CA1121375A - Derivatives of amines and amino acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel compounds of the formula wherein A is methylene, ethylene or ehtylidene; R1 is -C?CH
or -CH=CH2; R2 is hydrogen or COR wheretn R ts hydroxy, a stralght or branched alkoxy group of from 1 to 8 carbon atoms, -NR4R5 wherein each of R4 and R5 is hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms or wherein R5 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; Ra is hydrogen, , alkyl-carbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy motety has from 1 to 4 carbon atoms and is straight or branched or wherein R7 is selected from hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; and Rb has the same meaning as defined for Ra except Rb is not , and Ra and Rb can be the same or different; with the provisos that when R2 is hydrogen, R1 is -C?CH; when A
is ethylidene, R2 is hydrogen; and when Ra is , A is methylene; and pharmaceutically acceptable salts and individual optical isomers thereof. The compounds are irreversible enzyme inhibitors and are useful as anti-infective agents, in the control of certain rapid growth processes and in the inhibition of the immune response.
The compounds are also useful as intermediates in the preparation of novel cephalosporin derivatives.

Description

~ ~ Z~ M~-91 FIELD OF INVENTION
This lnvention relates to novel pharmaceutically useful acetylenic derivatives of amines and amino acids and novel vtnyl derivatives of amino acids~
SUMMARY OF INVENTION
.
The compounds of the present invention are represented by the following general Formula I

RaHN(A) C=f-C-R2 Formula I
H NHRb wherein A is methylene, ethylene or ethylidene; R1 is -CeCH
or -CH=CH2; R2 is hydrogen or COR wherein R is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, -NR4R5 wherein each of R4 and Rs is hydrogen~ or a straight or branched lower alkyl group of from 1 ~o 4 car-bon atoms or -NH-CHCOOH wherein R~ is hydrogen, a straight R~ -5 or branched lower alkyl group of from 1 to 4 carbon a~oms3H~
benzyl or p-hydroxybenzyl 3 Ra iS hydrogen, H2N-C-~ alkyl-carbonyl wherein the alkyl moiety has from 1 to 4 carbon a~oms and is straight or branched,~alko~ycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms and is straight or branched or -~-CH-R7 wherein R7 is hydrogen, a NHz straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; and Rb has the same mean-HN
7ng defined for Ra except Rb iS no~ H2N-C-, and Ra and Rb 3~7~

can be the same or different; with the provisos that when R2 is hydrogen, R1 is -C-CH; when A is ethylidene, Rz is HN
hydrogen; and when Ra iS HlN-C-~ A Ts methylene.
The pharmaceutically acceptable sal~s and individual opttcal isomers of the compounds of general Formula I are included within the scope of the present invention.
DETAILED DESCRIPTION OF INVENTION
In the above general Formula I methylene is taken to mean -CH2-; ethylene is taken to mean -CH2CH2-; ~nd ethyli-dene is taken to mean -CH-.
It is evident from the foregoing general Formula I that . the compounds of the presen~ invention are acetylene deriva-tives of amines and amino acids or are vinyl derivatives of amino acids.
As set forth hereinabove Rb has the same meaning as Ra H~
except Rb is not H2N-C-. That is, Rb is hydrogen, alkyl-carbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy motety has from 1 to 4 carbon atoms and i5 straight or branched or -~ CH-R7 wherein R7 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p~hydroxybenzyl.
As used in general Formula I the term alkylcarbonyl is taken to mean the group -C~alkyl wherein the alkyl moie~y

-2-~ 37 5 Ml-913 has from 1 to 4 carbon atoms and is straight or branched, for example, methyl, ethyl, n-propyl, isopropyl, n^butyl, isobutyl and tert-butyl.
As used in general Formula I the term alkoxycarbonyl Ts taken to mean the group -C-O~alkyl wherein the alkoxy moiety, that is, -0-alkyl, has from 1 to 4 carbon atoms and is straight or branched, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butGxy, and tert-butoxy.
Illustrative examples of straigh~ or branched alkyl groups having from 1 to 4 carbon atoms as used in general Formula I are methyl, ethyl, n-propyl, n-butyl, isopropyl and tert-butyl.
Illustrative example~ of alkoxy groups having from 1 to 8 carbon atoms as used in general Formula I are methoxy, ethoxy, propoxy, butoxy, pentyloxy, and octyloxy.
Illustrative examples of pharmaceutically acceptable salts of the compounds of this invention include non-toxic acid addition salts formed with inorganie acids, such as3 hydrochloric, hydrobromic, sulfuric and phosphoric acid3 and organic acids, such as, methane sulfonic, salicylic, maleic, malonic, tartaric, citric and ascorbic acids; and non-toxic salts formed with inorganic or organic bases such as those of alkali metals, for example, sodium, potassium and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of Group lll A, for example, alumi-num, organic amines, such as, primary, secondary or tert;ary amines, for example, cyclohexylamine, ethylamine, pyridine~
me~hylamino ethanol, ethanolamine and piperazine. The salts are prepared by conventional means.

- ~ ~2 ~ 37 5 Ml-913 Preferred compounds of this invention are those of g~neral Formula I wherein R3 is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is s~raTght or branched with compounds wherein R3 is hydro-gen being more preferred. Compounds wherein A is methylene or ethylidene are also preferred with compounds wherein A
is methylene being more preferred. Also compounds wherein R2 is hydrogen or COR wherein R is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms represents another preferred embodiment of this invention.
Illustrative examples of compounds of the present inven-tion are the following:
1,4-hex-2 en-5-ynediamine, 1,5-hept-3-en-6-ynediamine, 2,5-hept-~-en-6-ynediamine, 2-acetylene-2,5-diaminopent-3-enoic acid~
2-acetylene-2,6 diaminohex-3-enoic acid, 2,6-diamino-2-vinylhex-3-énoic acid, N-(1-acetylene-4-aminobut-2-enyl)~2-aminoace~amide, N-(1-acetylene-4-aminobut~-enyl)acetamide, N-(1-acetylene-5-aminopent-2-enyl)butyramide~
N-(1-acetylene-4-aminopent-2-enyl)acetamide, methyl N-(1-acetylene-4-aminobut-2-enyl)carbamate, methyl 2-acetylene-2,6-diaminohex-3-enoate, tert-butyl 2l5-diamino-2-vinylpent-3-enoate3 n-hexyl 2,6-diamino-2-vinylhex 3-enoate, ethyl 2-acetylene-5-amino-2-(1-oxoethylamino~pent-3-enoate, n-butyl 5-amino~2-ethoxycarbonylamino-2-vinylhex-~-enoate, 2-acetylene-5-amino-2-(1-oxoethylamino)hex-~-enamide, N-ethyl-2-acetylene-2,5 diaminopent-~-enamideg ~ 3~ 5 MI-913 N,N'-di-n-propyl-5-amino-2-mathoxycarbonylamino-2-vinylpent-

3-enamide, 2-acetylene-2,5-di-(1-oxopropylamino)pent-3-enoic acid, isopropyl 2,5-di-(n-butoxycarbonylamino)-2-vinylhex-~
enoate, 2-[2-acetylene-2~5-diamino-1-oxopent-3-enylamino]acetic acid, and 2~5-diamino-2-vinylpen~-~-enois acid.
The compounds of general Formula I are irreversible inhibitors of decarboxylase enzymes which are involved in polyamine formation rendering said compounds useful as pharmacological agents. Polyamines, particularly putrescine, spermidine and spermine are present in plant and animal tissues and in some microorganisms. Al~hough the exact physiological role of polyamines has not been clearly delin-eated there is evidence to suggest that polyamines are involved with cell division and growth. (H.G. Williams-Ashman et al., The Italian J. Biochem~ 25, 5-32 (1976), A. Raina and J. Janne, Med. BiolO 5~3 121-147 (1975) and D~H. Russell, Life Sciences 13, 16~5-1647 (lg7~)). Poly-amines are essential growth factors for or involved in the growth processes of certain microorganisms, for example, E. colT, Enterobacter, Klebsiella~ Staphylococcus aureus, C. cadaveris~ Salmonella typhosa and Haemophilus parainflu-?5 enza. Polyamines are associated with both normal and neo-plastic rapid growth ~here being an increase in ~he synthe-sis and accumulation of polyamines foilowing a stimulus causing cellular proliferation. Also~ levels of polyamines are known ~o be high in embryonic systems, leukemic cells ~0 and other rapidly growing tissues. !t is known that ~here l~L23L3~5 M I - 91~

Is a correlation between the activity of the decarboxylase enzymes of ornithine, S-adenosylmethionine, arginine and lysine and polyamine formation.
The biosyntheses of putrescine, spermidine and spermine are interrelated. Putrescine is the decarboxylation product of ornithine, catalyzed by ornithine decarboxylase. Putres-cine formation may also occur by decarboxylation of arginine to form agmatine which is hydrolyzed to give pu~rescine and urea. Arginine is also involved in ornithine formation by action of the enzyme arginase. Activation of methionine by S-adenosylmethionine synthetase forms S-adenosylmethionine which is decarboxylated, after which the propylamine moiety of activated methionine may be transferred to putrescine to form spermidine and to spermidine to form spermine. Hence, putrescine serves as a pr~cursor to spermidine and spermine and additionally h~s been shown to have a marked regulatory effect upon the polyamine biosynthetic pa~hway in that it has been shown that increased synthesis of putrescine is the first indicatîon that a tissue will undergo renewed growth processes. Cadaverine which is the decarboxylation product of lysine has been shown to stimulate the activity of S-adenosyl methionine decarboxylase and is known to be essential to growth processes of many microorganisms, for example, H. paralnfluenza.
The compounds of general Formula I are irreversible inhibitors of ornithine decarboxylase and lysine decarboxy-lase rendering said compounds useful as an~iinfective agents being effective in the control of microorganisms, for ex-ample, bacteria, fungi and viruses which are dependent upon ~0 polyamines for growth~ for example, E co1i, Enterobacter, 3 MI-91~

~lebsiella, Staphylococcus aureus, C. cadaveris, viruses such as~ H. parainfluenza~ picornaviruses, for example, encephalomyocarditis, herpes simplex, poxviruses and arbo-viruses, for example, Semliki forest. The compounds of general Formula I wherein A is methylene or ethylidene are also useful in the control of certain rapid growth processes.
For example, said compounds are useful in the inhibition of spermatogenesis and embryogenesis and therefore the compounds find use as male antifertility a~ents and abortifacients.
The compounds are also useful in the inhibition of the immune response, thus the compounds are useful as immuno-suppressants for the treatment, for example, of myasthenia gravis, arthritis, multiple sclerosis and thè prevention of tlssue or organ transplant rejection, and are useful in the control of neoplastic growth, for example, solId tumors, leukemias and lymphomas. The compounds are also useful as inhibitors of prostatic ~hypertrophy, excessive scalp cell srowth as found with the occurrence of dandruff and as in-hibitors of abnormal cutaneous cell growth as found with a psoriatic condition. In administering the compounds of general Formula I wherein A is methylene or ethylene it may be desirable to administer concurren~ly by known procedures a monoamine oxidase inhibitor such as trans(~)-2-phenyl-cycloproponamine or N-benzyl-N-methyl-2-propynylamine~ The utility of compounds of general Formula I as irreversible inhibitors of ornithine or S-adenosylmethionine d~carboxy-lase enzymes may be measured as follows. An aqueous solu-tTon of an appropriate compound is given orally or paren-~erally to male rats or mice. From 1 to 48 hours after administration of the compound the animals are sacrificed ~ ~ ~ Ml-913 and the ventral lobes of the prostate removed and homogen-ized with the activity of ornithine and S-adenosylmethionine decarboxylases being measured as generally described by E.A. Pegg and H.G. Willaims-Ashman, Biochem. J. 108~ 573-539 (1968) and J. Janne and H.G. Will;ams-Ashman, Biochem.
and Biophysr Res. Comm. 42, 222-228 (1971).
The compounds of general Formula I wherein A is methyl-ene or ethylene are metabolic precursors of compounds having the following structure l-CH
Hooc(cH2)n- f H Formula ll wherein n is 2 or 3 which are known to be irreversible inhibitors of y-aminobutyric acid transaminase and upon administration resul~s in higher brain levels of y-amin butyric acid (GABA). As precursors of y-acetylenic-~-aminobutyric acid the above-described compounds of Formula I
are useful in the treatment of disorders of the central nervous system consisting o~ involuntary movement assoclated with Huntington's chorea, Parkinsonism, extra-pyramidal effects of drugs, for exampleJ neuroleptics, seizure dis-orders associated with epilepsy, alcohol withdrawal, barbi-turate withdrawal, psychoses associated with schizophreniaJ
depression, manic depression and hyperkinesis.
Several previous studies have shown that y-aminobutyric acid is a major inhibitory transmltter of the central ner-vous system as reportedJ for exampleg by Y. Godin et al., Journal Neurochemistry, 16, 869 (1969) and that disturbance of the excitation and inhibition ;nterplay can lead to diseased states such as Huntington's chorea (The Lancet, ~ 37 5 M~-91~

November 9, 1974g pp. 1122-112~) ~arkinsonism, schizophrenia, epilepsy, depression, hyperkinesis and manic depression dlsorders, Biochem. Pharmacol. 23, 2637-2649 (1g74).
That the compounds of general Formula I wherein A is methylene or ethylene and R2 i5 hydrogen are converted metabolically to the compounds of Formula ll may be demon-strated by the protect;ve effect of the compounds on audio-genic seizures in mice of the DBA strain measured by the general method described by Simler et al.~ Biochem. Pharma-co7. 22, 1701 (1g73) which is currently used to evidence antiepîleptic activity.
The compounds of general Formula I wherein R2 i5 hydro-gen are useful as chemical intermediates for the prepara~ion of novel cephalosporin derivatives of the following general Formula lll, and the compounds of general Formul~ I wherein R2 is COR and R is hydroxy are useful as chemical inter-mediates for the preparàtion of novel cephalosporin deriva-tives of the following general Formula IV. The cephalosporin compounds of Formulas lll and l~ are useful as antibioties.

H2N- (A) ~CH=CH-CH-NHCH2~CH2CNH~S
o , ~H2Y
COCM
Formula lll Rl O
H2N (A)-CH-CH-C - C-NH~
NH2 0 ~ ~ CHzY
COOM
Formula IV

1 ~Z~ 37 ~ MI-913 In the above general Formulas III and IV A and R1 have the meanlngs defined in general Formula I; M is hydrogen or a negative charge; and Y is hydrogen or acetoxy.
The compounds of general Formulas III and IV and the pharmaceutically acceptable salts and individual optical Isomers thereof are novel compounds useful as antibiotics and can be administered in a manner similar to that of many well known cephalosporin derivatives, for example, cepha-lexin, cephalothin, or cephaloglycine. The compounds of general Formulas III and IV and pharmaceutically acceptable salts and isomers thereof can be admînistered alone or in the form of pharmaceutical preparations either orally or parenterally and topically to warm blooded animals~ that is, birds and mammals, for example, cats, dogs, bovine cows, sheep, horses and humans. For oral administration the compounds can be administered in the form of tablets, capsules or pills or in the form of elixirs or suspensions.
For parenteral administration~ the compounds may best be used in the form of a sterile aqueous solution which may contain other solutes, for xample, enough saline or glucose to make the solution isotonic. For topical administrat;on the compounds of general Formulas III and IV, salts and isomers thereof may be incorporated ;nto creams or ointments, Illustrative examples of bacteria against which the compounds of general Formulas III and IV and the pharmaceu-t;cally acceptable salts and individual optical isomers thereof are active are Staphylococcus aureus, Salmonella schotmuehleri~ ~ , Diplococcus pneumoniae and Streptococcus pyo~enes.

~ ~z ~ Ml-913 Illustrative pharmaceutically acceptable non-toxic inorganic acid addition salts of the compounds of general Formula lll are mineral acid addition salts, for example, hydrogen chloride, hydrogen bromide, sulfates, sulfamates, phosphate, and organic acid addition salts are, for example, maleate, acetate~ citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate and ascorbate. The salts can be formed by conventional means.
Illustrative examples of compounds of general Formulas lll and IV are 7-[[2-[4~ acetylene-4-aminobut-2-enylamino~
methyl)phenyl]acetyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 7-[2-aee~ylene-2,5-diamino-1-oxopent-3-enamino]-3-acetyloxy-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbox-ylic acid.
The preparation of the compounds of general Formulas lll and IV is described`hereinbelow~
As pharmacolog;cally us~ful agents the compounds of general Formula I can be administered in various manners to the pa~ient being treated ~o ach;eve the desired effect.
The pharmacologically useful compounds of this invention can be used alone or in combination with one another. Also, the pharmacologically useful compounds of this invention may be administered in the ~orm of a pharmaceutical prepa-; 25 rat;on. The compounds may be admînistered orally, paren~-erally, for example, intravenously, in~raperitoneally, or ; subcutaneously, or topically. The amount of compound administered will vary over a wide range and can be any effective amount. Depending on the patient to be treated, the condftion being treated and the mode of administration, ~ ~ ~ ~ ~ ~ Ml-91~

the effective amount of compound administered will vary from about 0,1 mg/kg to 500 mg/kg of body weight of the patient per unit dose and preferably will be about 10 mg/kg to about 100 mg/kg of body weight of patient per unit dose. For example, a typical unit dosage form may be a tablet con-taining from 10 to ~00 mg of a compound of Formula I which may be administered to the patient being treated 1 to 4 times daily to achieve the desired effect.
As used herein the term patient is taken to mean warm blooded animals such as mammals, for example, cats, dogs, rats, mice, guinea pigs, horses, bovine cows, sheep and humans.
The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be of the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricant and inert fillers such as lactose, sucrose and corn starch. In another embodiment, the novel compounds are tableted with conventional tablet bases such as lactose, sucrose or corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as orn starch, potato -starch, or alginic acid and a lubricant such as stearic acid, or magnesium stearateO
For parenteral administration the compounds may be administered as injectable dosages of a solution or sus-pension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils with or without the addition of a surfactan~ and other pharmaceutically acceptable adjuvants. Illustrative of oils which can be employed in ~12-~Z~37~ MI-913 these preparations are those cf petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, and mineral oil. In general, water, saline, aqueous dex-trose, and related sugar solutions, ethanols and glycols ~uch as propylene glycol or polyethylene glycol are preferred liquid carriersj particularly for injectable solutions.
The compounds can be administered in the form of a depot injection or implant preparation which may be formu-lated in such a manner 25 to permit a sustained release of the active ingredient. The active ingredient can be com-pressed into pellets or smal1 cylinders and implanted sub-cutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Sîlastic, silicone rubber manufactured by the Dow-Corning Corporati~n.
The compounds of general Formula I wherein each of ~2, Ra and Rb is hydrogen and A is methylene or ethylidene are prepared by treating 1 equivalent of a suitably protected propargylamine with a strong base, optionally in the pr~-sence of a divalent metal cation, for example, zinc iodide or magnesium bromide to ~orm a protected propargylamine carbanion intermediate which is alkylated with 2-propenal or butenal then acylated with an acid halide, such as, ~5 alkanoyl halides, for example, acetyl chloride or propionyl chloride or aroyl halides, such as, benzoyl chloride or a lower alkyl haloformate, or tert-butoxycarbonylazide and subsequently hydrolyzed to an amide or carbamate of 1-amino-1-trimethylsilylacetylenebut-~-en-2-ol which is treated with a base, such as, sodium or potassium bicarbonate, sodium or 1~21375 Ml-9~3 potassium carbonate, sodium hydroxide or potassium hydroxide to give the carboxamide of 4-aminohex-1-en-5-yn-~-ol which is treated with trichloroacetonitrilP in a solvent, such as, ethers, for example, diethyl etherJ tetrahydrofuran, diox-ane, dimethoxyethaneJ hydrocarbons, such as, benzene or toluene in the presence of a catalytic amount of a base such as sodium hydride~ potassium tert-butoxide, lithium alkylamides, for example, lithium diisopropylamide or alkyl lithium at about -30C to 0C for about 1/2 hour to 3 hours to give the trichloromethylimidate ester which is heated to about 110 to 140C in a non-polar solvent, for example, xylene, toluene, nitrobenzene or chlorobenzene for about 1 to 10 hours to give the trichloromethyl acetamide which is hydrolyzed using aqueous acid, for example, hydrochloric acid or aqueous base, for example, sodium or potassium hydroxide.
The above described alkylation and acy1ation reaction may be carried out in an aprotic solvent, for example, benzene, toluene, e~hers, tetrahydrofuran, ~imethylsulfox-ide or hexamethyl phosphortriamide. The react7On tempera-tùre varies from about ~125 to 25C for about 1/2 hour to 24 hours.
Hydrolysis to give the amlde of 1-amino-1-trimethyl-silylacetylenebut-3-en-2-ol is achieved by treatment with hydrazine, phenylhydrazine or hydroxylamine or by treatment with mineral acids, for example, hydrochloric acid followed : by treatment with an organic base such as triethylamine or pyridine in a lower alcoholic solvent, such as, methanol or ethanol at about 80 to 110C for about 1/2 hour to 2 hours.
The suitably protected propargylamine employed in the ~ 2~L3~ ~ Ml-91~

above reaction may be represented by the following general Formula V
(R8 )3 -5 i -C-C -IH2 Formula V
N=CHRg wherein R8 is a straight or branched lower alkyl group hav-ing from 1 to ~ carbon atoms3 such as, methyl, ethyl, n-propyl and tert-butyl or triethylmethyl~ The compounds of Formula V are prepared by the addition of protecting groups on the acetylene function and the nitrogen function of pro-pargylamine~ Protection of the nitrogen function of the propargylamine is accomplished by forming in a known manner a Schiff's base with a non-enolizable carbonyl bearing com-pound selected from benzaldehyde, 2,2~dimethylpropanal and - 2,2-diethylbutanal. Protection of the acetylenic function is accomplished by reacting the above-described Schiff1s base with a trialkylsilyl chloride wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, f~r example, trimethylsilylchloride or ~riethylsilylchloride forming in a known manner the corresponding trialkylsilyl derivativeO
. Suitable strong bases which may be employed in the above reaction to form the carbanion are those which will abstract a proton from the carbon atom adjacent to the acetylene moiety, such as~ alkyl li~hium, for example, butyl lithium or phenyl lithium, lithlum di-alkylamide, for example, lithium diisopropylamide, lith7um amide~ tertiary potassium butylate or sodium amide.
: The compounds of general Formula I wherein each of R2, Ra and Rb iS hydrogen and A is ethylene are prepared by treating 1-hydroxypent-2-enal with a metal acetylide of the formula HC_CM' wherein M' is sodium, lithium or MgX' where-in X' is chlorine or bromine or with a complex of lithium acetylide/ethylenediamine in a solvent such as liquid ammonia, dimethylsulfoxide, ethers, for example, tetra-hydrofuran, dioxane, diethyl ether or dimethoxyethane atabout -~0 to 25C for about 1 minute to 3 hours to give hept-3-en-5-yne-1,5-diol. When sodium or lithium acetylide are employed liquid ammonia is the preferred solvent. When lithium acetylide is employed ether solvents are also pre-1~ ferred. Ether solvents are preferred when magnesium halideis employed with preferred reaction temperatures of about 0 to 25C. When the complex lithium acetylide-ethylene-diamine is employed the preferred solvent is dimethylsulfox-ide with a temperature of 25C and time of about 1 to 12 : 15 hoursO
The diol derivative ;s treated with phthalimide, tri-phenylphosphine and diethyl diazodicarboxylate in ethers such as tetrahydrofuranJ diethyl ether or dioxane for about 1 to 1 hours at about 25~ to 50C to a~ford the corres-ponding diphthalimido derivative which is treated with hydrazine hydrate in a lower alcohol solven~ such as methanol or ethanol for about 1 to 6 hours at about 5 to 50C followed by treatment with acid, for ~xample, 6NHCl, for 1 to 10 hours at 100C, The compounds of general Formula I wherein R, is -C-CH, each of Ra and Rb is hydrogen, A is methylene or ethylene, and R2 is COR wherein R is hydroxy are prepared by treating the çorresponding derivative wherein R2 is hydrogen and wherein the amino groups and the acetylene ~0 group are suitably protected~ having the structure ~16-~z~375 Mj-91~

C--CSi(R10)3 RllHC=N-(CH2)n CH=CH-CH-N-CHR11 Formula VI
with a strong base and acylating the thus formed carbanion intermed;ate followed by acid or base hydrolysis.
In the above general Formula VI R1o is a straight or branched alkyl group having from 1 to 4 carbon atoms such as methyl, ethyl, n-propyl3 isopropyl or n-butyl; R11 is phenyl, tert-butyl or triethylmethyl; and n is the integer 1 or 2.
Suitable strong bases which may be employed in the above reaction to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the acetylene moiety, such asJ alkyl lithium, for example, butyl lithium or phenyl lithium~ lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide~
tertiary potassium bu~ylate or sodium amide.
Suitable acylating agents which may be employed in the above reaction are halo-formates, such as chloro methyl-formate or chloro ethylformate, azido tert-butylformate, ~yanogen bromide, carbon dioxide, diethylcarbonate, phenyl-isocyanate, triethoxymethylium tetrafluoroborate, N,N-dimethylcarbamoyl chloride, 2-methylthio~1,3-dithiolinium iodide, ethylene carbonate or ethylene trithiocarbonate.
When 2-methylth;o~ -dithiolinium iodide is employed the additional step of alcoholysis with a lower alcohol, For example, ethanol or lsopropyl alcohol is required prior to deprotection by hydrolysisO
The acylating reaction may be carrled out in an aprotic solvent, for example, benzene~ toluene, ethers, tetrahydro-furan, dimethylsulFoxide, hexame~hyl phosphortriamide~ The ~17-31~2137~
Ml-91~

reaction temperature varles from -120C to about 25C, a preferred temperature being about -70C, and the reaction time vartes from about 1/2 hour to 24 hours.
Hydrolysis is achieved by treatment with aqueous acid, for example, hydrochloric acid, or aqueous base, for ex-ample, sodium hydroxide or potassium hydroxide.
The compounds of Formula Vl are prepared by the addi-tion of protecting groups on the acetylene function and the amino groups of a compound of the formula:
C_CH
H2NCH2(CH2) ~ CH~CH-CH Formula Vll o~ ~

Pro~ection of the amino groups is accomplished ~y forming in a known manner a Schiff's base with a nonwenolizable carbonyl bearing compound selected from benzaldehyde, 2~2-d;methylpropanal and 2,2-diethylbutanal. Protection of the acetylenic function is accomplished by reacting the above-described Schiff's base with a trialkylsilyl chlor-ide wherein the alkyl moiety has from 1 to 4 oarbon atoms and is straight or branched, for exampleJ trimethylsilyl-chloride or triethylsilylchloride forming in a known manner the corresponding trialkylsilyl derivative, The compounds of general Formula I wherein R1 is -CH=CH2, R2 is COR wherein R is hydroxy and each Qf Ra and Rb iS hydrogen are prepared by trcating the corresponding derivative wherein R1 is -C-CH with sodium~ potassium or lithium in liquid ammonia and ammonium sulfate at about -70 to 25~C until the blue color persists for about 15 minutes. These compounds may also be prepared by cata-lytic or organic semi-hydrogenation of the corresponding ~ ~ 2 ~ 37 5 Ml-913 derivative wherein R1 is -C--CH/ Rz is COR and R is alkoxy and each of Ra and Rb iS alkylcarbonyl. After reduction the protecting groups are rernoved by acid or base hydroly-sis~ Catalytic hydrogenation may be carried out in the presence of a base, for example, pyridine or triethylamine using inorganic catalysts as described by E.N. Marvell and 1. Li3 Synthesis, No. 8, August, 1973, pp. 457-468, for example, palladium-on-barium sulfate or the Lindlar cata-lyst, that is, lead-poisoned palladium-on-calcium carbo-nate. The hydrogenation process is continued until thereis a reduction in the uptake of hydrogen.
The organic semi-hydrogenation is achieved by reacting equimolar amounts of the appropriate acetylene derivative and catecholborane under a nitrogen atmosphere at abou~
70C for about 2 hours by the general procedures described by H.C. Brown and S.K. Gupta~ J. Am. Chem. Soc. 94

4~70-4~71 (1972) and H.C. Brownl et al., J. Am. Chem. Soc.
95, 5786-5788 and 6456-6457 (1973).
The compounds of general Formula I wherein Ra iS
H~
H2N-C-, R2 is hydrogen or COR wherein R is hydroxy and Rb has the meaning deflned in general Formula I are prepared by treating a compound of the formula ~1 H2NCH2c =f -C-R3 Formula Vlll H NHRb wherein R1 and Rb have the meanings defined in Formula I
and R3 is hydrogen or COOalkyl wherein the alkyl group has from 1 to 8 carbon atoms and is s~raight or branchedl for example, methylJ ethyl) isopropyl or n-butyl, with the ~ 3~ ~ M1-913 proviso that any free amino group is suitably protected with, for example, benzyloxycarbonyl,with an alkylisothio-uronium salt, for example, ethylisothiouronium hydroaro-mide, by procedures generally known in the art; for example, Organic Synthesis, Ill, p. 440 (1955). The reaction is carried out in the presence of a base, such as, aqueous sodium hydroxide or potassium hydroxide at a pH of about 10 at a temperature of about 25C for about 6 to 60 hours after which the reaction mixture is neutralized with con-centrated hydrochloric acid and the product isolated. When appropriate, protecting groups are removed by acid hydroly-sis, for example, treatment with HBr in dioxane. The preparation of compounds of Formula Vlll is described hereinbelow.
Following is d~scribed the preparation of compounds of general Formula I wherein Ra and/or Rb are other than HN
hydrogen and Ra is other than H2N-~- including compounds of general Formula Vlll. The following description is appli-çable to all the above said compounds, however, it is necessary to protect one or the other of the amino groups prior to ~reatment with the appropriate reactant, that is, acid halide or anhydride, alkyl haloformate or acid of the formula HOOCCH-Rz or anhydride thereof as described below to give compounds wherein either or bo~h of Ra and Rb iS
other than hydrogen as follows: When Ra is hydrogen and Rb is other than hydrogen, the amino group to which Ra iS
attached is protected as a phthalimido derivative by treating the correspond;ng derivative wherein R~ is hydro-~Z~3~i MI-91~

gen and R2 is hydrogen or COR wherein R ;s a straight or branched alkoxy group having from 1 to 8 carbon atoms, with a carbalkoxyphthalimide wherein the alkoxy moiety has from 1 to 4 carbon atoms, for example, carbethoxyphthalimide in a solvent such as an ether or a lower alcohol, such as, methanol, for 1/2 to 3 hours at about O to 50C followed by extraction with acid, for example, hydrochloric acid prior to treatment with the appropriate reactant described below to give compounds wherein Rb is other than hydrogen.
The phthalimide group is subsequently removed by treatment with hydrazine in a lower alcohol solvent, such as, metha-nol at about 50 to 100C for about 1 to 4 hours. The ~ thus obtained compounds, that is, compounds wherein Ra is `~ hydrogen and Rb iS other than hydrogen may be treated with the appropriate reactants described below to glve compounds .
wherein Ra and Rb are both other than hydrogen and Ra is H~
no~ HzN-C- and may be the same or different. In preparing compounds wherein R~ is other than hydrogen and Rb iS
hydrogen the amino group to which Rb iS attached is pro-tected with, for example, a benzyloxycarbonyl group bytreatment of the corresponding derivative wherein Rb is hydrogen and R2 is hydrogen or COR wherein R is a straight or branched alkoxy group having from 1 to 8 carbon atoms with a benzyl haloformate, such as, benzyl chloroformate prior ~o treatmen~ with the appropriate reactant described below to g;ve compounds wherein Ra 75 other than hydrogen HN
or HzN-C-. The benzyloxy group is subsequently removed by aeid hydrolysis, for example, by treatment with HBr in .

1 ~ Z ~ ~75 Ml-91~

dioxane. When desired, the compounds thus obtained wherein R2 is COR and R is a straight or branched alkoxy group hav-ing from 1 to 8 carbon atoms are hydrolyzed with base using for example, sodium hydroxide or sodium borate in an aqueous lower alcohol, for example, m~thanol, solvent for 2 to 4 hours at about 25C to give the corresponding acidsJ that is, compounds wherein R is hydroxyO
The compounds of general Formulas I and Ylll wherein Ra or Rb iS alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 ~o 4 carbon atoms and Rz is hydrogen or COR wherein R is hydroxy or a straight or branched alkoxy group having from 1 to 8 carbon atoms are pr~pared by treating the corresponding derivatives wherein Ra or Rb iS hydrogen or is suitably protected or as to compounds of Formula 1, Rb iS other than hydrogen as de-scribed above with an acid halide of the formula R13C-halo wherein halo is a halogen a~om, for exampleg chlorine or bromine and R~3 is a straight or branched alkyl group having from 1 to 4 carbon atoms or an appropriate acid anhydride, in water in the presence of a base such as sodium hydroxide or sodium borate at a temperature of about 0 to 25C for about 1/2 hour to 6 hours. When appropriate, protecting groups are removed as described hereinabove by treatment with hydrazine or acid.
The compounds of general Formulas I and Vlll wherein Ra or Rb iS alkoxycarbonyl wherein the alkoxy mo;ety is straight or bran~hed and has from 1 to 4 carbon atoms and R2 IS hydrogen or COR wherein R is hydroxy or a straight or branched alkoxy group having from 1 to 8 carbon atoms are -~2-~Z~ 3~7~ Ml-91~

prepared by treating the corresponding derivative wherein Ra or Rb i5 hydrogen or is suitably protected or as to com-pounds of Formula 1, Rb iS other than hydrogen as described hereinabove with an alkyl haloformate of the formula R
halo-C-QR14 wherein halo is a halogen atom such as chlorine or bromine and Rl~ is a straight or branched alkyl group having from 1 to ~ carbon atoms in water in the presenc~ of a base such as sodium hydroxide or sodium borate at a temperature of about 0 to 25C for about 1/2 hour to 6 hours. When appropriat~ protecting groups are removed as described hereinabove by treatment with hydrazine or acid.
The compounds of general Formulas I and Vl l l wherein Ra or Rb is -~-CH-R7 wherein R7 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon a~oms~
15 benzyl or p-hydroxybenzyl and R2 is hydrogen or COR wherein R is hydroxy or a straight or branched alkoxy group having from 1 to 8 carbon a~oms are prepared by ~reating the correspond ing derivative wherein Ra or Rb iS hydrogen or is suitably protected or as to compounds of.Formula 1, Rb is other than hydrogen as described hereinabove with an acid of the formula HOOC-IH-R7, or an anhydride thereof, wherein the amino group is pro~ectP.d wi~h a suitable blocking group such as benzyloxycarbonyl or tert-butoxycarbonyl and R7 has the meaning de~ined hereinabove in an ether, such as, tetra-hydrofuran or dioxane, methylenP chloride or chloroform and -2~-1~2~37~i Ml-91~

in the presence of a dehydrating agent, such as, dicyclo-hexylcarbodiimide when the free acid is employed, at a temp-erature o~ about 0 to 35C for about 1 to 12 hours followed by acid and base hydrolysis and when appropriate, treatment with hydrazine to remove the protecting groups.
The compounds of the general Formula I wherein R is a straight or branched alkoxy group of from 1 to 8 carbon ~toms may also be prepared by conver~ing the correspondin~
compound wherein Rl is hydroxy to the acid halide by, for example, treatment with thionyl chloride, followed by alcoholysis with an alcohol of the formula R80H as defined above by procedures generally known in the art.
The compounds of this invention wherein R is -NR4R5 wherein each of R4 and Rs is hydrogen or a lower alkyl group of from 1 to 4 carbon atoms are prepared by an acylation reaction of an acid halide, for example, an acid chloride, of the corresponding compound wherein R is hydroxy and Ra and Rb nave the meanings defined in general Formula I with the proviso that any free amino group is suitably protected with groups, such as~ carboben~yloxy or tert-butoxycarbonyl with an excess of an appropriate amine which may be repre-sented as HNR4R5. The reaction is carried out in methylene chloride, chloroform, dimethyl formamide, or ethers such as tetrahydrofuran and dioxane, or benzene at about 25C for about 1 to 4 hours. Suitable amines are ammonia, or a compound which is a poten~ial source of ammonTa, for example, hexamethylenetetramine; primary amines, for example, methylamine, ethylamine or n-propylamine; and secondary amlnes, for examplel dimethylamine, diethyl-~0 amine, or di-n-butylamine. Following ~he acylation -2~-~Z~37~
Ml-91~

reaction the protecting groups are removed by treatment with acid, for example, trifluoroacetic acid or hydrogen bromlde in dioxane~
The compounds of general Formula I wherein R is -NH-CH-COOH are prepared by reacting the corresponding derivative wherein R is hydroxy or a ~unctional derlvative thereof, such as, an acid anhydride and Ra and Rb have the meanings defined in Formula I ~ith the proviso that any ~ree amino group is protected with a suitable blocking group, such as, benzyloxycarbonylj tert-butoxycarbonyl by reacting the amine protected free acid with a compound of the structure NH2-fH-COOR12 wherein R~ has the meaning R~ .
deflned in general Formula I and R12 is a lower alkyl group, for example, methyl or ethyl in an ether solution9 such as, tetrahydrofuran or dioxane at about 0O to 35C for about 1 to 20 hours followed by acid then base hydrolysis5 for example, with 2 N aqueous NH3 at about 0 to 50C for about 1 to 20 hours, to remove the protecting group(s), - with the proviso that when the amine protected free acid is employed the reaction is carri~d out using a dehydrating agent such as dicyclohexylcarbodiimide.
The individual optical isomers of the compounds of general Formula I wherein Ra and Rb are hydrogen and R2 is hydrogen or COR wherein R is hydroxy may be sep~rated by protecting the amino group distal to the acetylene functio~ using carboethoxyphthalimide in a solvent such as tetrahydrofuran, diethyl ether or lower alcohols such as methanol or ethanol. When R2 is COR and R is hydroxy llZ137S Ml-913 the compound is first converted to the lower alkyl ester, for example, the methyl ester. The protected amine deriva-tive is then resolved using either a (+) or (-) binaphthyl-phosphoric acid salt by the method described by R. Viterbo et al., in Tetrahedron Letters 48, 4617-4620 (lg71) and in U.S. patent 3,848,o~o or by using (~) camphor-10-sulfonic acid. The resolved phthalimido compound is then depro-tected using hydrazine to remove the phthalimide group followed by acid or base hydrolysis to cleave the ester when R2 is COR and R is hydroxy. The thus resolved acids and amines may be employed to prepare the individual iso-mers of compounds of the invention wherein Ra or Rb iS
other than hydrogen and R~ is COR and R is other than hydroxy in the same manner as described hereinabove for the racemic mixtures of compounds wherein Ra or Rb is hydrogen and R2 is hydrogen or COR wherein R is hydroxy.
The compounds of general Formula I wherein A is methylene, R1 is -C--CH, R2 is COR wherein R is hydroxy and each of Ra and Rb iS hydrogen, that is, 2-ace~ylene-2,5-diam;nopent-~-enoic acld may also be prepared by treating a suitably protected propargylam;ne of Formula V with a strong base, alkylating the thus formed carbanion inter-mediate with alkylbromide, treating the alkylated inter-; mediate with a strong base and acylating the thus formed second carbanion intermediate with a suitable acylating reagen~ and subsequently remov;ng the protecting groups by treatment with phenylhydrazine or hydra~ine and a base such as potassium or sodium hydroxide to give 2-acetylene-2-aminopent-4-enoic acid. The acid is converted to the ester using methanol/HCl then treated with an acid halide ~26~

- l~Z137$ Ml-913 such as a lower alkanoyl halide, for example, acetyl chloride or an aroyl halide, such as, benzoyl chloride or with a lower alkyl haloformate such as methyl chloroformate followed by treatment with an organic base such as pyridine or triethylamine and treating the thus formed ester amide in aqueous lower alcohols, such as, methanol or ethanol with selenium dioxide For 1 to 6 hours at about 80 to 110C
to give the es~er amide of 2~acetylene-2-amino-3-hydroxy-pent-4-enoic acid which is treated with trichloroacetroni-trile in a solvent, such as, ethers, for example, diethylether, tetrahydrofuran, dioxane, dimethoxyethane, hydro-carbons, such as, benzene or toluene in the presence of a catalytic amount of a base such as sodium hydride, potassium tert-butoxide, lithium alkylamides, for example, lithium diisopropylamide or alkyl lithium at about -30 to 0C for ; about 1/2 hour to 3 hours followed by heating to about 110 to 140C in a non-polar solvent, for example, xylene, toluene, nitrobenzene, or chlorobenzene for about 1 to 10 hours and subsequently hydrolyzing with aqueous acid, for -20 example, hydrochloric acid or aqueous base, for example, sodium hydroxide.
Suftable strong bases which may be employed in the - above reaction to form each carbanion are those which will abstract a proton from the carbon atom adjacent to the acetylene moiety, such as, alkyl lithium, for example, butyl lithium or phenyl lithium, lithium di-alkylamide, for example, lithium diisopropylamide, lithium amide, tertiary po~assium butylate or sodium amide.
Suitable acylating reagents which may be employed in the above reaction are halo-formates, such as chloro methyl-llZl 37 ~ Ml-913 formate or chloro ethylformate, azido tert-butylformate, cyanogen bromide, carbon dioxide, diethylcarbonate, phenyl-isocyanate, triethoxymethylium tetrafluoroborate, N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodide, ethylene carbonate or ethylene trithiocarbonate.
When 2-methylt~io~ dithiolinium iodide is employed the additional step of alcoholysis with a lower alcohol, for example ethanol or isopropyl alcohol is required prior to deprotection by hydrolysisO
The acylating reaction may be carried out in an aprotic solvent, for example, benzene, toluene, ethers, tetrahydro-furan, dimethylsulfoxide, hexamethyl phosphortriamide. The reaction temperature varies from -120C to about 25C, a preferred temperature being about -70C, and the reaction time varies from about 1/2 hour to 24 hours.

7-~2-~4-(l-Acetylene-5-aminopent-2-enylaminomethyl)phen acetyl~amino~-3-acetyloxymethyl-~-oxo-5-thio-1-az_bicyclo-l4.2.0~oct-2-ene-2-carboxy iC acid .
- A mixture of 1 9 of 3 acetyloxymethyl-7-[[2-[4-chloro-methyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.03-oct-2-ene-2-carboxylic acid and 1 g of 1,5-hept-3-en-6-ynedi-amine whereln the amino group distal to the acetylene func-- tion is protected as phthalimido in 50 ml of ethanol was stirred at 25C for 24 hours after which the solvent is removed leaving a residue which is treated with hydrazine and chromatographed on 5 i lica gel using benzPne-acetone as the eluant to give 7-[[2-[4-1-acetylene-5-aminopent-2-enyl-acetyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo-(4.200]oc~-2-ene-2-carboxylic acidO

3~ ~
Ml-913 7-r2-Acetylene-2,5-diamino-1-oxopent-3-enamino]-~-acetyloxy-methyl-~-oxo-5-thio-1-azabicycloL4.2.0~oct-2-ene-2-carboxylic aci A mixture of 1 9 of 3-acetyloxymethyl-7-amino-8-oxo-

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 9 of 2-acetylene-2,5-diaminopent-3-enoic acid chloride wherein the free amino groups are protected with tert-butoxy-carbonyl in 50 ml of ethyl acetate is refiuxed for 2 hours after which the solvent is r~moved leaving a residue which is chromatographed on silica gèl using benzene-acetone as the eluant to give 7-[[2-acetylene-2,5-diamino-1-oxopent-3-enamino]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid wherein the amino groups are protected with tert-butoxycarbonyl. The protected cephalo-sporin compound is treated with trifluoroacetic acid for 1/2 hour at 25C under nitrogen atmosphere then diluted with ether until precipitation stops and filtered to give the di-trifluoroacetic salt of the title cephalosporin which can be converted to the free base by use of ion cxchange resin.
The following examples are illustrative of pharmaceuti-cal preparations of compounds of general Formula 1.
F XAMPLE ~
An illustrative compositTon for hard gelatin capsules is as follows:
(a) 1,4-hex-2-en-5-ynediamine 20 mg (b) talc 5 mg (c) lactose 90 mg The formulation is prepared by passing the dry powders of (a) and (b~ through a fine mesh screen and mixing them ~9~

1 ~%~5 Ml 91~

well. The powder is then filled into hard gelatin capsules at a net fill of 115 mg per capsule.

An illustrative composition for tablets is as follows:
(a) 2-acetylene-2,5-diaminopent- 20 mg ~-enoic acid (b) starch 4~ mg (c) lac~ose 45 mg (d) magnesium s~earate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried, screened, and mixed with the magne-sium stearate3 The mixture is compressed into tablets weighing 110 ~9 each.

An illustrative ~omposition for an injectable suspen-sion is the following 1 ml ampul for an intramuscular in-jection.
Wei~ht per cent (a) 2,5-hept-~-en-6-ynediamine loO
(b) polyvinylpyrroiidone 0.5 (c) lecithin 0.25 (d~ water for injectton to make 100.0 The materials (a)~(d) are mixed, homogenized and filled into 1 ml ampuls which are sealed and autoclaved 20 minutes at 121C. Each ampul contains 10 mg per ml of novel com-pound (a)~
The following examples further illustrate the compounds of the invention.

-~0-~ 375 Ml-913 1,4 Hex 2-en 5 ynediamine dihydrochloride A solution of 21.5 g (0.1 M) of ~-trimethylsilylprop-2-ynyl-1-iminobenzyl in 500 ml of tetrahydrofuran at -70C
is treated with 66.5 ml of a 1.5 M solution of n-butyl-lithium. After 5 minutes at -70C a solution of zinc iodide, prepared from 8.o 9 of ~inc and 25.4 9 of iodine in 100 ml of tetrahydrofuran, is added. The resulting solution is stirred at -70C for 20 minutes ~fter which 5.6 g (0.1 M, 6.65 ml) of 2-propenal is added dropwise at ~70C. The solution is maintained at -70C for 30 minutes then 7.8 9 (0.1 M, 7.0 ml) of acetyl chloride is added.
The solution is allowed to warm to room temperatyre and diluted with ether, washed well with aqueous sodium bi-- carbonate followed by aqueous sodium chloride then dried over magnesium su1fate and evaporated leaving an oil which is taken up in 200 ml of isopropyl alcohol and treated with 10 9 (0.0~3 M) of phenylhydrazine. The mixture is heated at reflux for 20 minutes then the solvent evapora~ed.
The residue is dissolved in chloroform and applied to a column of silicon dioxide packed with chloroform. Elution with chloroform followed by 5~0 methanol/chloroform gives ~he acetamide of 1-trimethylsilylacetylene-1-aminobut-3-en-2-ol which is dissolved in 30 ml of methanol and trea~ed with 2.5 9 of potassium hydroxide in 30 ml of water at room temperature after which the methanol is filtered off.
The aqueous residue is saturated with sodium chloride and extracted well with methylene chloride. The organic phase Ts dried over magnesium sulfate and concentra~ed leaving ~0 a residue which is recrystallized from chloro~orm/petroleum llZ1375 Ml-91~
.

ether to give the acetamide of 4-aminohex-1-en-5-yn-3-ol (M.P. 94C) of which 994 mg (6.5 mM) is taken up in 15 ml of tetrahydrofuran and added to 24 mg of a 50~ dispension (0.5 mM) of sodium hydride. After 5 minutes at about 25C
the solution is added dropwise via syringe to a solution nf 9~5 mg (6.5 mM) of trichloroacetonitrile in 30 ml of te~rahydrofuran precooled to -23C ~dry ice/carbon tetra-chloride). The resulting solution is stirred for 1-1/2 hours at -23~C then evaporated at about 25C leaving an oil whieh is dissolved in 30 ml of xylene and heated at reflux for ~ hours then allowed to stand overnight at about 25C. The resulting precipitate is collected, recrystal~
li~ed from chloroform and combined with 40 ml of 6 N HCl and 100 ml of methanol. The solution is heated at reflux for 12 hours ~hen concentrated. The resulting residue is washed well with chloroform, treated with charcoal, filtered and evaporated leaving a residue which is recrys-tallized from ethanol to give 1,4-hex-2-en-5-ynediamine dihydrochloride, M.P. 175C (dec.).

1,5-He~t-3-en-6-ynediam7ne To a solution of sodium acetylide, prepared from 2.3 9 (0.1 M) of sodium in 500 ml of ammonla, is added 35 9 (35 mM) of 5-hydroxypent-2-enal. One hour later ammonium chloride is added and the ammonia allowed to evaporate.
The residue is taken up in ether, filtered and concentrated leaving a residue which is taken up in 200 ml of tetra-hydrofuran and stirred for 48 hours at 25~ with 18.~ 9 (70 mM) o~ triphenylphosphine, 12.1 9 (70 mM) of diethyl ~0 azodicarboxylate and 10.2 (70 mM) of phthalimide. Th~

~Z~3~S Ml-91~

precipitate which forms is filtered of~, recrystallized from methanol then dissolved in 30 ml of ethanol. The ethanol solution is treated with hydrazine hydrate (1.74 9) at reflux overnight after which the solvent is evaporated and the residue treated with 5~ aqueous potassium hydroxide until basic, eXtracted with dichlorome~hane~ evaporated and distilled to give 1.5-hept-~ en-6-ynediam;ne.

2-Acetylene-2,5-diaminopent-3-enoic acid hydrochloride A solution of 2 9 (18 mM) of 1,4-hex-2-en-5-ynediamine tn ~0 ml of benzene is treated with ~.8 9 (~6 mM) of ben~al-dehyde at 25C in the presence of magnesium sulfate. After 1 hour the solution is filtered and the benzene distilled off using a Dean-Stark apparatus leaving a residue which iS distilled (Kugelrohr, 160C, 0.1 mM) to glve an oil which is taken up in 100 ml of tetrahydrofuran and trea~ed with 14 ml of a 1.0 M solution (14 mM) of ethyl magnesium bromide at 0C. After 30 minutes 1.5 9 (14 mM) of chloro-trimethylsilane in 15 ml of tetrahydrofuran is added. The solution îs stirred for 1 hour at 0C then brine is added and the mixture extracted with ether~ The organic layer is washed wel! with brine, then dried and concentrated. The res;due is dis~illed (Kugelrohr, 175C, 0.1 mm) to afford an oil which is taken up in 10 ml of tetrahydrofuran and treated with lithium diisopropylamide, prepared from 8.4 mM
of diisopropylamide and 4.2 ml of a 2 M solution of n-butyl-lithium, at -78C~ After 5 minutes o.8 9 (8.4 mM) of methyl chloroformate in 5 ml of tetrahydrofuran is added and the solution is immediately quenched wi~h brille and extracted with ether. The ether extract is dried and evaporated -~3-~ ~ ~ ~ ~ ~ ~ Ml~

leav;ng a residue which is refluxed in 50 ml of 6 N hydro-chloric acid for three hours. On cooling the solution is extracted with methylenechloride. The aqueous solution is evaporated to dryness and the resulting residue triturated with ethanol. The insoluble salts are filtered off and the ethanol solution is treated with 800 ,~9 (8.4 mM) of tri-ethylamine. The resulting precipitate is filtered off and recrystallized from ethanol/water (9:1) to give 2-acetylene-2,5-diaminopent-3-enoic acid hydrochloride.

2,5-Diamino-2-vinylpent-3-enoic ac;d To a suspension of 1.54 9 (10 mM) of 2-acetylene-2~5-diaminopent-~-enoic acid and 2 9 (1.4 mM) of ammonium sul-fate in 100 ml of ammonia is added lithium at reflux until the blue color persists for 15 minutes after which ammonium ' chloride is added and the ammonia allowed to evaporate.
The residue is dissolved in water and applied to a column of Amberlite 120 H+. The product is eluted with 2 M ammon-ium hydroxide and recrystall-ized from water/ethanol to give 295-diamino-2-vinylpent-3-enoic acid.

2-Acetylene-2,5-diaminoQent-3-eno~c acid A solution of 2105 9 (0.1 M) of 3-trimethylsilylprop-~-ynyl-1-iminobenzyl in 600 ml of tetrahydrofuran at -78C
iS treated with 50 ml of a 2.0 M solution of n-butyllîthium followed by the addition of 12.1 g (0.1 M) of allyl bromide After 3 hours at ~78~C 50 ml of a 2,0 ~ solution of n-butyl-lithtum is added followed by the addition of 9.4 9 (0.1 M) of methyl chloroformate~ After 30 min~tes at -78~C the ~0 r action mixture is treated with brine then extracted wi~h -~4-~ Z ~ 37 5 Ml-91~

ether. The ether solution is dried over magnesium sulfate and evaporated to afford an oil which is dissolved in 100 ml of pentane and treated with 10.8 9 (0~1 M) of phenylhydra-zine. After 1 hour at 25C the precipitate is filtered off and the filtrate evaporated and treated with 12 9 (0.7 M) of potassium hydroxide in 40 ml of methanol and 40 ml of water overnight at 25C. The methanol is evaporated off and the aqueous solution washed with dich!oromethane, acidi-fied using 6 N hydrochloric acid, rewashed with dichloro-methane and evapora~ed to dryness. The residue is triturated with ethanol, filtered and the filtrate evaporated leaving a residue which is dissolved in water. The pH of the water solution is adjusted to 6 and applied to an Amberlite resin.
Elution with 1 M ammonium hydroxide affords 2-acetylene-2-aminopent-4-envic acid which is treated overnight at 25C
with methanol saturated with dry HCl after which the solvent is evaporated to give the methyl ester hydrochloride. The methyl ester hydrochloride (10 g, 0905 M) is suspended in 20 ml of dichloromethane and treated with 10 9 (0.1 M) of triethylamine and 3.9 g (0.05 M) of acetyl chloride over-night at ~5C. The solut;on is then washed with water, dried and evaporated leaving a residue which is recrystal-li~ed from ethylacetate ~o give methyl ~-acetylene~
oxoethylamino)pen~-4-enoate (10 mM) which is taken up in 20 ml of ethanol and 5 ml of water and treated with 1.11 g (10 mM) of selenium dioxide. The mixture is heated to re-flux for 4 hours after which the solvent is evaporated9 .
The resulting residue is taken up in ~ther and washed with sodlum bioarbonate solution. The ether solution is dried~

-~5-~12~375 Ml-91~

evaporated and the mixture of diastereomeric alcohols puri-fied by chromatography on Florisil. The alcohol is dis-so1ved in 15 ml of tetrahydroFuran and added to 24 mg of a 50~ dispension (0.5 mM) of sodium hydride. After 5 min-utes at about 25C the solution is added dropwise viasyringe to a solution of 9~5 mg (6~5 mM) of trichloro-methylacetonitrile in 15 ml of tetrahydrofuran precoo!ed to -23C. The resulting solution is stirred for 1-1/2 hours at -2~C then evaporated at about 25C leaving an ~0 oil which is dissolved in 30 ml of xylene and heated to reflux for 3 hours then allowed to stand overnight at about 25Co The precipitate is collected, recrystallized from chloroform and combined with 40 ml of meth~nol and 40 ml of 6 N HCl and heated at reflux for 12 hours then concentrated. The resulting residue is washed well with chloroform, treated with charcoal, filtered and evaporated leaving a residue which is recrystal1ized from ethanol to give 2-acetylene-2,5~diaminopent-~-enoic acidO
When tn the procedure of Example 5 an appropriate amount of 2-butenal is substituted for 2-propenal, 2,5 hept-~-en-6-ynediamine dihydrochloride Is obtained.
When in the procedure of Example 7 an appropriate amount of 1J5-hept-~-en-6-ynediamine is substituted for 1,4-hex-2-en-5-ynediamine, 2-acetylene-2,6-diaminohex-3-enoic acld is obtained.

N-(1-Acetylene-4-aminobut-2-enyl)acetamide A solution of 242 mg (1 mM) of N-(4-acetylene-4-amino~
but-2-enyl)phthalimide în 10 ml of chloroform is treated ~0 with 1 ml of triethylamine followed by 78 mg (1 mM~ of 1~21375 Ml-91~

acetyl chloride in 5 ml oF chloroform. After 1 hour at 25C the solution is washed with water~ dried and concen-trated. The resulting residue is dissolved in 10 ml of ethanol and treated with 60 mg (1~1 mM) of hydrazine hy-drate at reflux for 2 hours after which the solvent isevaporated. The residue is treated with 1 N sodium hydrox-ide solution until the solid dissolves then is extracted with dichloromethane. The organic phase is dried and con-centrated to give N-(1-acetylene-4-amino-but-2-enyl)acet-amide.
N-(4-Acetylene-4-aminobut-2-enyl)phthalimide us~d in the above procedure is prepared as follows A solution of 1~.5 9 (6106 mM) of carbethoxyphthalimide in 70.ml of tetrahydrofuran is added dropwise to a solution of 6.91 g (61.6 mM) of 1-acetylene-1l4-but-2 endiamine in 30 ml of tetrahydrofuran in an ice-bath. After completion of the addition the mixture is stirred for 2 hours at 25C then diluted with ether, and the solution is extracted with 1 N hydrochloric acid (3 x 100 ml). The aqueous phase is washed several times with ether then concentrated to dry-ness leOving a residue which is recrystalli~ed from etha-nol to give N-(4-acetylene-4-aminobut-2-enyl)phthamlimide HCl which is converted to the free baseO
When în the procedure of Example 10 an appropriate 25 amount of ethyl chloroformate is used in place of acetyl chlorid N-(1-ace~ylene-4-aminQbut-2-enyl)ethyl carbamate is obtained~
When in the procedure of Example lU an appropriate amoun~ of benzyl chloroformate is subs~itu~ed for acetyl chloride, N-(1-acetylene-4-aminobut-2-enyl)ben~yl.car--37~

~ 37 ~ Ml-913 bama$e is obtained.

N~ Acetylene-4-aminobut-2-enYl)-2-aminopropionamide A solution of 492 mg (2 mM) oF N~ acetylene-4-amino-but-2-enyl)benzyl carbamate in 4 ml o$ dichloromethane is treated with 446 mg (2 mM) of N-carbobenzoxyalanine and 412 mg (2 mM) of N,N' dicyclohexylcarbodiimide for about 15 hours at 25C af~er which the solution is cooled to 0C and the precipitated dicyclohexylurea filtered off.
The filtrate is diluted with 20 ml of dichloromethane and washed with 1 N hydrochloric acid, water and aqueous sodium bicarbonate, then dried and concentrated. The resulting residue is treated with 6 ml of a 40~ (w/w) solution of hydrogen bromide in dioxane at 25C for 30 minutes then diluted with ether and the precipitated N-(4~acetylene-4-aminobut-2-enyl)-2-aminopropionamide di-hydrobromide collectedO

N-(4-Acetylene-4-am~nobut-2-enyl)acetamide A solution of 492 mg (2 mM) of N-(1-acetylene-4-aminobut-2-enyl)benzyl carbamate in 10 ml of chloroform is treated with 202 mg (2 mM) of triethylamine followed by 160 mg (~.1 mM) o~ acetyl chloride. After 1 hour at 25C
the solution is washed with water, dilute hydrochloric 2$ acid, and aqueous sodlum carbonate, then dried and con-centratedO The resulting residue is treated with 6 ml of a 40~ (w/w) solution of hydrogen bromide in dioxane for ~0 minutes at 25CJ then e~her is added on the preci-pitated N-(4-ace~ylene-4-aminobut-2-enyl)acetamide hydro-~0 bromide is collected.

~ 12 ~ 37 5 Ml-91~

When in the above procedure an appropriate amount of ethyl chloroformate is substituted For acetyl chloride, N-(l~-acetylene-4-aminobut-2-enyl)ethyl carbamate is obtained.

N~ Acetylene-4-aminobut-2-enyl)-2-aminopropionamide i HBr A solution of 450 mg (2 mM) of N-carbobenzoxyalanine in 10 ml of dichloromethane is treated with 202 mg (2 mM) of triethylamine followed by 218 mg (2 mM) of ethyl chloro-forma~e. After 1 hour at 25C the solution is treatedwith 484 mg (2 mM) of N-(4-acetylene-4-aminobut-2-enyl)-phthalimide in 10 ml of chloroform and maintained at 5C
for one hour after which the solution is washed with 1 N
hydrochloric acid, water and aqueous sodium carbonate then dried and concentrated. The residue is dissolved in 15 ml of ethanol and treated with 110 mg (2 mM) of hydrazine hydrate at reflux for 2 hours after which the solvent is evaporatedO The residue is trea~ed with 5~ aqueous sodium hydroxide and extracted with dichloromethane. The organic phase is dried and concentrated and the resulting residue is treated with 5 ml o~ a 40% (w/w) solution of hydrogen bromide in dioxane. After ~0 minutes at 25C the mixture is treated with ether and the precipitated N~ acetylene-4-aminobut-2-enyl)-2-aminopropionamide dihydrobromide ~5 collected.

1 Acetylen2~1,4 but 2 en~1ene-bls 2 amino~ro~ionamlde HBr A solution of 900 mg (4 mM) of N-carbobenzoxyalanine in 10 ml of dichloromethane is treated with 405 mg (4 mM) ~39~

~lZ~375 of triethylamine followed by ~35 mg (4 mM) of e~hyl chloro-formate. After 1 hour at 25C the solution is treated with 224 mg (? mM) of l-acetylene-lJ4-but-2-enediamine in 5 ml of dichloromethane. The solution is maintained a~ 25C
for 1 hour then is washed with water, dried and concentrated.
The resulting residue is trea~ed with 6 ml of a ~0% (w/w) solution of hydrogen bromide in dioxane for 30 minutes at 25~C then diluted with ether. The precipitate is collected ~o afford 1-acetylene-1,4-but-2-enylene-bis-2-aminopropion-~0 amide dihydrobromide.

1 Acetylene-1,4 but 2 enylene bis-acetamlde A solution of 0.5 g (4.5 mM) of 1-acetylenç-1,4-but-2-endiamine in 50 ml of ether containing 0.91 g (9.0 mM) of triethylamine is treated with 0.7 g (9.0 mM) of ace~yl chloride. After 1 hour the ether solution is washed with brine~ dried and evapor`ated to afford 1-acetylene-t,4-bu~-2-enylene-bis-acetamide.

_ Methyl 2-acetylene-2,5-d _minopent-3-enoate di HCl 2-Acetylene-2,5-dlaminopPn-t-~-enoic acid ~500 mg, .2 mM) is added to 40 ml of methanol which had been sat-urated with dry hydrogen chloride~ The solu~ion is hea~ed at reflux for 12 hours, then the solvent is evaporated to afford methyl 2-acetylene-2J5-diaminopent-~-enoate di-hydrochloride.
EXAMPLE_l~
2-Acetylene-2,5-di-(1-oxoethylamino)pent-~-enoic acid To a solution of ~12 mg ~2.~ mM) of 2-acetylene-2,5-~0 diaminop~nt-3-enoic acid in 2~5 ml of 1 N sodium hydroxide - ~0-~l~ ~ ~ Ml-91~

at 0C are added simultaneously from two syringes 312 mg (4 mM) of acetyl chloride diluted in 1 ml of THF and 4 ml of 1 N sodium hydroxideO After ~0 minutes at 0C the solu-tion is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethaneO The organic phase is dried and concentrated to afford 2-acetylene-2~5-di-(1-oxoethylamino)pent-3-enoic ac;d.
In a similar manner only substituting an appropriate amount of ethyl chloroformate ~or acetyl chloride~ 2-acetyl-ene-2,5-di-(1-ethoxycarbonylamino)pent-~-enoic acid ;s obtaîned.

2-Acetylene-2~5-di-N-(2-aminopropylcarbonylamino)pent-~enoic aci A solution of 240 mg (1 mM) of methyl 2-acetylene-2,5-diam;nopent-~-enoate dihydrochlor;de in 4 ml of me~hylene chloride containing 200~mg of triethylamine iS treated with 440 mg (2 mM) of N-carbobenzoxy alanine and 412 mg (2 mM~ of N~N'-dicyclohexylcarbodiimide overnight at 25C~
The mixture is then cooled to 0C and the precipitated di-cyclohexyl urea filtered offO The flltrate is diluted withmethylene fhloride) washed with wat r, bicarbonate~ dilute hydroehlorîc acid, then dried and concentrated. The resi-due ;s treated with 10 ml of ethanol and 10 ml of a 40~
(w/w) solutton of hydrogen bromide in dioxane for 30 min-~tes at 25C after which 50 ml of ether is added and theresulting precipi~atP collPcted. The precipitate is treated with 15 ml of 1 N aqueous sodium hydroxide over-nlght at 25C. The p~ of the solution is adjusted to neutral and the product isolated from an*Amberlite 120 H~

* Trade Mark -i -41-375 ~1-gl~
resin by elution with 2 M ammonium hydroxlde to give 2-acetylene-2,5-di-N-(2-aminopropylcarbonylamino)pent-~-enoic acid.

N-Propyl-2-acetylene-2~5-dtaminopent-~-enamide dihydro-romi e To a solution of 312 mg (2 mM) of 2-acetylene-2,5-diaminopent-3-enoic acid di HBr acid in 2.5 ml of 1 N
aqueous sodium hydroxide at 0C are added simultaneously from two syringes 680 mg (4 mM) of benzyl chloroformate in dioxane (2 ml) and 4 ml of 1 N sodium hydroxlde. After 30 minutes at 0C the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with di-chloromethane. The organic phase is dried and concentrated to afford 2-acetylene-~,5-di-(benzyloxycarbonylamino)pent-3-enoic acid which is dissolved in 15 ml of dichloromethane and treated with 220 mg of thionyl chloride at 25C for one hour. Propylamine (250 mg) is then added and the solu-tion stirred at 25C for one hour, then washed with water, dried and concentrated~ The residue is treated with 12 ml of a solution of dioxane containing hydrogen bromide (~0 w/w) and allowed to stand for 30 minutes at 25C. Ether (50 ml) is then added and the resulting precipitate col-lected to afford N-propyl-2-acetylene-2,5-diaminopent-~-enamide dihydrobromide.

2-~2-Acetylene-2~5-diamlno-1-oxopent-3-en~lamino)propionic acl To ~ mg (1 mM) of 2-acetylene-2/5-di-(benzyloxy-carbonylamino)pent-~-enoic acid in 15 ml or methyl~ne chloride is added 205 mg (2 mM) of triethyTamine followed 1 1Z ~ 37 5 Ml-913 109 mg (1 mM) of ethyl chloroformate. The solution is stirred for one hour at 25C, then 103 mg (1 mM) of alanine mPthyl ester tn 5 ml of methylene chloride is added. This solution is kept overnight at 25C, washed with water, dried and evaporated to dryness. The residue iS treated with 10 ml of a 40~ (w/w) solution of hydrogen bromide in dioxane at 25C for 30 minutes. Ether (50 ml) is then added and the precipitate collected. The precipitate is treated with ~0 ml of a 1 N sodium hydroxide solution overnight at 25C, the pH adjusted to 6.5~ and applied to an Amberlite 120 H~
resin. Elution with 2 N ammonium hydroxide affords 2-(2-acetylene-2,5-diamino-1-oxopent-3-enylamino)propionic acidO

, M th l 2-acet lene-2 5-di-(1-oxoeth lamino) ent-3-enoate e y _ Y l ~ ~ P_ _ A solution of 170 mg (1 mM) of 2-acetylene-2,5-di-(1-oxoethylamino)pent-3-enoic acid in 10 ml of chloroform is cooled to -5C and 78 mg of thionyl chloride in chloro-form ls addedO After ~0 minutes 1 ml of methanol is addedO
Evaporation of the solvent y~telds methyl 2-acetylene-2,5-di-(1-oxoethylamino)pent-3-enoate.
Alternatively the compounds of general Formula I
wherein A is methylene, R1 is -C-CH, R2 is COOH and R3 is hydrogen may also be prepared by treatlng 1 equivalent of a tert-butyl carbamate of 1-amino-1-trimethylsilylacetylene-but 3-en-2-ol with 1 equivalent of trichloroacetonitrile in a solvent, such as) ethers, for example/ die~hyl e~her, - - tetrahydrofuran, dioxane, dimethoxyethane, hydrocarbons, such as, benzene or toluene in the presence of a catalytic amount of a base such as sodium hydr7de~ potassium ter~-butoxide~ lithium alkylamides3 for examplej lithium diiso-~43~

~lZ1375 Ml-91~

propylamide or alkyl lithium at 110 to 140C in a non-polar solvent, for example, xylene, toluene, nitrobenzene or chlorobenzene for about 1 to 10 hours to give the tri-chloromethyl.acetamide which is treated with trifluoro-acetic acid at about 0 to 25C for about 1/2 hour to ~hours followed by treatment with 1 equivalent o~ benzalde-hyde a~ about 0 to 25C for about 1 to ~ hours to give N-(4-benzylimino-4-trimethylsilylacetylenebut-2-enyl)tri-chloromethylacetamide which is treated with 2 equivalents of a strong base, such as, an alkyl lithium, for example, butyl lithium or phenyl lithium, lithium dialkylamide, such as, lithium diisopropylamide, lithium amide, tertiary potassium butylate or sodium amide followed by acylation with a suitable acylating reagent and subsequent hydrolysis using aqueous acid~ for example, hydrochloric or toluene sulfonic acidc Suitable acyla-ting reagents for use in the above reaction are for example, halo-formates, such as, methyl chloroformate, azido tert-butylformate, cyanogen bromtde, carbon dioxide, diethylcarbonate, phenylisocyanate, tri ethoxymethylium tetrafluoroborateJ N,N-dimethylcarbamoyl chloride, 2-methylthio-1,3-dithiolinium iodide, eth~lene carbonate or ethylene trithiocarbonateO When 2-methylthio-~ dithiolinium iodide is employed the additional step of a1coholysis with a lower alcohol, for example, ethanol or Isopro?yl alcohol is required prior to deprotection by hydrolysis. The acylating reaction is generally carried out at abou~ -120~ to 25C, preferably -70C and for about 1/2 hour ~o 24 hours in an aprot;c soivent, for ~0 example, benzene, toluene, e~hers, such as, tetrahydro-~ 3~ ~ Mi-91~

furan, dimethylsulfoxide, or hexamethylphosphortriamide.
The following specific ~xample furthPr illustrates the processO

2-Acetylene-2,5-diaminopent-3-enoic acid A solution of 21.5 9 (0.1 M) of ~-trTmethylsilylprop-2-ynyl-1-iminoben~yl in 500 ml of tetrahydrofuran at -70C
is treated with n-butyllithium (66.7 ml of a 1.5 M solu-tion) and five minutes later a solution of zînc iodide, prepared from 8.0 9 of zinc an`d 25.4 g (0.1 M) of iodide in 100 ml of tetrahydrofuran, is added. The resulting solution is stirred at -70C for 20 minutcs after whieh 506 g (0.1 M, 6.65 ml) of 2-propenal is added dropwise at -70C. The solution is maintained at -70C for 30 minutes then 14.7 g (0.1 M) of tert-butoxycarbonyl a~ide is added.
The solution is allowed to warm to room temperature, di-luted with ether, washe~d well with aqueous sodium bicar-bonate, followed by aqueous sodium chloride, dried over rnagnesium sulfate and evaporated to afford an oil which ; 20 is taken up in 200 ml of isopropyl alcohol, treated with 10 9 (0.093 M) of phenylhydrazine, heated to reflux for 20 minutes then evaporated~ The resulting residue is dissolved in chloroform and applied to a column of silicon dioxide (300 9) packed with chloroform. Elution with chloroform followed by 5% methanol/chloroform gives the carbama~e of 1-amino-1-trimethylsilylacetylenebut-3 en-2-ol, 1.94 9 (605 mM) of which is dissolved in 15 ml of tetrahydrofuran and added to sodium hydride (24 mg of a 50% dispension, 0O5 mM). After 5 minu~es a~ room tempera~
~0 ture this solution i5 added dropwise via syringe to a _1~5_ ~12~375 Ml~913 solution of 935 mg (6.5 mM) of trichloroacetonitrile in 30 ml of tetrahydrofuran precooled to -23C. The resulting solution ts stirred for 1-1/2 hours at -~C then evaporated at room temperature leaving an oil which is dissolved in xylene and heated to reflux for ~ hours then allowed to stand overnight at room temperature. The resulting precipi-tate is collected and recrystallized from chloroform to give a white solid 4.0 9 (10 mM) of which is added to 4 ml of trifuloroacetic acid at 0C. Thirty minutes later the 0 solvent is evaporated leaving a residue which is suspended in 20 ml of dichloromethane and loO 9 (10 mM) of benzalde-hyde and 2 9 of triethylamine are added. The mixture is st7rred for 4 hours at 25C then washed well with water~
dried and evaporated. The resulting residue is recrystal-lized from ethyl acetate, and 4.1 9 (10 mM) of the solid Tn 10 ml of tetrahydrofuran is added to lithium diisopropyl-amTde, prepared from 2.02 g (20 mM) of d;isopropylamine and 10 ml of a 2 M solution (20 mM) of n-butyllithium, contain-ing 10 ml of hexamethylphosphortriamide at ~78Co After 20 minutes at -78C, 940 mg (10 mM) of methyl chloroformate ;n 5 ml of tetrahydrofuran ls added and after 30 minutes at -78C 600 mg of acetic acid is added followed by waterO
The mixture is extracted with ether, the ether solution wash d with brine, dried and concentrated. The resulting residue is treated with ~0 ml-of 6 N HCl and ~0 ml of ethanol for 24 hours at reflux. ~n cooling the solution is washed with dich10romethane then concentrated to dryness leaving a residue which is taken up in the minimum quantity oF water. The pH of the aqueous solution is adjusted to 6 and applied to an Amberlite resin 120 H~ Elution with ~2~37~ gl~
1 M ammonium hydroxide affords 2-acetylene-2~5-diaminopent-~-enoic acid which is recrystallized from wat~r/ethanol.

2-Acetylene-2-amino-5-guanidinopent-3-enoic acid To a solution of 1.9 9 (10 mM) of 2-acetylene-2,5-diaminopent-3-enoic acid monohydrochloride in 10 ml of 2 M
sodium hydroxide solution is added ~.7 9 (20 mM) of ethyl-thiouronium hydrobromide. The pH of the solution is main-tained at 10 by the addition of 2 ~ sodium hydroxide dur-ing 48 hours at 28C after which the pH is adjusted to 6, and the solution applied to an Amberlite resin 120 H~.
The product is eluted with 2 M ammonium hydroxide solu~ion and recrystallized from methanol-water to give 2-acetylene-2-amino-5-guanidinopent-3-enoic acid.
EX~MPLE 24-~-Acetylene-2-acetamido-5-aminopent-~-enoic acid (A) A solution of~1.68 9 ~10 mM) of methyl 2-acetyl-ene-2,5-diaminopent-~-enoate in 15 ml of tetrahydrofuran is added to 2.2 g (10 mM) of N-carboethoxyphthalimide in ~0 30 ml of tetrahydrofuran at 0C. After ~ hours at 25C
the solution is diluted with ether then extracted wlth 1 N
HCl. The aqueous phase ts washed with e~her than concen-trated to dryness leaving a residue which is recrystal-li2ed from ethanol to give methyl 2-acetylene-2-amino 5;
phthalimidopent-~-enoate hydrochloride.
(e) A solution of ~O0 9 (10 mM) of methyl 2-aeetylene-2-amino-5-phthalimidopent-3-enoate, prepared from the hydro-chloride obtained above, in 50 ml of chloroform is trea~ed with 2.0 9 (20 mM~ of ~r ieth`jlam,nQ followed by trea~ment with 780 mg (10 mM) of acetyl chloride~ After 1 hour at ~ 37S Ml-913 25C the solution is washed with 1 N HCl, dried and concen-trated to give methyl 2-acetylene-2-acetamido-5-phthal-imidopent-3-enoate which is dissolved in 100 ml of ethanol.
The ethanol solution is treated with 600 mg (10 mM) of hydra ine hydrate at reflux for 2 hours then the solvent is evaporated~ The remaining residue is treated with 1 N
sodium hydroxide until the solid dissolves then extracted with dichloromethane. The organic phase is dried and concentrated to give methyl 2-acetylene-2-acetamido~5-aminopent-3-enoate which is trèated with 40 ml of 2 N
sodium hydroxide at 25C for 4 hours after which the pH
is adjusted to 6~ and the solution is applied to an Amberlit~ 120 H~ resin. Elution with 2 M sodium hydroxide gives 2-acety1ene-2-acetamido-5-amînopent-~-enoic acid.
When in procedure (B) above an appropriate amount of benzyl chloroformate or ethyl chloroformate is substituted for acetyl chloride, 2-acetylene-2-benzyloxycarbonyl-amino-5-aminopent-3-enoic acid and 2-acetylene-2-ethoxy-carbonylamino-5-aminopent-~-enoic acid are obtained ` 20 respectively.

2-Acetylene-2-amino-5-acetamidopent-3-enoic acid A solution of 2.8 g (10 mM) of methyl 2-acetylene-2-benzyloxycarbonylamino-5-aminopent-~-enoate prepared by treating 2-acetylene-2-benzyloxycarbonylamino-5-aminopent-~-enoic acid with methanol saturated with HCl, in 20 ml of chloroform is treated with 1 g (10 mM) of triethylamine followed by treatment with 780 mg (10 mM) of acetyl chlor-Ide. After 1 hour at 25C the 531u~60~ is w3shed with 1 N
HCl, dried and evaporated. The resulting residue is -~8-l~Z1375 M1~913 $reated with ~0 ml of a 40% (w/w) solution of hydrogen bro-mide in dioxane for ~0 minutes at 25C then ether is added and the precipitated 2-acetylene-2-amino-5-acetamidopent-3-enoic acid hydrobromide collected.

N-Propyl 2-acetylene-2-acetamido-5-aminopent-3-enamide Methyl 2-acetylene-2-acetamido-5-phthalimidopent-3-enoate (~O4 9, 10 mM) is treated with 40 ml of 2 N sodium hydroxide at 25C for ~ hours after which the solution is acidified and extracted well with dichloromethane. The organic phase is dried and concentrated to afford 2-acetyl-ene-2-acetamido-5-phthalimidopent-3-enoic acid. The acid is dissolved in 40 ml of chloroform and treated with 1.2 9 (10 mM) of thionyl chloride at 25C for 4 hours after which 1.2 g (20 mM) of propylamine is addedO The solution is stirred at 25C for 2 hours then washed with 1 N HCl, dried and concentrated to afford N-propyl-2-acetylene-2-acetamido-5-phthalimidopent-3-enamide~ The amide is dissolved in 40 ml of ethanol and treated with 600 mg (10 mM) of hydrazine hydrate at reflux for 2 hours. The solution is then concentrated, and the residue treated with 1 N sodium hydroxide until the solid dissolves then extracted well with dichloromethane. The organic phase is dried and concentrated to afford N-propyl-2-acetylene-2-acetamido-5-aminopent-~-enamide.

2-Acetylene-2-(2-aminopr~plonamido~-5-amlnopent-~-enoic aci A solu~ion of 2.1 g (10 mM) of N-carbobenzoxyalanine in 50 ml of dichloromethane is treated with 1.0 9 (10 mM) .

~9 1~2~375 . Ml-913 of triethylamine followed by 1.1 9 (10 mM) of ethyl chloro-formateO After 1 hour at 25C the solution is treated with 3.0 g (10 mM) of methyl 2-acetylene-2-amino-5-phthalimido-pent-3-enoate in 40 ml of chloroform and maintained at 25C for 1 hour after which the solution is washed with 1 N
HCl, water and aqueous sodium carbonate then dried and con-centrated. The residue is dissolved in 60 ml of ethanol and treated with 550 mg (10 mM) of hydrazine hydrate at reflux for 2 hours, after which the solvent is evaporated.
The residue is treated with 5~ aqueous sodium hydroxide ; and extracted with dichloromethane. The organic phase is dried and concentrated, and the resulting residue is treated with 5 ml of a 40~ (w/w) solutlon of hydrogen bromide in dioxane. After 30 minutes at 25C the mixture ~5 is treated with ether and the precipitated methyl 2-acetyl-ene-~-(2-aminopropionamido)-5-aminopent-~-enoate dihydro-bromide collected. The ester dihydrobromide salt is treated with 40 ml of 2 N sodium hydroxide for 4 hours a~
25C, the pH is adjusted to 6 and ~he solution is applied to an Amberlite 120 H resin. Elution with 2 M ammonium hydroxide affords 2-acetylene-2-(2-amtnopropionamtdo)-5-aminopent-3-enoic acido EXAMPLE_28 Methyl~ t~ ene-2-amino-5-(2-aminopropionamido)pent-2-noate I y ro romi e an 2-acety ene-2-amlno-5-~2~amino-oroDionam laol ~ent-2-eno ic ac l A solution of 2.9 9 (10 mM) of mPthyl-2-acetylene-2-benzyloxycarbonylamino-5-aminopent-3-enoate in 40 ml of dichloromethane is treated with 2020 mg (10 mM) of N-car-bobenzoxyalanine and 2.1 9 ~10 m~) of N,N'-uioyclohexyl carbodiimide for about 15 hours at 25C after which the 5 0 r ~ lZl 37 5 Ml-913 solutlon is cooled to 0C and the precipitated dicyclo^
hexylurea fil~ered off. The filtrate is diluted with 20 ml of dichloromethane and washed with 1 N hydrochlorîc acidJ
wat~r and aqueous sodium bicarbonate~ then dried and con-centrated. The resulting residue is treated with 40 ml of a 40% (w/w) solutTon of hydrogen bromide in dioxane at 25C for 30 minutes then diluted with ether. The precipi-tate is collected to afford methyl 2-ace~ylene-2-amino-5-(2-aminopropionamido)pent-2-enoate dihydrobromide. The methyl ester dihydrobromide is treated with 40 ml of 2 N
sodium hydroxtde for 4 hours at 25C. The pH of the solu-tion is adjusted to 6 and applied to an Amberlite resin 120 H~. Elution with 2 M ammonium hydroxide affords 2-acetylene-2-amino-5~(2-aminopropionamido)pent-2~enolc acid.
When R is a straigh~ or branched alkoxy group of from 1 to 8 carbon atoms, reacting an acid halide of the corres-ponding derivative wherein R is hydroxy with an~alcohol of the formula R8-OH wherein R8 is a straight or branched alkyl group having from 1 to 8 carbon atoms, saturated~wlth HCl gas at about 25'C for from 12 to ~6 hours~

.
~51~

Claims (16)

M1-913 Ca.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the Formula wherein A is methylene, ethylene or ethylidene; R1 is -CH=CH2 or -C?CH; R2 is hydrogen or COR wherein R is hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, -NR4R5 wherein each of R4 and R5 is hydrogen or a straight or branched lower alkyl group of from 1 to 4 carbon atoms, or wherein R6 is hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl or p-hydroxybenzyl; Ra is hydrogen, alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched, alkoxycarbonyl wherein the alkoxy moiety has from 1 to 4 carbon atoms, and is straight or branched or wherein R7 is hydrogen, a straight or branched lower alkyl M1-913 Ca.

group of from 1 to 4 carbon atoms, benzyl or p-hydroxy-benzyl; and Rb has the same meaning as defined for Ra except Rb is not and Ra and Rb can be the same or different; with the provisos that when R2 is hydrogen, R1 is -C?CH; when A is ethylidene, R2 is hydrogen; and when Ra is , A is methylene; and pharmaceutically accept-able salts thereof; which comprises (a) when each of R2, Ra and Rb is hydrogen and A is methylene or ethylidene treating one equivalent of a suitably protected propargylamine derivative of the formula (R8)3-Si-C?C-CH2-N=CHR9 wherein R8 is C1-4,alkyl or triethylmethyl and R9 is phenyl, (CH3)3C- or (CH3CH2)3C-, with a suitable strong base, optionally in the presence of a divalent metal cation, alkylating the thus formed protected pro-pargylamine carbanion intermediate with 2-propenal or 2-butenal, acylating the alkylated derivative with an appro-priate acid halide, lower alkyl haloformate or tert-butoxycarbonylazide followed by hydrolysis to give an amide or carbamate which is treated with a suitable base to give the carboxamide which is treated with trichloroacetonitrile in a suitable solvent in the presence of a catalytic amount of base at about -30° to 0°C for about 1/2 hour to 3 hours to give the trichloromethylimidate ester which is heated MI-913 Ca.

to about 110° to 140°C in a non-polar solvent for about 1 to 10 hours to give the trichloromethylacetamide which is hydrolyzed using aqueous acid or base, said alkylating and acylating reactions being carried out in an aprotic solvent at about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when each of R2, Ra and Rb is hydrogen and A is ethylene, treating 1-hydroxypent-2-enal with a metal acetyl-ide of the formula HC?CM' wherein M' is sodium, lithium or MgX' wherein X' is chlorine or bromine or with a complex of lithium acetylide/ethylenediamine in a suitable solvent at about -30° to 25°C for about 1 minute to 3 hours to give hept-3-en-6-yne-1,5-diol which is treated with phthalimide, triphenylphosphine and diethyl diazodicarboxylate in ether solvents for about 1 to 12 hours at about 25° to 50°C to give the diphthalimido derivative which is treated with hydrazine hydrate in a lower alcohol solvent for about 1 to 6 hours at about 25° to 50°C followed by acid hydrolysis;
(c) when R2 is COR wherein R is hydroxy, R1 is -C?CH
and each of Ra and Rb is hydrogen, treating the correspond-ing derivative wherein R2 is hydrogen and the amino and acetylene groups are suitably protected as follows wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or triethylmethyl and n is 1 or 2, with a suitable strong base and acylating the thus formed carbanion inter-mediate with a suitable acylating reagent in an aprotic solvent at about -120°C to about 25°C for about 1/2 hour to 24 hours followed by acid or base hydrolysis;

M1-913 Ca.

(d) when R2 is COR wherein R is hydroxy, R1 is -CH=CH2, and each of Ra and Rb is hydrogen, treating the corresponding derivative wherein R1 is -C?CH with a suit-able alkali metal in liquid ammonia and ammonium sulfate at about -70° to 25°C until the blue color persists for about 15 minutes or by reducing the corresponding deriva-tive wherein R1 is -C?CH, each of Ra and Rb is alkylcarbon-yl and R2 is COR wherein R is alkoxy by catalytic or organic semi-hydrogenation;

(e) when Ra is , R2 is hydrogen or COR wherein R is hydroxy and Rb has the meaning defined in the generic formula, treating a compound of the formula wherein R1 and Rb have the meanings defined in the generic formula and R3 is hydrogen or COOalkyl wherein the alkyl moiety has from 1 to 8 carbon atoms and is straight or branched wherein any free amino group is suitably protected by a benzyloxycarbonyl group or by reaction with an appropriate alkylisothiouronium salt, in the presence of a base at a pH of about 10 and a temperature of about 25°C for about 6 to 60 hours fol-lowed by neutralization and acid hydrolysis when appro-priate to remove any protecting group;

MI-913 Ca.

(f) when Ra or Rb is alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms and R2 is hydrogen or COR wherein R is hydroxy, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably protected by a benzyloxycarbonyl group or as an alkylisothiouronium salt or Rb is other than hydrogen with an acid halide of the formula wherein halo is a halogen atom and R13 is a straight or branched alkyl group of from 1 to 4 carbon atoms, or an appropriate acid anhydride, in water in the presence of a base at about 0° to 25°C for about 1/2 hour to 6 hours;
(g) when Ra or Rb is alkoxycarbonyl wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably protected or Rb is other than hydrogen with a halo alkylformate of the formula wherein halo is a halogen atom and R14 is a straight or branched alkyl group having from 1 to carbon atoms in water in the presence of a base at about 0° to 25°C for 1/2 hour to 6 hours;

(h) when Ra or Rb is wherein R7 has the meaning defined in the generic formula, treating the cor-responding derivative wherein Ra or Rb is hydrogen or is suitably protected or Rb is other than hydrogen with an MI-913 Ca.

acid of the formula or an anhydride thereof wherein the amino group is suitably protected and R7 has the meaning defined above in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed at about 0° to 35°C for about 1 to 12 hours followed by base hydrolysis;

(i) when R is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting an acid halide of the corresponding derivative wherein R is hydroxy with an alcohol of the formula R8-OH wherein R8 is a straight or branched alkyl group having from 1 to 8 carbon atoms, saturated with HCl gas at about 25°C for from 12 to 36 hours;
(j) when R is -NR4R5 treating an acid halide of the corresponding derivative wherein R is hydroxy and Ra and Rb have the meaning defined in the generic formula with the proviso that any free amino group is suitably protected with an excess of an amine of the formula HNR4R5 wherein R4 and R5 have the meanings defined in the generic formula or hexamethylenetetramine in a suitable solvent at about 25°C for about 1 to 4 hours followed by acid hydrolysis when appropriate to remove any protecting group;
(k) when R is wherein R6 has the meaning defined in the generic formula, treating the corresponding derivative wherein R is hydroxy or a functional derivative M1-913 Ca.

thereof and Ra and Rb have the meanings defined in the generic formula with the proviso that any free amino group is suitably protected with a compound of the formula , wherein R6 has the meaning defined above and R12 is a lower alkyl group followed by acid and base hydrolysis with the proviso that when the free acid is employed the reaction is carried out with a dehydrating agent; and (1) when a pharmaceutically acceptable salt is desired reacting the thus obtained compound with a pharmaceutically acceptable acid base.

2. A compound of the formula wherein Ra, Rb, A, R1 and R2 have the meanings defined in claim 1 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 1.

3. The process of claim 1 wherein Ra and/or Rb is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched which comprises (a) when each of R2, Ra and Rb is hydrogen and A is methylene or ethylidene treating one equivalent of a suit-ably protected propargylamine derivative of the for-mula (R8)3-SiC?C-CH2 N=CHR9 wherein R8 is C1-4 alkyl M1-913 Ca.

or triethylmethyl and R9 is phenyl, (CH3)3C- or (CH3CH2)3C-, with a suitable strong base, optionally in the presence of a divalent metal cation, alkylating the thus formed protected propargylamine carbanion intermediate with 2-propenal or 2-butenal, acylating the alkylated derivative with an appropriate acid halide, lower alkyl haloformate or tert-butoxycarbonylazide followed by hydrolysis to give an amide or carbamate which is treated with a suitable base to give the carboxamide which is treated with trichloroacetonitrile in a suitable solvent in the presence of a catalytic amount of base at about -30° to 0°C for about 1/2 hour to 3 hours to give the trichloromethylimidate ester which is heated to about 110° to 140°C in a non-polar solvent for about 1 to 10 hours to give the trichloromethylacetamide which is hydro-lyzed using aqueous acid or base, said alkylating and acyla-ting reactions being carried out in an aprotic solvent at about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when each of R2, Ra and Rb is hydrogen and A is ethylene, treating 1-hydroxypent-2-enal with a metal acetyl-ide of the formula HC?CM' wherein M' is sodium, lithium or MgX' wherein X' is chlorine or bromine or with a complex of lithium acetylide/ethylenediamine in a suitable solvent at about -70° to 25°C for about 1 minute to 3 hours to give hept-7-en-6-yne-1,5-diol which is treated with phthalimide, triphenylphosphine and diethyl diazodicarboxylate in ether solvents for about 1 to 12 hours at about 25° to 50°C to give the diphthalimido derivative which is treated with M1-913 Ca.

hydrazine hydrate in a lower alcohol solvent for about 1 to 6 hours at about 25° to 50°C followed by acid hydrolysis;
(c) when R2 is COR wherein R is hydroxy, R1 is -C?CH
and each of Ra and Rb is hydrogen, treating the correspond-ing derivative wherein R2 is hydrogen and the amino and acetylene groups are suitably protected as follows wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or triethylmethyl and n is 1 or 2, with a suitable strong base and acylating the thus formed carbanion inter-mediate with a suitable acylating reagent in an aprotic solvent at about -120°C to about 25°C for about 1/2 hour to 24 hours followed by acid or base hydrolysis;
(d) when R2 is COR wherein R is hydroxy, R1 is -CH=CH2, and each of Ra and Rb is hydrogen, treating the corresponding derivative wherein R1 is -C?CH with a suit-able alkali metal in liquid ammonia and ammonium sulfate at about -70° to 25°C until the blue color persists for about 15 minutes or by reducing the corresponding deriva-tive wherein R1 is -C?CH, each of Ra and Rb is alkylcarbon-yl and R2 is COR wherein R is alkoxy by catalytic or organic semi-hydrogenation;
(e) when Ra or Rb is alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms and R2 is hydrogen or COR wherein R is hydroxy, treating the corresponding derivative wherein Ra or Rb is MI-913 Ca.
hydrogen or is suitably protected by a benzyloxycarbonyl group or as an alkylisothiouronium salt or Rb is other than hydrogen with an acid halide of the formula wherein halo is a halogen atom and R13 is a straight or branched alkyl group of from 1 to 4 carbon atoms, or an appropriate acid anhydride, in water in the presence of a base at about 0° to 25°C for about 1/2 hour to 6 hours;
(f) when R is a straight or branched alkoxy group of from 1 to o carbon atoms, reacting an acid halide of the corresponding derivative wherein R is hydroxy with an alcohol of the formula R8-OH wherein R8 is a straight or branched alkyl group having from 1 to 8 carbon atoms, saturated with HCl gas at about 25°C for from 12 to 36 hours;
(g) when R is -NR4R5 treating an acid halide of the corresponding derivative wherein R is hydroxy and Ra and Rb have the meanings defined in claim 1 with the proviso that any free amino group is suitably protected with an excess of an amine of the formula HNR4R5 wherein R4 and R5 have the meanings defined in claim 1 or hexamethylenetetramine in a suitable solvent at about 25°C for about 1 to 4 hours followed by acid hydrolysis when appropriate to remove any protecting group;
(h) when R is wherein R6 has the meaning defined in claim 1, treating the corresponding derivative wherein R is hydroxy or a functional derivative thereof MI-913 Ca.

and Ra and Rb have the meanings defined in claim 1 with the proviso that any free amino group is suitably protected with a compound of the formula herein R8 has the meaning defined above and R12 is a lower alkyl group followed by acid and base hydrolysis with the proviso that when the free acid is employed the reaction is carried out with a dehydrating agent;
and (i) when a pharmaceutically acceptable salt is desired reacting the thus obtained compound with a pharmaceutically acceptable acid or base.

4. A compound of the formula wherein Ra and/or Rb is hydrogen or alkylcarbonyl wherein the alkyl moiety has from 1 to 4 carbon atoms and is straight or branched and A, R1 and R2 have the meanings defined in claim 3 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 3.

5. The process of claim 1 which comprises (a) when each of R2, Ra and Rb is hydrogen and A is methylene or ethylidene treating one equivalent of a suit-ably protected propargylamine derivative of the formula (R8)3-Si-C?C-CH2-N=CHR9 wherein R8 is C1-4 alkyl or tri-ethylmethyl and R9 is phenyl, (CH3)3C- or (CH3CH2)3C-, MI-913 Ca.

with a suitable strong base, optionally in the presence of a divalent metal cation, alkylating the thus formed protec-ted propargylamine carbanion intermediate with 2-propenal or 2-butenal, acylating the alkylated derivative with an appro-priate acid halide, lower alkyl haloformate or tert-butoxycar-bonylazide followed by hydrolysis to give an amide or carbamate which is treated with a suitable base to give the carboxamide which is treated with trichloroacetonitrile in a suitable solvent in the presence of a catalytic amount of base at about -30° to 0°C for about 1/2 hour to 3 hours to give the trichloromethylimidate ester which is heated to about 110° to 140°C in a non-polar solvent for about 1 to 10 hours to give the trichloromethylacetamide which is hydro-lyzed using aqueous acid or base, said alkylating and acylating reactions being carried out in an aprotic solvent at about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when each of R2, Ra and Rb is hydrogen and A is ethylene, treating 1-hydroxypent-2-enal with a metal acetyl-ide of the formula HC?CM' wherein M' is sodium, lithium or MgX1 wherein X1 is chlorine or bromine or with a complex of lithium acetylide/ethylenediamine in a suitable solvent at about -30° to 25°C for about 1 minute to 3 hours to give hept-3-en-6-yne-1,5-diol which is treated with phthalimide, triphenylphosphine and diethyl diazodicarboxylate in ether solvents for about 1 to 12 hours at about 25° to 50°C to give the diphthalimido derivative which is treated with hydrazine hydrate in a lower alcohol solvent for about 1 to 6 hours at about 25° to 50°C followed by acid hydrolysis;

MI-913 Ca.

(c) when Ra is , R2 is hydrogen and Rb has the meaning defined in claim 1, treating a compound of the formula wherein R1 and Rb have the meanings defined in claim 1 and R3 is hydrogen wherein any free amino group is suitably protected by a benzyloxycarbonyl group or by reaction with an appropriate alkylisothiouronium salt, in the the presence of a base at a pH of about 10 and a temperature of about 25°C for about 6 to 60 hours followed by neutraliza-tion and acid hydrolysis when appropriate to remove any protecting group;
(d) when Ra or Rb is alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms and R2 is hydrogen or COR wherein R is hydroxy, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably protected by a benzyloxycarbonyl group or as an alkylisothiouroniumsalt or Rb is other than hydrogen with an acid halide of the formula wherein halo is a halogen atom and R13 is a straight or branched alkyl group of from 1 to 4 carbon atoms, or an appropriate acid anhydride, in water in the presence of a base at about 0° to 25°C for about 1/2 hour to 6 hours;

MI-913 Ca.

(e) when Ra and Rb is alkoxycarbonyl wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably protected or Rb is other than hydrogen with a halo alkylformate of the formula 4 wherein halo is a halogen atom and R14 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base at about 0° to 25°C for 1/2 hour to 6 hours;

(f) when Ra or Rb is wherein R7 has the meaning defined in claim 1, treating the corresponding derivative wherein Ra or Rb is a hydrogen or is suitably pro-tected or Rb is other than hydrogen with an acid of the formula or an anhydride thereof wherein the amino group is suitably protected and R7 has the meaning defined above in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed at about 0° to 35°C for about 1 to 12 hours followed by base hydrolysis; and (g) when a pharmaceutically acceptable salt is desired reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.

6. A compound of the formula MI-913 Ca.

wherein R2 is hydrogen, and Ra, Rb, R1 and A have the mean-ings defined in claim 5 when prepared by the process of claim 5.

7. The process of claim 1 which comprises (a) when R2 is COR wherein R is hydroxy, R1 is -C?CH and each of Ra and Rb is hydrogen, treating the corresponding derivative wherein R2 is hydrogen and the amino and acetylene groups are suitably protected as follows wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or tri-ethylmethyl and n is 1 or 2, with a suitable strong base and acylating the thus formed carbanion intermediate with a suitable acylating reagent in an aprotic solvent at about -120°C to about 25°C for about 1/2 hour to 24 hours followed by acid or base hydrolysis;
(b) when R2 is COR wherein R is hydroxy R1 is -CH=CH2, and each of Ra and Rb is hydrogen, treating the corresponding derivative wherein R1 is -C?CH with a suitable alkali metal in liquid ammonia and ammonium sulfate at about -70° to 25°C until the blue color per-sists for about 15 minutes or by reducing the corres-ponding derivative wherein R1 is -C?CH, each of Ra and Rb is alkylcarbonyl and R2 is COR wherein R is alkoxy by catalytic or organic semi-hydrogenation;

MI-913 Ca.

(c) when Ra is , R2 is hydrogen or COR wherein R is hydroxy and Rb has the meaning defined in claim 1 treating a compound of the formula wherein R1 and Rb have the meanings defined in claim 1 and R3 is hydrogen or COOalkyl wherein the alkyl moiety has from 1 to 8 carbon atoms and is straight or branched wherein any free amino group is suitably protected by a benzyloxycarbonyl group or by reaction with an appropriate alkylisothiouronium salt, in the presence of a base at a pH of about 10 and a temperature of about 25°C
for about 6 to 60 hours followed by neutralization and acid hydrolysis when appropriate to remove any protecting group;
(d) when Ra or Rb is alkylcarbonyl wherein the alkyl moiety is straight or branched and has from 1 to 4 carbon atoms and R2 is hydrogen or COR wherein R is hydroxy, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably protected by a benzyloxycarbonyl group or as analkylisothiouronium salt or Rb is other than hydrogen with an acid halide of the formula wherein halo is a halogen atom and R13 is a straight or branched alkyl group of from 1 to 4 carbon atoms, or an MI-913 Ca.

appropriate acid anhydride, in water in the presence of a base at about 0° to 25°C for about 1/2 hour to 6 hours;
(e) when Ra or Rb is alkoxycarbonyl wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably protected or Rb is other than hydrogen with a halo alkylformate of the formula wherein halo is a halogen atom and R14 is a straight or branched alkyl group having from 1 to 4 carbon atoms in water in the presence of a base at about 0° to 25°C for 1/2 hour to 6 hours;

(f) when Ra or Rb is wherein R7 has the meaning defined in claim 1, treating the corresponding derivative wherein Ra or Rb is hydrogen or is suitably pro-tected or Rb is other than hydrogen with an acid of the formula or an anhydride thereof wherein the amino group is suitably protected and R7 has the meaning defined above in a suitable solvent and in the presence of a dehydrating agent when the free acid is employed at about 0° to 35°C for about 1 to 12 hours followed by base hydrolysis;
(g) when R is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting an acid halide of the corresponding derivative wherein R is hydroxy with an MI-913 Ca.

alcohol of the formula R8-OH wherein R8 is a straight or branched alkyl group having from 1 to 8 carbon atoms, saturated with HCl gas at about 25°C for from 12 to 36 hours;
(h) when R is -NR4R5 treating an acid halide of the corresponding derivative wherein R is hydroxy and Ra and Rb have the meanings defined in claim 1 with the proviso that any free amino group is suitably protected with an excess of an amine of the formula HNR4R5 wherein R4 and R5 have the meanings defined in claim 1 or hexamethylenetetramine in a suitable solvent at about 25°C for about 1 to 4 hours followed by acid hydrolysis when appropriate to remove any protecting group;
(i) when R is wherein R6 has the meaning defined in claim 1, treating the corresponding derivative wherein R is hydroxy or a functional derivative thereof such as an acid anhydride and Ra and Rb have the meanings defined in claim 1 with the proviso that any free amino group is suitably protected with a compound of the formula wherein R6 has the meaning defined above and R12 is a lower alkyl group followed by acid and base hydrolysis with the proviso that when the free acid is employed the reaction is carried out with a dehydrating agent; and (j) when a pharmaceutically acceptable salt is desired reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.

MI-913 Ca.

8. A compound of the formula wherein R2 is COR and R, R1, Ra, Rb and A have the meanings defined in claim 7 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 7.

9. The process of claim 1 wherein each of Ra and Rb is hydrogen or Ra is , and R2 is hydrogen or COR
wherein R is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms which comprises (a) when R2 is hydrogen and A is methylene or ethylidene treating one equivalent of a suitably pro-tected propargylamine derivative of the formula (R8)3-Si-C?C-CH2-N=CHR9 wherein R8 is C1-4 alkyl or triethylmethyl and R9 is phenyl, (CH3)3C- or (CH3CH2)3C-, with a suitable strong base, optionally in the presence of a divalent metal cation, alkylating the thus formed protected propargylamine carbanion inter-mediate with 2-propenal or 2-butenal, acylating the alkyl-ated derivative with an appropriate acid halide, lower alkyl haloformate or tert-butoxycarbonylazide followed by hydrolysis to give an amide or carbamate which is treated with a suitable base to give the carboxamide which is treated with trichloroacetonitrile in a suitable solvent in the presence of a catalytic amount of base at about MI-913 Ca.

-30° to 0°C for about 1/2 hour to 3 hours to give the trichloromethylimidate ester which is heated to about 110° to 140°C in a nonpolar solvent for about 1 to 10 hours to give the trichloromethylacetamide which is hydrolyzed using aqueous acid or base, said alkylating and acylating reactions being carried out in an aprotic solvent at about -125° to 25°C for about 1/2 hour to 24 hours;
(b) when R2 is hydrogen and A is ethylene, treating 1-hydroxypent-2-enal with a metal acetylide of the formula HC?CM' wherein M' is sodium, lithium or MgX' therein X' is chlorine or bromine or with a complex of lithium acetylide/
ethylenediamine in a suitable solvent at about -30° to 25°C
for about 1 minute to 3 hours to give hept-3-en-6-yne-1,5-diol which is treated with phthalimide, triphenylphosphine and diethyl diazodicarboxylate in ether solvents for about 1 to 12 hours at about 25° to 50°C to give the diphthalimido derivative which is treated with hydrazine hydrate in a lower alcohol solvent for about 1 to 6 hours at about 25°
to 50°C followed by acid hydrolysis;
(c) when R2 is COR, R1 is -C?CH and each of Ra and Rb is hydrogen, treating the corresponding derivative wherein R2 is hydrogen and the amino and acetylene groups are suitably protected as follows wherein R10 is C1-4 alkyl, R11 is phenyl, t-butyl or tri-ethylmethyl and n is 1 or 2, with a suitable strong base and acylating the thus formed carbanion intermediate with a suit-able acylating reagent in an aprotic solvent at about -120°C

MI-913 Ca.

to about 25°C for about 1/2 hour to 24 hours followed by acid or base hydrolysis;
(d) when R2 is COR R1 is -CH=CH2, and each of Ra and Rb iS hydrogen, treating the corresponding derivative wherein R1 is -C-CH with a suitable alkali metal in liquid ammonia and ammonium sulfate at about -70° to 25°C
until the blue color persists for about 15 minutes or by reducing the corresponding derivative wherein R1 is -C?CH, each of Ra and Rb is alkylcarbonyl and R2 is COR wherein R
is alkoxy by catalytic or organic semi-hydrogenation;

(e) when Ra is treating a compound of the formula wherein R1 and Rb have the meanings defined in claim 1 and R3 is hydrogen or COOalkyl wherein the alkyl moiety has from 1 to 8 carbon atoms and is straight or branched wherein any free amino group is suitably protected by a benzyloxycarbonyl group or by reaction with an an appropriate alkylisothiouronium salt, in the presence of a base at a pH of about 10 and a temperature of about 25°C
for about 6 to 60 hours followed by neutralization and acid hydrolysis when appropriate to remove any protecting group;
(f) when R is a straight or branched alkoxy group of from 1 to 8 carbon atoms, reacting an acid halide of the MI-913 Ca.

corresponding derivative wherein R is hydroxy with an alcohol of the formula R8-OH wherein R8 is a straight or branched alkyl group having from 1 to 8 carbon atoms, saturated with HCl gas at about 25°C for from 12 to 36 hours;
and (g) when a pharmaceutically acceptable salt is desired reacting the thus obtained compound with a pharma-ceutically acceptable acid or base.

10. A compound of the formula wherein each of Ra and Rb is hydrogen or Ra is R2 is hydrogen or COR wherein R is hydroxy or a straight or branched alkoxy group of from 1 to 8 carbon atoms and A and R1 have the meanings defined in claim 9 or a pharmaceutical1y acceptable salt thereof when prepared by the process of claim 9.

11. A process for preparing 1,4-hex-2-en-5-ynediamine or a pharmaceutically acceptable salt thereof which comprises treating one equivalent of a suitably protected propargyl-amine derivative of the formula (CH3)3-Si-C?C-CH2-N=CHR9 wherein R9 is phenyl, (CH3)3C- or (CH3CH2)3C-, with a suitable strong base, optionally in the presence of a divalent metal cation, alkylating the thus formed protected propargylamine carbanion intermediate MI-913 Ca.

with 2-propenal acylating the alkylated derivative with an appropriate acid halide, lower alkyl haloformate or tert-butoxycarbonylazide followed by hydrolysis to give an amide or carbamate of 1-amino-1-trimethylsilylacetylenebut-3-en-2-ol which is treated with a suitable base to give the carboxamide of 4-aminohex-1-en-5-yn-3-ol which is treated with trichloroacetonitrile in a suitable solvent in the presence of a catalytic amount of base at about -30° to 0°C
for about 1/2 hour to 3 hours to give the trichloromethyl-imidate ester which is heated to about 110° to 140°C in a nonpolar solvent for about 1 to 10 hours to give the tri-chloromethylacetamide which is hydrolyzed using aqueous acid or base, said alkylating and acylating reactions being carried out in an aprotic solvent at about -125° to 25°C for about 1/2 hour to 24 hours; and when a pharma-ceutically acceptable salt is desired reacting the thus obtained compound with a pharmaceutically acceptable acid.

12. The compound 1,4-hex-2-en-5-ynediamine or a pharmaceutically acceptable salt thereof when prepared by the process of claim 11.

13. A process for preparing 2,5-hept-3-en-6-ynedi-amine or a pharmaceutically acceptable salt thereof which comprises treating 1-hydroxypent-2-enal with a metal acetylide of the formula HC?CM' wherein M' is sodium, lithium or MgX' wherein X' is chlorine or bromine or with a complex of lithium acetylide/ethylenediamine in a suit-MI-913 Ca.

able solvent at about -30° to 25°C for about 1 minute to 3 hours to give hept-3-en-6-yne-1,5-diol which is treated with phthalimide, triphenylphosphine and diethyl diazo-dicarboxy1ate in ether solvents for about 1 to 12 hours at about 25° to 50°C to give the diphthalimido derivative which is treated with hydrazine hydrate in a lower alcohol solvent for about 1 to 6 hours at about 25° to 50°C followed by acid hydrolysis; and when a pharmaceutically acceptable salt is desired reacting the thus formed compound with a pharmaceutically acceptable salt.

14. The compound 2,5-hept-3-en-6-ynediamine or a pharmaceutically acceptable salt thereof when prepared by the process of claim 13.

15. A process for preparing a compound of the formula wherein A is methylene, R1 is -C?CH, R2 is COOH and each of Ra and Rb is hydrogen which comprises treating 1 equiva-lent of a carbamate of 1-amino-1-trimethylsilylacetylenebut-3-en-2-ol with 1 equivalent of trichloroacetonitrile in a suitable solvent in the presence of a catalytic amount of base at about -30° to 0°C for about 1/2 hour to 3 hours to give the trichloromethylimidate ether which is heated to about 110° to 140°C in a non-polar solvent for about 1 to 10 hours to give the trichloromethylacetamide which is MI-913 Ca.

treated with trifluoroacetic acid followed by treatment with 1 equivalent of benzaldehyde to give N-(4-benzylimino-4-trimethylsilylacetylenebut-2-enyl)trichloromethyl-acetamide which is treated with 2 equivalents of a strong base, acylated with a suitable acylating reagent and sub-sequently hydrolyzed using aqueous acid.

16. The compound of the formula wherein Ra, A, Rb, R1 and R2 have the meanings defined in claim 15 or a pharmaceutically acceptable salt thereof when prepared by the process of claim 15.