8- (2-butylamino-ethylamino) -octylamino] -ethyl} -a Mino) -ethanethiol production   Reaction Route V, Step A: Deprotection dia prepared in Example 5, Reaction Route IV, Step A The amide (10 mmol) is dissolved in 10% sodium hydroxide (50 mL) and cooled to 0 ° C. Or 1 hour after adding p-toluenesulfonyl chloride (10 mmol) with stirring, Warm to room temperature and stir for 2 days. The reaction product was neutralized with 0.5N hydrochloric acid, and methylene chloride (2 × 100mL). Combine the combined organic extracts with water (100 mL), brine (100 mL) Rinse, dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to give monoprotection. This produces a diamide.   Reaction Route V, Step B: The mono-protected diamide prepared in Step A of Reaction Route V Dissolve in trahydrofuran (50 mL) and add ethylene sulfide (1.2 mmol) dropwise. Anti The reaction is heated to reflux for 4 hours. After cooling, the reaction was concentrated under vacuum and the residue was Purify by flash chromatography (silica gel, methanol / methylene chloride) This produces an N-alkylated diamide.   Reaction Route IV, Step C: N-alkylated diamide prepared in Step B of Reaction Route V (10 mmol) was dissolved in 1,2-dimethoxyethane (50 mL) and aluminum hydride lithium Treat with Um (40 mmol). The reaction is heated to reflux for 18 hours. After cooling, water (1.5m l), 10% sodium hydroxide (2.3 mL) and water (4.5 mL) were added in sequence to add the reaction mass. Finish. Then dilute with methylene chloride (200 mL), water (100 mL) and brine (100 mL). ) Rinse, dry over anhydrous sodium sulfate, Filter and concentrate in vacuo. The residue is flash chromatographed (silica gel). Purification, methanol / methylene chloride) yields the title compound. Example 8 Synthesis of 5,8,17,20-tetraaza-5- [2 (thiophosphoryl) ethyl] -tetradodecane   Reaction Pathway V, optionally in Step D: 2- {prepared in Example 7 Butyl- [2- (8- {2- [butylamino-ethylamino) -octylamino] -ethyl} -amino ) -Ethanethiol (10 mmol) with triethyl phosphite (20 mmol) and bromotrichloro Treat with dichloromethane (10 mmol). The reaction is stirred under reflux for 2 hours. Reactants Concentrate under vacuum and flash chromatograph the intermediate cyethylphosphorothioate. Purify with raffin (silica gel, ethyl acetate). Purified diethyl phosphorothioate Dissolved in methylene chloride (50 mL) and treated with excess trimethylsilyl bromide. The reaction is stirred at -20 ° C for 4 hours. The reaction is concentrated under vacuum. 2-p Dissolve in lopanol, add hydrochloric acid and collect the title compound as the hydrochloride salt by filtration. You.   Polyamine derivatives of formula (II) can be prepared using techniques well known in the art. . The choice of any particular preparation route depends on various factors. For example, the reactants The general Availability and cost, applicability of certain generalized reactions to specific compounds, etc. Preparation of any specific compound well understood by those skilled in the art and all encompassed by formula (II) Has contributed to the selection of the synthesis method in.   The following reaction routes are illustrative of routes for preparing compounds of formula (II). other Unless otherwise indicated, all substituents are as previously defined. Reagents and starting materials Fees are readily available to one of ordinary skill in the art. Preparation of starting materials for reaction routes VII, VIII and IX Production is described in Reaction Route VI.   Protecting the amino acid described in structure (23) in Reaction Pathway VI, Step A, This produces the N-tosylated amino acid described in 4).   For example, amino acid (23) is dissolved in 10% sodium hydroxide and cooled to 0 ° C. Or 1 equivalent of p- chloride in the stirred solution Toluenesulfonyl is added dropwise. After about 1 hour, warm the reaction to room temperature and allow for about 2 days. Mix. Neutralize the reaction with 0.5N hydrochloric acid and use a suitable organic solvent such as methylene chloride. Extract. The organic phase is rinsed with water, brine, dried over anhydrous sodium sulfate, filtered, Concentration under vacuum yields the N-tosylated amino acid (24).   In step B, the N-tosylated amino acid (24) was appropriately placed under conditions well known in the art. Subjected to an amidation reaction with a converted primary amine (1), it is described by structure (25) This produces an amide.   For example, the N-tosylated amino acid (24) is dissolved in a suitable organic solvent such as tetrahydrofuran. It is dissolved in the medium and subsequently 1 equivalent of an appropriately substituted primary amine (1) is added. next , 1.1 equivalents of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) And stir the reaction at room temperature for 2-24 hours. Then concentrate the reaction under vacuum . The residue is removed by techniques well known in the art, such as flash chromatography. And purified to give the amide (25).   Alternatively, the amide (25) can be prepared by the following method. 1 equivalent of N-tosylated Minoic acid (24) was dissolved in a suitable organic solvent such as tetrahydrofuran and 1 equivalent of N- Treat with methylmorpholine. The reaction was cooled to -20 ° C and 1 equivalent of isobutyl Treat with loroformate. Stir the reaction mixture for about 30 minutes and dimethylformamide. Dissolved in An equivalent amount of appropriately substituted primary amine (1) is added. Stir the reaction to -20 ° C for several hours. Mix, warm to room temperature and dilute with ether and water. Separate the layers and add the organic layer to magnesium sulfate. Dry with sium, filter and concentrate under vacuum. Flash chromatograph residue Purification by techniques well known in the art, such as raffin, yields no amide (25). You.   In step C, the amide (25) was N-alkylated with an appropriately substituted haloamide of structure (26). Upon formation, the protected diamide described by structure (27) is produced.   For example, the amide (25) is dissolved in a suitable solvent such as tetrahydrofuran and Treat with an appropriate amount of a suitable base such as sodium hydride. Stir the reaction product for about 30 minutes Add 1 equivalent of an appropriately substituted haloamide (26) [haloamide (26) is X Is a chloride or bromide atom, X (CH₂)_m-1COX and RNH₂Between (1) Can be prepared under conditions well known in the art, such as the amidation reaction of. Next, the reaction Is heated to about 30 ° C to 67 ° C for about 1-24 hours. Protected diamide (27) It is isolated from the reaction medium by well known techniques. For example, the reaction product may be methylene chloride. Diluted with water, rinsed with water, brine, dried over anhydrous sodium sulfate, filtered, and in vacuo. Concentrate. Silica gel with a suitable eluent mixture, eg methanol / methylene chloride By techniques well known in the art, such as flash chromatography on The residue is purified to give the protected diamide Gives rise to (27).   In step H, the protected diamide (27) was deprotected under conditions well known in the art to give the structure This produces the deprotected diamide described in (28).   For example, the procedure described in European Patent Application No. 349 224, published March 1, 1990. The protected diamide (27) can be deprotected according to the general procedure in sequence. Dry the protected diamide (27) Dissolve in dry tetrahydrofuran, cool to -78 ° C and treat with excess concentrated ammonia. You. Excess sodium is slowly added at -78 ° C and the reaction is stirred for about 4 hours. Next Then warm it to room temperature overnight and evaporate the ammonia. Add diethyl ether , Then carefully add ethanol and finally water to stop the reaction. Add caution. The solvent was removed under vacuum and the residue was washed with diethyl ether and chloroform. Extract with Holm. The combined extracts were dried over anhydrous sodium sulfate, filtered, Concentrate under vacuum. This technique such as flash chromatography of the residue Purification by techniques well known in. Yields the deprotected diamide (28).   B₂And B_ThreeIs H, B₁But -CH₂CH₂SH or -CH₂CH₂SPO_ThreeH₂Formula (II) compounds when Can be prepared as described in Reaction Pathway VII. Unless otherwise indicated, all The substituents are as previously defined. Reagents and starting materials readily available to one of ordinary skill in the art it can.   Reaction route VII, step A, appropriately substituted prepared in reaction route VI, step C The diamide (27) is a monoamide described by structure (29) under conditions well known in the art. Is reduced to   For example, diamide (27) is dissolved in a suitable solvent such as tetrahydrofuran, Treat with 1 equivalent of borane (1M solution in tetrahydrofuran) at 0 ° C. Then this Stir for 3 hours under reflux, isolate and purify by a method well known in the art, and This produces the amide (29).   In step B, the mono-amide (29) was mono-N-alkylated with ethylene sulfide to give the structure ( This gives the appropriately substituted mono-N-alkylated amides described under 30).   For example, monoamide (29) is dissolved in a suitable organic solvent such as benzene and ~ Treatment with 1 equivalent of ethylene sulfide at reflux temperature for 2-10 hours gives mono-N-alkyl This gives the amide (30).   In step C, the mono-N-alkylated amide (30) was deprotected and at the same time treated with a suitable reducing agent. Reduction by treatment with the mono-N-alkylated triamides described in structure (31). Cause   For example, a mono-N-alkylated amide (30) may be converted into a suitable compound such as 1,2-dimethoxyethane. Dissolve in a suitable organic solvent and reduce appropriately 4 equivalents of lithium aluminum hydride Treat with agent. The reaction is heated to reflux for about 18 hours. Next, the reaction product was mixed in a volume ratio of 1.0: 1.5: Stop by addition of 3.0 water: 10% sodium hydroxide: water. First here Water addition equals the weight used of lithium aluminum hydride. The product is then Mono-N-alkylated triamines (31) when isolated by extraction and purification methods well known in the art Cause   In step D, which may optionally be carried out, the mono-N-alkylated triamine (31) Already in step D, the thiol functional group may optionally be added to Reaction Pathway III. The corresponding mono-phosphorothioate of structure (32) was generally followed according to the procedure described. Can be converted.   For example, mono-N-alkylated triamine (31) was added with 2 equivalents of triethyl phosphite and And 1 equivalent of bromochloromethane To process. The reaction is stirred at room temperature to reflux temperature for 1-3 hours. In correspondence The interstitial diethyl phosphorothioate removes the volatiles under vacuum and flash flushes. Recovered from the reaction by purification by chromatography. Intermediate diethylpho Sforothioate is cleaved by treatment with excess trimethylsilyl bromide . Reactants in a suitable organic solvent such as methylene chloride in the range of -20 ° C to reflux temperature. Contact for about 2-24 hours. Then the volatiles were removed under vacuum and the residue was removed by this technique. Purification by well known techniques yields the mono-phosphorothioate of structure (32) .   B₁And B_ThreeIs H, B₂But -CH₂CH₂SH or CH₂CH₂SPO_ThreeH₂Formula (II) compounds when Can be prepared as described in Reaction Pathway VIII. Unless otherwise indicated, all The substituents are as previously defined. Reagents and starting materials readily available to one of ordinary skill in the art it can.   Reaction route VIII, step A, appropriately substituted prepared in reaction route VI, step D Mono-N-alkylation of the diamide (28) with ethylene sulfide yields the structure (33). To give an appropriately substituted mono-N-alkylated diamide defined by   For example, the appropriately substituted diamide (28) in a suitable organic solvent such as benzene. , And treat with 1 equivalent of ethylene sulfide at room temperature to reflux temperature for 2-10 hours. Yields a mono-N-alkylated diamide (33).   In step B, the mono-N-alkylated diamide (33) was deprotected and at the same time a suitable reducing agent Reduction by treatment with a mono-N-alkylation described by structure (34) Thoria This produces Min (34).   For example, a mono-N-alkylated diamide (33) may be used in a suitable solution such as 1,2-dimethoxyethane. Dissolve in a suitable organic solvent and prepare a suitable solution such as 4 equivalents of lithium aluminum hydride. Treat with the base material. The reaction is heated to reflux for about 18 hours. Next, the reaction mixture was mixed with a volume ratio of 1.0: 1. Stop by addition of 5: 3.0 water: 10% sodium hydroxide: water. First here The water addition of is equal to the weight of lithium aluminum hydride used. Then the product Isolation by extraction and purification methods well known in the art yields mono-N-alkylated triamines (34 ) Occurs.   In step C, which may optionally be carried out, the mono-N-alkylated triamine (34) The thiol functional group has already been described in step D, which may optionally be carried out in reaction pathway V. The general procedure was followed to convert the corresponding mono-phosphorothioate of structure (35). Can be   For example, an appropriately substituted mono-N-alkylated triamine (34) is added with 2 equivalents of sulfite. Treat with triethyl acidate and 1 equivalent of bromochloromethane. -20 ℃ ~ Stir for 1-3 hours at the reflux temperature range. Corresponding intermediate diethylphosphorothioe The volatiles can be purified by flash chromatography by removing the volatiles under vacuum. And are recovered from the reaction. The intermediate diethyl phosphorothioate is It is cleaved by treatment with trimethylsilyl bromide. Suitable like methylene chloride In an organic solvent The reactants are contacted at room temperature to reflux temperature for about 2-24 hours. Then put the volatiles under vacuum Upon removal and purification of the residue by techniques well known in the art, the mono-structure of structure (35)- This produces phosphorothioates.   B₁And B_ThreeBut -CH₂CH₂SH or -CH₂CH₂SPO_ThreeH₂And B₂Compounds of formula (II) when is H Can be prepared as described in Reaction Pathway IX. Unless otherwise specified, all The substituents are as previously defined. Reagents and starting materials are readily available to one of ordinary skill in the art. Wear.   In Reaction Pathway IX, Step A, the appropriately substituted diamine prepared in Step C of Reaction Pathway VI. Amide (27) is well known in the art Is reduced to the triamine described by structure (36).   For example, diamide (27) is dissolved in a suitable organic solvent such as tetrahydrofuran. Treat with 2 equivalents of borane (1M solution in tetrahydrofuran) at 0 ° C. Then this Stir under reflux for 18 hours, isolate and purify by methods well known in the art, and This produces lyamine (36).   In step B, the triamine (36) was di-N-alkylated with ethylene sulfide to give the structure (37 ) To give the appropriately substituted mono-N-alkylated triamines.   For example, triamine (36) is dissolved in a suitable organic solvent such as benzene and ~ Di-N-alkylation upon treatment with 2 equivalents of ethylene sulfide at reflux temperature for 2-10 hours This produces the triamine (37).   In step C, the di-N-alkylated triamine (37) was deprotected under conditions well known in the art. Protection yields the deprotected triamine described by structure (38).   For example, a di-N-alkylated triamidate (37) may be used with a suitable solvent such as 1,2-dimethoxyethane. Dissolve in a suitable organic solvent and prepare a suitable solution such as 4 equivalents of lithium aluminum hydride. Treat with the base material. The reaction is heated to reflux for about 18 hours. Next, the reaction mixture was mixed with a volume ratio of 1.0: 1. Stop by addition of 5: 3.0 water: 10% sodium hydroxide: water. First here The water addition of is equal to the weight of lithium aluminum hydride used. Next raw The product was isolated by extractive purification methods well known in the art to yield the deprotected triamine (38). Cause   Instead, it is described in European Patent Application No. 349 224, published March 1, 1990. The di-N-alkylated triamine (37) can be deprotected according to the general procedure followed. Dissolve di-N-alkylated triamine (37) in dry tetrahydrofuran and cool to -78 ° C. And treat with excess concentrated ammonia. Add excess sodium slowly at -78 ° C , Stir the reaction for about 4 hours. Then warm it to room temperature overnight and steam with ammonia. Fire. Add diethyl ether carefully, followed by ethanol carefully, and Carefully add water to stop the reaction eventually. Remove the solvent under vacuum, The residue is extracted with diethyl ether and chloroform. The combined extracts are anhydrous Dry over sodium sulfate, filter, and concentrate under vacuum. Flush residue Purification by techniques well known in the art, such as chromatography, results in deprotection. This produces lyamine (38).   Optionally in step D, the thiol function of the deprotected triamine (38) The group can be converted to the corresponding phosphorothioate of structure (39).   For example, an appropriately substituted deprotected triamine (38) is treated with 4 equivalents of triethyl phosphite. And 2 equivalents of bromochloromethane. Allow the reaction to range from room temperature to reflux temperature Stir for 1-3 hours. Corresponding intermediate bis (diethylphospho) Volatiles were removed under vacuum and flash chromatography Recovered from the reaction by purification. Intermediate bis (diethyl phosphorothio The ate) is cleaved by treatment with excess trimethylsilyl bromide. Chloride React the reaction in a suitable organic solvent such as ethylene at room temperature to reflux temperature for about 2-24 hours. Contact. The volatiles are then removed under vacuum and the residue is removed by techniques well known in the art. Purification by yields the phosphorothioate of structure (39).   The following examples, as described by Reaction Pathways VI, VII, VII, and IX, 1 represents a typical synthesis of compounds of formula (II). These examples are exemplary only. However, it is not intended to limit the invention in any way. Reagents and And starting materials are readily available to one of ordinary skill in the art. In the following examples the following terms are indicated It has the meaning. "Eq" is equivalent, "g" is gram, "mg" is milligram, "mmol" is millimolar "ML" is in milliliters, "℃" is in degrees Celsius, "TLC" is thin layer chromatography, “Rf” is the retention constant and “δ” is the downfield ppm of tetramethylsilane. . Example 9 2- {butyl- [3- (3-butylamino-propylamino)- Production of propyl] -amino} -ethanethiol   Reaction route VI, step A: β-alanine (10 mmol) dissolved in 10% sodium hydroxide And cool to 0 ° C. P-Toluenesulfonyl chloride (10 mmol) is added dropwise to the solution. After 1 hour, warm the reaction to room temperature and stir for 2 days. Neutralize the reaction with 0.5N hydrochloric acid. Extract with methylene chloride (3 x 50 mL). Combine the organic extracts and add water (75 mL) Rinse with brine (75 mL), dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. This produces 3- (toluene-4-sulfonylamino) -propionic acid.   Reaction Route VI, Step B: 3- (Toluene-4-sulfone prepared in Reaction Route VI, Step A Nylamino) -propionic acid (20 mmol) was dissolved in tetrahydrofuran (50 mL) and Cylamine (20 mmol) is added. N-ethoxycarbonyl-2-ethoxy-1,2-dihydride Add roquinone (EEDQ) (22 mmol). Stir the reaction at room temperature for 6-7 hours and vacuum. Concentrate down. The residue is flash chromatographed (silica gel, methanol N-butyl-3- (toluene-4-sulfonyl) This gives rise to amino) -propionamide.   Instead, the 3- (toluene-4-sulfonylacetic acid prepared in Step A of Reaction Route VI was prepared. Mino) -propionic acid (20 mmol) was dissolved in tetrahydrofuran (50 mL), followed by By adding N-methylmorpholine (20mmmol), reaction pathway VI N-butyl-3- (toluene-4-sulfonylamino) -propionamide was added in step B of You can come. The reaction was cooled to -20 ° C and isobutyl chloroformate (2 0 mmol) is added. Stir the reaction mixture for 30 minutes and dissolve in dimethylformamide (5 mL). Added butylamine (20 mmol). Stir the reaction at -20 ° C for 2 hours, then Warm up to room temperature. Dilute the reaction with water (150 mL) and diethyl ether (3 x 75 mL). Extract with. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, Concentrate under vacuum. The residue is flash chromatographed (silica gel, meta N-Butyl-3- (toluene-4-sulfonylacetate) This gives rise to (mino) -propionamide.   Reaction pathway VI, step C: N-butyl-3- (toluene prepared in step B of reaction pathway VI -4-Sulfonylamino) -propionamide (10 Ammol) was added to tetrahydrofuran (50 mL) and treat with sodium hydride (10 mmol). Stir the reaction for 30 minutes , 3-Bromo-N-butyl-propionamide (10 mmol) [ Br (CH₂)₂CO₂Prepared from amidation of H with butylamine] Add. The reaction is heated to reflux for 5 hours. After cooling, the reaction product was diluted with methylene chloride (150 m L), rinse with water (100 mL) and brine (100 mL), and dry with anhydrous sodium sulfate. Dry, filter, and concentrate in vacuo. Hula residue Purify by flash chromatography (silica gel, methanol / methylene chloride) And N-butyl-3-[(2-butylcarbamoyl-ethyl)-(toluene-4-sulfonyl) -a- This produces mino] -propionamide.   Reaction Pathway VII, Step A: N-Butyl-3-[(2-butyrate prepared in Step C of Reaction Pathway VI Lucarbamoyl-ethyl)-(toluene-4-sulfonyl) amino] -propionamide ( 10 mmol) is dissolved in tetrahydrofuran (50 mL). Cool the solution to 0 ° C and spin Solution (10 mmol, 1M tetrahydrofuran solution) is added. Then heat the reaction for 18 hours Bring to reflux. After cooling, dilute the reaction with methylene chloride (200 mL) and add water (100 mL). Rinse with brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate under vacuum. I do. Flash chromatography (silica gel, methanol / chlorination) of the residue N-butyl-3-[(3-butylamino-propyl) -toluene-4- This gives a sulfonyl) -amino] -propionamide.   Reaction pathway VII, step B: N-butyl-3-[(3-butane prepared in step A of reaction pathway VII Cylamino-propyl) -toluene-4-sulfonyl) -amino] -propionamide (10 mmol) in tetrahydrofuran (50 mL) and ethylene sulfide (10 mmol) is added dropwise. I do. The reaction is heated for 4 hours and returned to Ryukyu. After cooling, the reaction was concentrated under vacuum and the residue Flash chromatography (silica gel, methanol / medium chloride). It was purified with 3- (Tylene) to give 3- (benzensulfonyl- {3- [butyl- (2-mercapto-ethanol This yields (tyl) -amino] -propyl} -amino) -N-butyl-propionamide.   Reaction Pathway VII, Step C: 3- (benzenesulfone prepared in Step B of Reaction Pathway VII Nyl- {3- [butyl- (2-mercapto-ethyl) -amino] -propyl} -amino) -N-butyl -Dissolve propionamide (10 mmol) in 1,2-dimethoxyethane (50 mL) and add hydrogen. Treat with lithium aluminum iodide (20 mmol). Heat the reaction to reflux for about 18 hours . After cooling, add water (0.8 mL), 10% sodium hydroxide (1.2 mL) and water (2.2 mL) next. Add to each to finish the reaction. Then dilute with methylene chloride (200 mL) and add water (100 mL). mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and under vacuum. Concentrate to. The residue is flash chromatographed (silica gel, methanol / Methylene chloride) to give the title compound. Example 10 Production of 5,9,13-triaza-5-[(2-thiophosphoryl) ethyl] heptadecane   Reaction Pathway VII, Step D, which may optionally be carried out: Prepared in Example 92-{ Butyl- [3- (3-butylamino-propylamino) -propyl] -amino} -ethanethio- Le (10 mmol) triethyl phosphite (20 mmol) and bromotrichloromethane (10 mmol) ). The reaction is stirred under reflux for 2 hours. The reaction was concentrated under vacuum, The intermediate diethyl phosphorothioate was flash chromatographed (silica gel). And ethyl acetate). Purified diethyl phosphorothioate with methylene chloride Dissolve (50 mL) and treat with excess trimethylsilyl bromide. Reaction at -20 ° C Stir for 4 hours. The reaction is concentrated under vacuum. Dissolve the residue in 2-propanol Hydrochloric acid is added and the title compound is collected as the hydrochloride salt by filtration. Example 11 Preparation of 2- [bis- (3-butylamino-propyl) -amino] -ethanethiol   Reaction Pathway VI, Step D: N-Butyl-3 prepared in Example 9, Reaction Pathway VI, Step C -[(2-Butylcarbamoylethyl)-(toluene-4-sulfonyl) amino] -propion Dissolve the amide (10 mmol) in dry tetrahydrofuran (50 mL) and bring the solution to -78 ° C. Cooling. Excess dry ammonia is added, followed by excess sodium. Anti Stir the reaction for 4 hours, then warm to room temperature overnight. Diethyl ether (100 mL) Is added, followed by careful addition of ethanol (30 mL). After stirring for 30 minutes, Be careful with water (5 mL) Drip dropwise and concentrate the reaction under vacuum. Diethyl ether (100 mL) ) And chloroform (100 mL). Combine the organic extracts and mix with anhydrous sodium sulfate. Dry with ium, filter and concentrate under vacuum. Flash chromatograph residue Purification with raffin (silica gel, methanol / methylene chloride) yielded N-butyl-3- ( This gives 2-butylcarbamoyl-ethylamino) -propionamide.   Reaction Pathway VIII, Step A: N-butyl-3- (2-butyrate prepared in Step D of Reaction Pathway VI Rucarbamoyl-ethylamino) -propionamide (10 mmol) was added to tetrahydrofuran. Dissolve in orchid (50 mL) and add ethylene phosphite (22 mmol) dropwise. 4 o'clock reaction Let it boil for heating. After cooling, the reaction was concentrated under vacuum and the residue flash flashed. Purification by chromatography (silica gel, methanol / methylene chloride) yields N-butane. Tyl-3-[(2-butylcarbamoylethyl)-(2-mercapto-ethyl) amino] -propyi This produces onamide.   Reaction Pathway VIII, Step B: N-Butyl-3-[(2- Butylcarbamoylethyl)-(2-mercapto-ethyl) amino] -propionamide (10 mmol) was dissolved in 1,2-dimethoxyethane (50 mL) and aluminum hydride lithium Treat with um (20 mmol). The reaction is heated to reflux for about 18 hours. After cooling, water (0.8m L), 10% sodium hydroxide (1.2 mL) and water (2.2 mL) were added one after the other to allow the reaction to proceed. Finish. Next, dilute with methylene chloride (200 mL) , Rinse with water (100 mL) and brine (100 mL), dry over anhydrous sodium sulfate, and filter. And concentrated under vacuum. The residue is flash chromatographed (silica gel, Purification with (methanol / methylene chloride) yields the title compound. Example 12 Production of 5,9,13-triaza-9-[(2-thiophosphoryl) ethyl] -heptadecane   Reaction Route VIII, Step C, which may optionally be carried out: Prepared in Example 11 2- [Bis- (3-butylamino-propyl) -amino] -ethanethiol (10 mmol) was added Treat with triethyl acidate (20 mmol) and bromotrichloromethane (10 mmol). reaction Stir the mixture under reflux for 2 hours. The reaction was concentrated under vacuum and the intermediate diethylphos Chlorothioate by flash chromatography (silica gel, ethyl acetate) Purify. Dissolve the purified diethyl phosphorothioate in methylene chloride (50 mL), Treat with excess trimethylsilyl bromide. The reaction is stirred at -20 ° C for 4 hours. The reaction is concentrated under vacuum. Dissolve the residue in 2-propanol and add hydrochloric acid. The title compound is collected by filtration as the hydrochloride salt. Example 13 2- [butyl- (3- {3- [butyl- (2-mercapto-ethyl) -amino] -propylamino} -propyl Ropyl) -amino] -ethanethiol production   Reaction Pathway IX, Step A: N-Butyl-3 prepared in Example 9, Reaction Pathway VI, Step C -[(2-Butylcarbamoylethyl)-(toluene-4-sulfonyl) amino] -propion The amide (10 mmol) is dissolved in tetrahydrofuran (50 mL). Cool the solution to 0 ° C Then, borane (20 mmol, 1M tetrahydrofuran solution) is added. Then add the reactants to 18 Heat to reflux for hours. After cooling, dilute the reaction with methylene chloride (200 mL) and add water (1 mL). 00mL) and brine (100mL), dried over anhydrous sodium sulfate, filtered, and vacuumed. Concentrate down. The residue is flash chromatographed (silica gel, methanol (N / N-bis- (3-butylamino-propyl) -4-methyl) This produces ru-benzenesulfonamide.   Reaction Pathway IX, Step B: N, N-bis- (3-butylacetate prepared in Step A of Reaction Pathway IX Mino-propyl) -4-methyl-benzenesulfonamide (10 mmol) was added to Dissolve in orchid (50 mL) and add ethylene sulfide (20 mmol) dropwise. Add reaction for 4 hours Heat to reflux. After cooling, the reaction was concentrated under vacuum and the residue flash chromatographed. Graphi Purified with Rica gel, methanol / methylene chloride), N, N-bis- {3- [butyl- (2 -Mercapto-ethyl) amino] -propyl} -4-methyl-benzenesulfonamide Occurs.   Step IX, Step C: N, N-bis- {3- [butyl- (2- Mercapto-ethyl) amino] -propyl} -4-methyl-benzenesulfonamide (10m mol) is dissolved in dry tetrahydrofuran (50 mL) and the solution is cooled to -78 ° C. Excessive Excess dry ammonia is added, followed by excess sodium. Reaction for 4 hours Stir, then warm to room temperature overnight. Add diethyl ether (100 mL), then And carefully add ethanol (30 mL). After stirring for 30 minutes, add water (5 mL) Carefully add dropwise and concentrate the reaction under vacuum. The residue was converted to diethyl ether (10 Extract with 0 mL) and chloroform (100 mL). Combine the organic extracts and mix with anhydrous sodium sulfate. Dry with thorium, filter and concentrate under vacuum. Flash chromatography of the residue Purify by graphy (silica gel, methanol / methylene chloride) to give the title compound. Cause Example 14 Production of 5,9,13-triaza-5,9-bis [(2-thiophosphoryl) ethyl] -heptadecane   Reaction Pathway IX, Stage D, which may optionally be carried out: Actual 2- [butyl- (3- {3- [butyl- (2-mercapto-ethyl) -amino] prepared in Example 13 ] -Propylamino} -propyl) -amino] -ethanethiol (10 mmol) Treat with trimethyl (40 mmol) and bromotrichloromethane (20 mmol). Reactants Stir under reflux for 2 hours. The reaction was concentrated under vacuum and the intermediate bis (diethylpho Flash chromatography (silica gel, ethyl acetate) ). Purified bis (diethyl phosphorothioate) was added to methylene chloride (50 mL ) And treated with excess trimethylsilyl bromide. Reaction at -20 ° C for 4 hours Stir. The reaction is concentrated under vacuum. Dissolve the residue in 2-propanol and salt Acid is added and the title compound is collected by filtration as the hydrochloride salt.   Is the present invention a harmful cell effect caused by exposure to ionizing radiation or exposure to DNA reactive agents? To protect the cells.   Ionizing radiation is similar to X-rays and gamma rays that have the effect of forming ion pairs in substances. High energy radiation. Exposure to ionizing radiation is the result of a nuclear explosion, leakage of radioactive material, It can occur as a result of environmental radioactivity, such as from proximity to radioactive materials. More generally, ionizing radiation exposure is a combination of radiation therapy for various types of cancer. Such radiation may result from medical procedures.   DNA-reactive agents can be covalently or non-covalently with cellular DNA Agents such as alkylating agents, cross-linking agents, and DNA interrupt agents that interact with each other And bring some harmful cellular effects. For example, DNA reactive agents include cisplatin, Clofosfamide, diethylnitrosamine, benzo (a) pyrene, carboplatin , Doxorubicin, mitomycin C and the like. Cisplatin, cyclophore Multiple DNA reagents such as Sfamide, Doxorubicin, and Mitomycin C In other words, it is useful in cancer therapy as a DNA-reactive chemotherapeutic agent.   The harmful cellular effects caused by exposure to ionizing radiation and exposure to DNA reactive agents are Damage to cell DNA such as strand breaks, cells due to disruption of DNA function, etc. Includes functional disruption, cell death, tumor induction such as therapy-induced secondary ones, etc. I do. These detrimental cellular effects can be secondary tumors, myelosuppression, kidney damage, peripheral nerve loss. This may cause scratches and gastrointestinal damage. For example, radiation exposure to cancer radiation therapy It is for killing cells. Unfortunately, the adverse effects associated with the therapy The larger part is the harmful cellular effects of radiation on normal cells, rather than on cancer cells. Happens by.   The present invention prevents or eliminates these effects or reduces the degree thereof. Provide a method of protecting cells from harmful cellular effects. According to the invention Prior to exposure of cells to ionizing radiation and exposure to DNA reactive agents. Standing or in the middle, contacting the cells to be protected with a compound of formula (I) or (II) . A solution of the compound of the invention is applied to cells or the compound of the invention is administered to a mammal. This allows direct contact with the cells. Thus, the compounds of the present invention It provides a protective effect, with harmful cellular effects that would otherwise result from exposure to radiation. Eliminate or reduce the degree.   More specifically, the present invention relates to exposure of mammals to ionizing radiation or DNA reactive agents. How to protect mammalian non-cancerous or normal cells from the harmful cellular effects of exposure Provide the law. As used herein, the term "mammal" refers to the mouse, rat or rat. Warm-blooded animals such as pigs, dogs, and humans. The compounds of the present invention are used for cancer radiotherapy. During cancer and during chemotherapy with DNA-reactive chemotherapeutic agents, normal but not cancer cells Provides selective protection of cells. In accordance with the present invention, inventive compounds are exposed to ionizing radiation. Exposure to mammals prior to or during exposure to or exposure to DNA-reactive agents . The present invention is directed to non-cancer caused by exposure of mammals to ionizing radiation and DNA reactive agents. Provide a method by which harmful effects on cells are eliminated or reduced in severity I have.   In addition, the present invention provides for chemotherapies in patients in need of radiation therapy and in DNA-responsive chemotherapeutic agents It provides treatments for patients in need of therapy. As used herein, the term "patient " Neoplastic disease requiring radiation therapy or chemotherapy with DNA-reactive chemotherapeutic agents And mammals including cancer-bearing mice, rats, dogs, and humans. As used herein, the term “neoplastic disease” refers to rapidly proliferating cell growth or neogenesis. An abnormal condition or medical condition characterized by an object.   In association with radiation therapy or chemotherapy with a DNA-reactive chemotherapeutic agent, the formula (I) or (II ) Neoplastic diseases for which treatment with a compound is particularly useful include acute lymphoblastic, acute Includes myeloid, chronic lymphocytic, acute myoblastic, or chronic myocytic leukemia But not limited to: cervical, esophagus, stomach, pancreas, breast, ovary, small intestine, Cancers including but not limited to colon and lung cancers; osteosarcomas, lipomas, sebum Sarcomas including but not limited to liposarcoma, hemangiomas, and angiosarcomas; Melanoma, including nitric and melanic; and carcinosarcoma, lymphoid tissue type, Such as follicular reticulum, cytosarcoma, Hodgkin's disease, and non-Hodgkin's lymphoma, but Includes, but is not limited to, mixed tumorigenesis. With radiation and chemotherapy In combination, neoplastic diseases where treatment with a compound of formula (I) or (II) is particularly useful are: It includes Ziekin's disease, pancreatic cancer, advanced cancer, breast cancer, ovarian cancer, colon cancer and the like.   In addition, treatment with the compounds of the present invention may include treatment with radiotherapy or DNA-responsive chemotherapeutic agents. Therapy induction caused by academic therapy It provides selective protection against deleterious cellular effects such as sexual secondary tumor induction. This Thus, treatment with a compound of the present invention is associated with radiation or chemotherapy for the treatment of Hodgkin's disease. -Like therapy-induced acute myelogenous leukemia and non-Hodgkin's lymphoma It is useful in eliminating or reducing the risk of significant secondary tumor induction.   In accordance with the present invention, prior to radiation therapy or chemotherapy with a DNA-responsive chemotherapeutic agent , Or in the process of administering the compound of formula (I) or (II) to the patient, Selective protection of non-cancerous cells rather than cells is provided. Therefore, ionizing radiation and DN Adverse cell effects on non-cancerous cells resulting from treatment of patients with A-reactive chemotherapeutic agents Eliminated or lessened   The protective dose of the compound of formula (I) or (II) is determined by exposure to ionizing radiation or treatment with a DNA reactive agent. To eliminate or reduce the harmful cellular effects caused by Means an amount that is effective by single or multiple administration to a patient. Also, the formula (I ) Or (II) compounds, depending on exposure to ionizing radiation or exposure to DNA reagents. In order to eliminate or reduce the degree of harmful cell effects caused by The dose should be effective in multiple doses.   Protective doses to mammals or patients may be obtained using known techniques and in similar circumstances. By observing the results Therefore, it can be easily determined by the attending physician as a person skilled in the art. For the determination of protective dose or dose Here, several factors are considered by the attending physician. These are the types of mammals , Its physique, age, and general health; the specific illnesses involved: the extent and severity of illness How to get around; Response of individual patient; Specific compound to be administered; Mode of administration; Bioavailability Characteristics of Agents; Optimal Dosing Schedule Selected; Concomitant Drug Use; and Others , But not limited to.   The compound of formula (I) or (II) is administered in a single dose or in multiple doses, Administration prior to or during exposure to ionizing radiation or exposure to DNA reactive agents Is done. Generally, when the compounds of this invention are administered in conjunction with radiation therapy, The compounds are calculated to provide the maximum selective protective effect during radiation therapy. Be administered in single or multiple doses prior to radiation therapy according to the schedule U. Generally, the compounds of this invention are administered in association with a DNA-responsive chemotherapeutic agent. In some cases, the compounds of the present invention are calculated to provide maximum protective effect during chemotherapy. The dose should be given in a single dose or multiple doses prior to or during the chemotherapy, according to the schedule. Will be given in a dose.   Maximum selective protective effect against exposure to ionizing radiation or exposure to DNA reactive agents Details of the dosing schedules for the compounds of this invention necessary to provide the fruit can be determined using known techniques. Well, Observing the results obtained under similar circumstances, it will be I can decide.   The protective amount of the compound of formula (I) or (II) administered to a mammal or patient is the body weight per day. It is in the range of about 5 mg to about 1000 mg per kg (mg / kg / day). A preferred amount is about 50 to about 5 Expected to be in the range of 00 mg / kg / day.   The protective amount of the compound of formula (I) or (II) contacted with the cell is about 100 micromolar to about It will be in the concentration range of 5 micromolar.   The compounds of formula (I) or (II) may be administered in an effective amount, including oral and parenteral routes. It can be administered in any form or manner that makes it bioavailable. For example, oral, subcutaneous, The compound can be administered intramuscularly, intravenously, transdermally, intranasally, rectally and the like. Oral administration Generally preferred. Those of ordinary skill in the art of formulating formulations will understand the particular nature of the compound of choice, treatment. Appropriate mode and mode of administration depending on the medical condition, stage of disease, and other related circumstances Can be easily selected.   The compounds may be formulated alone or in combination with pharmaceutically acceptable carriers or excipients. It can be administered in the form of a product. The proportion and nature of the pharmaceutical composition refers to the solubility of the selected compound. And chemical properties, route of administration chosen, and standard pharmaceutical practice. Of the present invention The compound is effective in its own right, but it has stability, convenience of crystallization, increased solubility, etc. For the purpose, formulated and administered in the form of a pharmaceutically acceptable acid addition salt obtain.   In another aspect, the invention is combined or otherwise combined with one or more inert carriers. Compositions comprising a combined compound of formula (I) or (II) are provided. These compositions Is, for example, as a calibration standard, as a convenient means of transporting bulk goods, or as a pharmaceutical composition. It is useful as a thing. A testable amount of a compound of formula (I) or (II) may be any amount known to those skilled in the art. It is an amount that can be readily measured by standard assay procedures and techniques described. Formula (I) Alternatively, the assayable amount of the (II) compound is generally in the range of about 0.001 to about 75% by weight of the composition. There will be. The inert carrier does not decompose or does not decompose the compound of formula (I) or (II) Also, any material that does not react covalently may be used. Suitable inert carrier Examples are water; aqueous buffers commonly useful in high performance liquid chromatography (HPLC) analysis. Liquid; organic solvent such as acetonitrile, ethyl acetate, hexane, etc .; and pharmaceutical acceptance It is a carrier or excipient that can be incorporated.   More specifically, the invention is mixed with one or more pharmaceutically acceptable carriers or excipients. Or an effective amount of a compound of formula (I) or (II) combined in any other way The following pharmaceutical compositions are provided.   Pharmaceutical compositions or agents are prepared by methods well known in the pharmaceutical art. Carrier or shape An agent is a solid, semi-solid, or liquid that acts as a vehicle or medium for the active ingredient. In material It is possible. Suitable carriers or excipients are well known in the art. The pharmaceutical composition is orally or Is adapted for parenteral use and may be given to the patient in the form of tablets, capsules, suppositories, solutions, suspensions, etc. Can be administered.   The compounds of the invention may be orally administered, for example, with an inert filler or an edible carrier. Wear. They can be enclosed in gelatin capsules or compressed into tablets. Oral cure For therapeutic administration, the compound may be mixed with excipients in tablets, troches, capsules. Agent, elixir, suspension, syrup, wafer, chewing gum, etc. Can be used. These formulations contain at least 4% of the compound of the invention which is the active ingredient. Should be included, but will vary from 4% to about 70% by weight of the unit, depending on the particular format. Is convenient. The amount of compound present in the composition is such that a suitable dosage will be obtained. Amount. Preferred compositions and formulations according to the invention are oral dosage units of the present invention. Is made up to contain an amount of the compound of between 5.0 and 300 milligrams.   Tablets, pills, capsules, lozenges, etc. also contain one or more of the following auxiliaries: Can have Binders such as microcrystalline cellulose, tragacanth gum or gelatin; Excipients such as starch or lactose; disintegrants such as alginic acid, primogel, tow Sorghum starch and the like; lubricants such as magnesium stearate or styrotex Lubricants, such as colloidal silicon dioxide; and sweeteners, such as sucrose or Is added saccharin. Also fragrances such as peppermint, methyl salicylate , Or orange flavor is added. When the dosage unit format is capsule , Which is a liquid carrier in addition to the substances of the above types, eg polyethylene glycol or It may contain fatty oils. Other dosage unit formats modify the physical form of the dosage unit. Various other materials such as coatings may be included. Therefore tablets or pills should be sugar , Shellac or other enteric coatings. In addition to active ingredients, syrups , Sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The materials used to make these various compositions are pharmaceutically pure. And should be non-toxic in the amounts used.   For the purpose of parenteral administration, the compounds can be incorporated into a solution or suspension. Made of these The agent should contain at least 0.1% of a compound of the invention, but from 0.1 to about 0.1% by weight of the formulation. It can range up to 50%. The amount of compound present in such compositions depends on the appropriate dosage. This is the amount that can be obtained. Preferred compositions and formulations according to the present invention have a parenteral dosage The unit form is made up to contain the compound of the invention in an amount between 5.0 and 100 milligrams. .   The solution or suspension may also contain one or more of the following auxiliaries. Sterile dilution Agents such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin Rin Ropylene glycol or other synthetic solvents; antimicrobial agents such as benzyl alcohol or Methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; Chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate Acid salts or phosphates; and tonicity adjusting agents such as sodium chloride or dextrose. Parenteral preparations include glass or plastic ampoules, disposable syringes, Alternatively, it can be enclosed in multi-dose vials.   Is any group of structurally related compounds that have a particular general use As such, certain groups and configurations may have end uses for compounds of formula (I) or (II) preferable.   Compounds of formula (I) in which R is ethyl, propyl or butyl are generally preferred. m Compounds of formula (I) in which is 2 or 3 are generally preferred. Formula (I) where n is 7 or 8 Compounds are generally preferred.   Compounds of formula (II) in which R is ethyl, propyl, or butyl are generally preferred. Compounds of formula (II) in which m is 3 or 4 are generally preferred. A compound of formula (II) in which n is 3 Are generally preferred.   The usefulness of the compounds of the present invention is demonstrated in vitro (in vitro) as a radioprotectant. And in vivo (in vivo).   For example, cultured cells form clones Ability to evaluate can be assessed as a function of exposure to x-ray dose or chemical dose. cell Are untreated or treated with test agent 30 minutes before exposure. After exposure, untreated fine The degree of retention of the clonogenic ability compared to the vesicles is proportional to the protective effect of the drug. is there. Typical experiments of this type are Snyder and Lachmann. ) [Radiation Res. 120, 121 (1989)] Can be implemented   Instead, DNA strand breaks caused by exposure to X-ray doses or chemical doses. You can evaluate loss. Cells should not be treated with drug, or test agent should be administered approximately 30 minutes before exposure. To process. The extent of DNA strand breaks after exposure compared to untreated cells was associated with drug protection. It is in inverse proportion to the effect. A typical experiment of this kind is Snyder [Int. J. Ra diat. Biol. 55, p. 773 (1989)]. .   In addition, it is possible to evaluate the survival rate of Mus musculus exposed to total body irradiation or DNA reactive agents. You. The animals pretreated with the test agent or untreated (control group) were subjected to total body irradiation (1500 doses). Call). Untreated control animals are expected to survive for approximately 12-15 days. place The survival rate of animals was proportional to the protective effect of drug treatment compared to the untreated control group. It is in. A typical experiment of this kind is Carroll et al. [J. Med. Chem. 33 Vol. 2501 (1990)] It can be implemented qualitatively.   Live in lymphocytes collected from test animals exposed to total body irradiation or DNA reactive agents. Breakage of the DNA strand can be evaluated by comparison with an untreated control. Instead Of bone marrow cells collected from test animals exposed to total body irradiation or DNA reactive agents. Viability and clonogenicity are shown by Pike and Robinson [J . Cell Physiol. 76, p. 77 (1970)], as described by Can be evaluated by comparison with.

[Procedure Amendment] Patent Law Article 184-8 [Submission Date] November 3, 1994 [Amendment Content] The reaction product is concentrated under vacuum. The residue is extracted with diethyl ether (100 mL) and chloroform (100 mL). The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, methanol / methylene chloride) to give the title compound. Example 2 5, 8,17,20- tetraaza -8,17- bis - [2- (thiophosphoryl) ethyl] - producing Scheme II tetra dodecane, step sometimes performed optionally additionally E: Preparation Example 1 2-((2-butylamino-ethyl)-{8-[(2-butylamino-ethyl)-(2-mercapto-ethyl) -amino] -octyl} -amino-ethanethiol (10 mmol) Treat with triethyl phosphate (40 mmol) and bromotrichloromethane (20 mmol) Stir the reaction under reflux for 2 h Concentrate the reaction under vacuum and flash chromatograph the intermediate bis (diethylphosphorothioate) on silica gel, Purified bis (diethyl phosphorothioate) is dissolved in methylene chloride (50 mL) and treated with excess trimethyldilyl bromide.The reaction is stirred for 24 hours.The reaction is concentrated under vacuum, This gives the title compound. Example 3 2 - {(2-butylamino - ethyl) - [8- (2-butylamino - ethylamino) - octyl] - amino} - manufacture of ethanethiol 16. A method of protecting human non-cancerous cells from the adverse effects on cells caused by exposure to ionizing radiation, which method comprises administering to a person a protective amount of a compound of claim 1 or 2. 17． A method of protecting human non-cancerous cells from the deleterious effects on cells caused by exposure to a DNA reactive agent, which method comprises administering to a human a protective amount of a compound of claim 1 or 2. 18. A method of treating a patient in need of radiation therapy comprising administering to a person a protective amount of a compound of claim 1 or 2. 19. A method of treating a patient in need of chemotherapy with a DNA-reactive chemotherapeutic agent, which method comprises administering to a person a protective amount of a compound of claim 1 or 2. 20. A pharmaceutical composition comprising an assayable amount of a compound according to any one of claims 1 or 2 mixed or otherwise combined with an inert carrier. twenty one. A pharmaceutical composition comprising a protective amount of a compound according to claim 1 or claim 2 mixed or otherwise combined with an inert carrier. twenty two. A compound according to claim 1 or 2 for use as a pharmaceutically active compound. twenty three. 3. A compound according to claim 1 or 2 for use in protecting human cells from the detrimental effects on cells caused by exposure to ionizing radiation. twenty four. The compound of claim 1 or 2 used to protect human cells from the adverse effects on the cells caused by exposure to DNA reactive agents. twenty five. 3. A compound according to claim 1 or 2 for use in protecting human non-cancerous cells from the detrimental effects on cells caused by exposure to ionizing radiation. 26. 3. A compound according to claim 1 or 2 for use in protecting human non-cancerous cells from the adverse effects on cells caused by exposure to DNA reactive agents. 27. A compound according to claim 1 or 2 for use in the treatment of a patient in need of radiation therapy. 28. The compound of claim 1 or 2 for use in a patient in need of chemotherapy with a DNA-responsive chemotherapeutic agent. 29. 3. A compound according to claim 1 or 2 for the preparation of a pharmaceutical composition used to protect mammalian cells from the adverse effects on cells caused by exposure to ionizing radiation, which may be combined with a pharmaceutically acceptable carrier. Use of. 30. The method of claim 1 or 2 for preparing a pharmaceutical composition for use in protecting mammalian cells from the adverse effects on cells caused by exposure to a DNA-reactive agent, which may be combined with a pharmaceutically acceptable carrier. Uses of compounds. 31. A method for producing a pharmaceutical composition for use in protecting human non-cancerous cells from adverse effects on cells caused by exposure to ionizing radiation, which may be combined with a pharmaceutically acceptable carrier. Use of compounds. 32. 14. A method for preparing a pharmaceutical composition for use in protecting non-cancerous cells of a human from adverse effects on cells caused by exposure to a DNA reactive agent, which may be combined with a pharmaceutically acceptable carrier. Use of 2 compounds. 33. Use of a compound of claim 1 or 2 for the manufacture of a pharmaceutical composition for use in treating a patient in need of radiation therapy, which may be combined with a pharmaceutically acceptable carrier. 34. Use of a compound of claim 1 or 2 for treating a patient in need of chemotherapy with a DNA-reactive chemotherapeutic agent, which may be combined with a pharmaceutically acceptable carrier. 35. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula Consisting of treating a compound of the formula where m, n and R are as defined above at reflux with a slight excess of lithium aluminum hydride in 1,2-dimethoxyethane for 18 hours. Method. 36. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula Compounds of the formula where m, n, and R are as defined above are treated with 2 equivalents of bromotrichloromethane at room temperature to Ryukyu for 1 to 3 hours, followed by odor. A method comprising treating with an excess of trimethylsilyl chloride. 37. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula A method comprising treating a compound of the formula where m, n and R are as defined above with 4 equivalents of a suitable reducing agent. 38. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula Treating a compound of the formula where m, n, and R are as defined above at room temperature to the temperature of Ryukyu for 1-3 hours with 2 equivalents of triethylphosphite and 1 equivalent of promotrichloromethane. , Followed by treatment with excess trimethylsilyl bromide. 39. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula A process comprising treating a compound of the formula where m, n and R are as defined above with 2 equivalents of a suitable reducing agent. 40. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R is C ₂ ~ C ₆ alkyl] A method for producing a compound of the formula A compound of the formula where m, n, and R are as defined above is treated with 4 equivalents of triethylphosphite and 2 equivalents of promotrichloromethane at room temperature to the temperature of Ryukyu for 1-3 hours. , Followed by treatment with excess trimethylsilyl bromide. 41. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula A method comprising treating a compound of the formula where m, n and R are as defined above with 4 equivalents of a suitable reducing agent. 42. formula Wherein, m is an integer of 2 to 4, n represents 4 to 10 integer, R is C ₂ ~ C ₆ alkyl] A method for producing a compound of the formula Treating a compound of the formula where m, n and R are as defined above from room temperature to the temperature of Ryukyu for 1 to 3 hours, with 2 equivalents of triethylphosphite and 1 equivalent of bromotrichloromethane. Followed by treatment with excess trimethylsilyl bromide. 43. formula Wherein, m is an integer of 2 to 4, n represents 3 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula A method comprising treating a compound of the formula where m, n and R are as defined above with 4 equivalents of a suitable reducing agent. 44. formula Wherein, m is an integer of 2 to 4, n represents 3 to 10 integer, R is C ₂ ~ C ₆ alkyl] A method for producing a compound of the formula Treating a compound of the formula where m, n, and R are as defined above with 2 equivalents of triethyl phosphite and 1 equivalent of bromotrichloromethane at room temperature to the temperature of Ryukyu for 1-3 hours. , Followed by treatment with excess trimethylsilyl bromide. 45. formula Wherein, m is an integer of 2 to 4, n represents 3 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula A method comprising treating a compound of the formula where m, n and R are as defined above with 4 equivalents of a suitable reducing agent. 46. formula Wherein, m is an integer of 2 to 4, n represents 3 to 10 integer, R is C ₂ ~ C ₆ alkyl] A method for producing a compound of the formula Treating a compound of the formula where m, n, and R are as defined above at room temperature to reflux for 1-3 hours with 2 equivalents of triethylphosphite and 1 equivalent of bromotrichloromethane, Subsequent treatment with excess trimethylsilyl bromide. 47. formula Wherein, m is an integer of 2 to 4, n represents 3 to 10 integer, R represents C ₂ -C a _alkyl] A method for producing a compound of the formula A method comprising treating a compound of the formula where m, n and R are as defined above with 4 equivalents of a suitable reducing agent. 48. formula Wherein, m is an integer of 2 to 4, n represents 3 to 10 integer, R is C ₂ ~ C ₆ alkyl] A method for producing a compound of the formula A compound of the formula where m, n, and R are as defined above is treated with 4 equivalents of triethylphosphite and 2 equivalents of bromotrichloromethane at room temperature to the temperature of Ryukyu for 1-3 hours. , Followed by treatment with excess trimethylsilyl bromide.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AT, AU, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, ES, FI, G B, HU, JP, KP, KR, KZ, LK, LU, LV , MG, MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE, SK, UA, UZ, VN (72) Inventor Snyder, Ronald Dee.             United States 45140 La Ohio             Brand, Quail Woods Drive             812

Claims (1)

[Claims] 1. formula (In the formula, m is an integer of 2 to 4, n is an integer of 4 to 10, R is C _{2 to} C ₆ alkyl, and B ₁ , B ₂ , B ₃ , and B ₄ are each independently. , H, —CH ₂ CH ₂ SH, or —CH ₂ CH ₂ SPO ₃ H ₂ provided that at least one of B ₁ , B ₂ , B ₃ or B ₄ is other than H. That is the condition. ] The compound of. 2. formula [In the formula, m is an integer of 2 to 4, n is an integer of 3 to 10, R is C _{2 to} C ₆ alkyl, B ₁ , B ₂ , and B ₃ are each independently H, -CH ₂ CH ₂ SH, or -CH ₂ CH ₂ SPO ₃ H ₂ , provided that at least one of B ₁ , B ₂ , or B ₃ is other than H. ] The compound of. 3. The compound according to claim 1, wherein m is 2. 4. The compound according to claim 1, wherein m is 3. 5. The compound according to claim 1, wherein n is 7. 6. The compound according to claim 1, wherein n is 8. 7. The compound according to claim 3, wherein n is 7. 8. The compound according to claim 4, wherein n is 7. 9. The compound according to claim 2, wherein m is 3. Ten. The compound according to claim 2, wherein m is 4. 11. The compound according to claim 2, wherein n is 3. 12． The compound according to claim 11, wherein m is 3. 13. The compound according to claim 11, wherein m is 4. 14. A method of protecting mammalian cells from the adverse effects on the cells caused by exposure to ionizing radiation, which comprises contacting the mammalian cells with a protective amount of a compound of claim 1 or 2. 15. A method of protecting mammalian cells from the deleterious effects on the cells caused by exposure to a DNA reactive agent, comprising contacting the mammalian cells with a protective amount of a compound of claim 1 or 2. 16． A method of protecting human non-cancerous cells from the adverse effects on cells caused by exposure to ionizing radiation, which method comprises administering to a person a protective amount of a compound of claim 1 or 2. 17． A method of protecting human non-cancerous cells from the deleterious effects on cells caused by exposure to a DNA reactive agent, which method comprises administering to a human a protective amount of a compound of claim 1 or 2. 18. A method of treating a patient in need of radiation therapy comprising administering to a person a protective amount of a compound of claim 1 or 2. 19. A method of treating a patient in need of chemotherapy with a DNA-reactive chemotherapeutic agent, which method comprises administering to a person a protective amount of a compound of claim 1 or 2.