US3567705A - N-(delta-(6-purinylthio)valeryl)amino acids and peptides - Google Patents

N-(delta-(6-purinylthio)valeryl)amino acids and peptides Download PDF

Info

Publication number
US3567705A
US3567705A US649432A US3567705DA US3567705A US 3567705 A US3567705 A US 3567705A US 649432 A US649432 A US 649432A US 3567705D A US3567705D A US 3567705DA US 3567705 A US3567705 A US 3567705A
Authority
US
United States
Prior art keywords
purinylthio
valeryl
ethyl ester
ester
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US649432A
Other languages
English (en)
Inventor
Antonin Cerny
Miroslav Semonsky
Vaclav Jelinek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Spofa Vereinigte Pharma Werke
Original Assignee
Spofa Vereinigte Pharma Werke
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Spofa Vereinigte Pharma Werke filed Critical Spofa Vereinigte Pharma Werke
Application granted granted Critical
Publication of US3567705A publication Critical patent/US3567705A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/36—Sulfur atom
    • C07D473/38—Sulfur atom attached in position 6

Definitions

  • n is an integer from to 5 R is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of:
  • alkyl having a straight or branched carbon chain of 1 to 5 atoms
  • CH OH, -CH SH, -(CH )SCH and m in the last member being an integer from 1 to 3 and R being alkoxy having a straight or branched chain of 1 to 8 carbon atoms.
  • the compounds have shown an antineoplastic effect in certain specific transplanta'ble mice tumors. They are distinguished by their high affinity to a particular organ or to the tissue of a particular organ and their acute and chronical toxicity is low.
  • Various cancerostatic agents are known and have been used clinically. Such agents are 6-(4-carboxybutyl)-thio purine, 6-mercaptopurine, and S-fluorouracil. However, some of these agents are quite toxic and some have only limited specificity for particular organs. Also, their effective action in the body may be limited in time as shown by radioactive tracing methods.
  • n is an integer from 0 to 5
  • R is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of:
  • alkyl having a straight or branched carbon chain of 1 to 5 atoms phenyl; --CH OH, -CH SH, (CH )SCH and (CH COR m in the last member being an integer from 1 to 3 and R being alkoxy having a straight or branched chain of 1 to 8 carbon atoms.
  • the compounds of the invention have shown an antineoplastic effect in certain specific transplantable mice tumors.
  • X is a chlorine atom or a N group.
  • n and Y have the same meaning as in the Formula I, and R is alkoxy with a straight or branched carbon chain of 1 to 8 carbon atoms, to form a N-[6-(6- purinylthio)valeryl]amino acid ester of the Formula IV:
  • n and Y have the same meaning as in Formula I and R has the same meaning as in Formula II.
  • the resulting product is then saponified with alkali.
  • it may be condensed once more, in succession, twice with an amino acid ester of the same type as shown in Formula III to form the corresponding ester either of the N-[-(6-purinylthio)valeryl]dipeptide, or of the N- [5- 6-purinylthio valeryl] tri peptide.
  • the amino acid ester first obtained may be converted to the azide and may then be condensed with an amino acid ester of the general Formula III to form the corresponding ester of the dipeptide.
  • the dipeptide may then be saponified by alkali to the free acid which latter thereupon is converted by another reaction with the amino acid ester in the presence of N,N-dicyclohexycarbodiimide to form the corresponding tripeptide ester.
  • the condensation of the 6-(4-carboxylbutyl)thiopurine derivative of Formula II with an amino acid ester of Formula III is preferably carried out if X in Formula II is chlorine in a medium of an inert organic solvent such as a halogenated aliphatic hydrocarbon having from 1 to 2 carbon atoms, preferably methylene chloride by using either at least two equivalents of the amino acid ester or by using one equivalent of an organic tertiary base, such as triethylamine.
  • an inert organic solvent such as a halogenated aliphatic hydrocarbon having from 1 to 2 carbon atoms, preferably methylene chloride
  • the reaction is carried out in an inert organic solvent which may again be methylene chloride but may also be a solvent such as dimethylformamide or dioxane, using at least two equivalents of the amino acid ester or using again one equivalent of the ester with one equivalent of the organic base such as triethylamine.
  • an inert organic solvent which may again be methylene chloride but may also be a solvent such as dimethylformamide or dioxane, using at least two equivalents of the amino acid ester or using again one equivalent of the ester with one equivalent of the organic base such as triethylamine.
  • an aqueous alkali metal hydroxide solution e.g., of sodium or potassium hydroxide, in an amount of at least two equivalents in case of a monocarboxylic amino acid, and of at least three equivalents in case of a dicarboxylic amino acid ester.
  • the reaction is carried out at a temperature of 025 C.
  • reaction of the free N-[6-(6-purinylthio)valeryl] dipeptide acid with an amino acid ester of the Formula III, in the presence of N,N'-dicyclohexylcarbodiimide, to form the corresponding N-[6-(6-purinylthio)valeryl]tripeptide is preferably performed in the medium of an inert organic solvent, such as a halogenated aliphatic hydrocarbon having 12 carbon atoms, preferably methylene chloride.
  • an inert organic solvent such as a halogenated aliphatic hydrocarbon having 12 carbon atoms, preferably methylene chloride.
  • the derivative of 6-(4-carboxybutyl) thiopurine of Formula II e.g., the acid chloride which is used as the starting compound
  • the condensation with the amino acid ester of Formula III can be carried out in the same medium without chloride isolation.
  • Methylene chloride, as reaction medium is useful also here because in preparing derivatives of optically active amino acids with it, no racemization takes place.
  • Another useful starting compound is the azide of 6-(4- carboxybutyl)thiopurine, which is easily available from the ester of the acid through the hydrazide thereof.
  • the azide method is suitable also for the synthesis of N-[6- (6-purinylthio)valeryl]dipeptides, that is, by reaction of N-[5-(6-purinylthio)valeryl]amino acids (easily available from the corresponding hydrazides) with amino acid esters.
  • the still slightly damp azide (6 g.) was placed into 30 ml. methylene chloride. To the suspension 16.1 g. (0.08 mole) of L-glutarnic acid diethyl ester were added and the mixture was left to stand for 2 days at laboratory temperatures. On extracting the reaction mixture by shaking with water (10 ml.) and with 1 M NaHCO and evaporation of the solvent in a water pump vacuum, the
  • N-[6-(6-purinylthio)valeryl]glycine To a solution of 4.4 g. (0.11 mole) sodium hydroxide in 85 ml. water, 16.87 g. (0.05 mole) of N-[6-(6-purinylthio)valeryl]- glycine ethyl ester were added. After the material was dissolved the solution was left standing for 2 days at 20- 25 C. It then was acidified with dilute hydrochloric acid to pH 2-3, and the eliminated N-[6-(6-purinylthio) valeryl1glycine (15.1 g. 98%) was crystallized from water; M.P. 210-211.
  • N-[6-(6-purinylthio)valeryl]-L-aspartic acid was was obtained by saponification of the N-[6-(6-purinylthio) valeryl]-L-aspartic acid diethyl ester (2.12 g., 5 mmole) with a solution of sodium hydroxide (0.66 g., 16 mmole) in water (21 ml.) at 0 to +5 (for 48 hours), or, alternatively, by the method of Example 6.
  • the yield was 1.84 g. (100%) of N-[6-(purinylthio)valeryl]-L-aspartic acid; M.P. 198-199 (water), [u] +11".
  • N [6 (6-purinylthio)valeryl]glycylglycine ethyl ester To a solution of 3.23 g. (0.01 mole) of N-[6- (6-purinylthio)valeryl]glycine hydrazide in 200 ml. of 0.1 M HCl, ml. of a 0.1 M NaNO- solution was added dropwise upon stirring at 0 to +5. Stirring was continued at that temperature until no more reaction with iodinestarch test paper occurred (about 1 hour). The suspension of the acid azide hydrochloride obtained was neutralized with 10 ml. of 1 M NaHCO 100 g.
  • N-[6-(6-purinylthio)valeryl] glycine hydrazide used as starting product was prepared in the following manner: 3.5 g. of N-[6-(6-purinylthio)valeryl]glycine ethyl ester was placed upon stirring at 20 into 17.5 ml. hydrazine hydrate. The solution was left standing for 2 days at the laboratory temperature. After distilling off the excess hydrazine hydrate by water pump vacuum, the evaporation residue was stirred up with 7 ml.
  • the compound formed colorless needles with a M.P. of 23 8-240.
  • the N-[6-(6-purinylthio)va1eryl]glycylglycyl glycine, with a M.P. of 231-233 (water) was obtained.
  • the following table illustrates the pharmaceutical action of some of the compounds of the invention.
  • the table shows a composition with three well known cancerostatics, which are 6-(4-carboxybutyl) thiopurine, 6-mercaptopurine, and 5-fiuorouracil.
  • mice H S180-Crocker sarcoma; SAK-the sarcoma originally induced by methylacridine; HK-milk gland adenocarcinoma; YYoshida ascitic reticulosarcoma of the Wister rat.
  • the antineoplastic action is expressed as a fraction, the numerator of which indicates the average tumor size in a treated group of ten animals in percent of the average tumor size in an untreated, equally large control group (:100% When the comparison with the control group (100/100) shows differences greater than 20%, Fischers probability coefficient (in the arrangement applied) assumes values below 12:0.05.
  • the substances tested were administered orally to mice at the optimum therapeutic doses established in 12 intervals during 24 hours, except that S-fluorouracil was applied subcutaneously. (In the table the doses in mg./kg. are quoted in parentheses.)
  • the administration was started at the 3rd day after transplantation of the tumors S180, SAR, HK, and at the 2nd day for the Y growth.
  • the tumor size was determined by weight after destruction of the animal.
  • N-[5-(6-purinylthio)valeryl]glycylglycyl glycine (not listed in the table) has significant therapeutical action in mice H with the ascitic sarcoma S37 (64/123) (with the same manner of application, dosage and test arrangement as used in the evaluation of the comparable derivative of the diglycine ester).
  • the analogous derivatives of glycine ethyl ester and diglycine ethyl ester were practically ineffective in case of the S37 tumor.
  • the substances of the invention are at least equally or even more active in animals with a particular tumor than the 6-mercaptopurine and 5- fiuorouracil used for comparison.
  • the feature of the amino acid or peptide, or ester thereof, as the case may be, which are attached to 6 (4 carboxybuty1)thiopurine by a peptidic bond, are effective in some instances and also quite significant in other parameters of the physiological action.
  • the chronic toxicity of the basal substance 6-(4-carboxybutyl) thiopurine in mice LD about 12 g./kg. in oral application
  • the analogous diglycine ethyl ester derivative is under the same conditions substantially less toxic. Its chronic toxicity expressed in LD exceeds 50 g./kg. in per os application.
  • the radioactivity concentration decreases rapidly in both tissues within lapse of time,
  • Y is hydrogen, lower alkyl, or (CH CO R'; m is 1 or 2; and R is H or lower alkyl.
  • the compound of claim 1 which is N-[5-(6-purinylthio valeryl] -DL-isoleucine.
  • Kaverzneva et al. Akad. Nauk SSSR., Izvestiia, Seriia Khimiia, 1966, 1l991203.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US649432A 1966-07-01 1967-06-26 N-(delta-(6-purinylthio)valeryl)amino acids and peptides Expired - Lifetime US3567705A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CS443666 1966-07-01

Publications (1)

Publication Number Publication Date
US3567705A true US3567705A (en) 1971-03-02

Family

ID=5387083

Family Applications (1)

Application Number Title Priority Date Filing Date
US649432A Expired - Lifetime US3567705A (en) 1966-07-01 1967-06-26 N-(delta-(6-purinylthio)valeryl)amino acids and peptides

Country Status (12)

Country Link
US (1) US3567705A (de)
JP (1) JPS4832119B1 (de)
AT (1) AT274000B (de)
BE (1) BE700727A (de)
CH (1) CH501652A (de)
DE (1) DE1695744C3 (de)
DK (1) DK118136B (de)
FI (1) FI48737C (de)
GB (1) GB1178329A (de)
NL (1) NL144615B (de)
SE (3) SE353715B (de)
YU (1) YU33829B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4180576A (en) * 1975-09-16 1979-12-25 Commonwealth Scientific Industrial Research Organization Purines useful for the potentiation of antibiotics
US5120740A (en) * 1989-11-03 1992-06-09 Wisconsin Alumni Research Foundation Prodrugs of 6-mercaptopurine and 6-thioguanine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5126896A (en) * 1974-08-22 1976-03-05 Funai Yaihin Kogyo Kk Ss inoshirushisuteinno seizoho
CS249576B1 (en) * 1984-12-22 1987-04-16 Antonin Cerny 6-purinyl n-(2-chlorethyl)carbamate and thiocarbamate and method of their production

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4180576A (en) * 1975-09-16 1979-12-25 Commonwealth Scientific Industrial Research Organization Purines useful for the potentiation of antibiotics
US5120740A (en) * 1989-11-03 1992-06-09 Wisconsin Alumni Research Foundation Prodrugs of 6-mercaptopurine and 6-thioguanine

Also Published As

Publication number Publication date
JPS4832119B1 (de) 1973-10-04
DE1695744C3 (de) 1981-09-24
SE353715B (de) 1973-02-12
FI48737B (de) 1974-09-02
DE1695744A1 (de) 1972-04-20
GB1178329A (en) 1970-01-21
NL6709151A (de) 1968-01-02
FI48737C (fi) 1974-12-10
AT274000B (de) 1969-09-10
YU33829B (en) 1978-06-30
DK118136B (da) 1970-07-13
NL144615B (nl) 1975-01-15
SE339473B (de) 1971-10-11
CH501652A (de) 1971-01-15
SE353716B (de) 1973-02-12
YU130167A (en) 1977-12-31
BE700727A (de) 1967-12-01
DE1695744B2 (de) 1980-09-11

Similar Documents

Publication Publication Date Title
DE69130408T2 (de) Endothelinantagonistische Peptidderivate
JPS59500863A (ja) ゴナドリベリン誘導体、その製造方法及びその医薬及び獣医薬組成物
NL192575C (nl) Op het centrale zenuwstelsel werkende tripeptiden.
CZ245992A3 (en) Hydantoin derivatives
JPH0144693B2 (de)
JP2694191B2 (ja) Ｌ−プロリン誘導体及びその製造方法並びにそれを含有する医薬組生物
Bhargava et al. Studies on the Structure of the Skin Protein-bound Compounds Following Topical Application of 1, 2, 5, 6-Dibenzanthracene-9, 10-C14. II. Nature of the 2-Phenylphenanthrene-3, 2'-dicarboxylic Acid-Protein Bond1, 2
US3567705A (en) N-(delta-(6-purinylthio)valeryl)amino acids and peptides
US4407794A (en) Peptides and therapeutic applications thereof
EP0077460A2 (de) Purin-Verbindungen, die immunregulierende Wirkung aufweisen
Balaev et al. Pentapeptide analogs of somatostatin containing a thiazolidine fragment: synthesis and cytotoxic activity
HU180925B (en) Process for producing tripeptide-amides trh-analogues,effectives on the central nerve systhem
US3766235A (en) Hydroxamic acid derivatives of alphaaminooxy carboxylic acids
US5089476A (en) Glutamic acid derivatives
PL101401B1 (pl) Sposob wytwarzania nowych pochodnych histydyny
EP0159396B1 (de) Carboxyalkyl-Peptid-Derivate
SE461042B (sv) Peptider med tillvaextbefraemjande aktivitet jaemte veterinaera kompositioner innehaallande naemnda peptider
US6172256B1 (en) Chiral-β-amino acid compounds and derivatives thereof
US3679655A (en) N,n-disubstituted aminoethylcarbamyl protecting groups for cysteine
US3891692A (en) N-(cyclopropylalkoxycarbonyl)amino acids
Elmore et al. Thioesters of amino acid derivatives as thioacylating agents in thiopeptide synthesis
Okawa Studies on Serine Peptides. III. Synthesis of l-Seryl-l-Histidine, l-Seryl-l-Histidyl-l-Leucine and Carbobenzyloxy-Glycyl-O-Benzyl-Dl-Serine Ethyl Ester
US3445447A (en) Tert-amyloxycarbonyl derivatives of amino acids
JPH0349918B2 (de)
Jones et al. Amino-acids and peptides. Part XXVII. Further studies on esters of 1-hydroxypiperidine