CA1088562A - Acetylene derivatives of amino acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE A process for preparing (+) 4-amino-5-yne-hexanoic acid, or a pharmaceutically acceptable salt thereof, by reacting 4-amino-5-yne-hexanoic acid with (+) binaphthyl-phosphoric acid.

Description

~U~8S~

BACKGROUND OF THE INVENTION ~-. .
Several previous studies have shown that y-aminobutyric acid is a major inhibitory transmitter of the centrat nervous system as reported, for example, by r. Godin et al., Journal Neurochemistry, 16, 869 (1969) and that disturbance of the excitation and inhibition interplay can lead to diseased states such as Huntington's chorea (The Lancet, November 9, ~ -1974, pp. 1122-1123) Parkinsonism, schizophrenia, epilepsy, depression, hyperkinesis ant manic depression disorders, Biochem. Pharmacol. 23, 2637-2649 (1974). Certain compounds are known to elevate brain leve1s of y-aminobutyric acid, -for examp1e, n-dipropylacetate [Simler et al., Biochem.
Pharm., 22, 1701 (1973)] by competitively inhibiting -y-aminobutyric acid transaminase result7ng in a reversible effect which lasts for only about 2 hours. Also, 4-amino-tetrolic acid [P.M. Beart et al., J. Neurochem. 19, 1849 (1972)J is known to be a competitive revers7ble inhTbitor of y-aminobutyric acid transaminase. We have now made the - ~-unexpected fIndtng that compounds of our invention are able to irreversibly inhibit y-aminobutyric acid transaminase and increase significantly the brain level of y-aminobutyric acid in animals, rendering them useful in the treatment of the aforementioned diseased states. Furthermore, this ;ncrease is long lasting (over 2~ hours~ and, therefore, compounds of the present invention are not only structurally novel but are quite different in their properties from -known compounds which elevate brain levels of y-aminobutyric acid only for a short period of time.
SUMMARY OF THE INVENTION
The compounds of the present invention may be repre----1-- , .

10~ Z

sented by the following ~eneral Formula l:
O
Hc--c-clH-[A]-c-R2 NHR Formula I
R is selected from hydrogen, alkylcarbonyl wherein the .
alkyl moiety contalns from 1 to 4 carbon atoms, alkoxy-carbonyl where;n the alkoxy moiety contains from 1 to 4 carbon atoms and may be straight or branched, and O -, -C-CH-R1o wherein Rlo is selected from hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl and p-hydroxybenzyl; R2 is selec~ed from hydroxy, a straight or branched alkoxy group of from 1 to 8 carbon atoms, a lower alkylamino group wherein the alkyl moiety contalns from 1 to 4 carbon atoms and -NH-ICH-COOH wherein R~
R~
Is selected from hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, benzyl, and - . IR~
p-hydroxybenzyl; [A~ is selected from (-CH-)n and -CH--CH-whereln R~ is selected from hydrogen, lower alkyl of from 1 to 4 carbon atoms, phenyl and substituted phenyl wherein the substituents on the substituted phenyl may be attached at the ortho, meta and para positions of the phenyl ring and are selected from halogen, lower alkoxy of from 1 to 4 carbon atoms, and lower alkyl of from 1 to 4 carbon atoms;
: n is an integer of from 1 to 5; and the lactams of said compounds wherein tA~ represents (-CH-)n; R and R1 represent hydrogen and n is the integer 2 or 3; and pharmaceutically acceptable salts and individual optical isomers thereof.
;-, . .

~8~5~2 The compounds of general Formula I are useful as seda-tives. The compounds of general Formula I whereTn [A]
R~
represents -CH=CH- and (-CH-) wherein R~ is hydrogen, and n is an integer of from 1 to 5, that is, compounds of the following general Formula Il and the lactams of the com-pounds of Formula 11 wherein [A'] represents (-CH2-)n and n Js the integer 2 or 3, as represented b~ Formula tlI, are useful as Inhibltors of y-aminobutyrTc acid transaminase resulting in an increase in brain levels of y-amtnobutyric .10 actd rendering the compounds useful Tn the treatment of disorders of the central nervous system functTon consisting ~ ~-of Tnvoluntary movement assocTated wTth Huntlngton's chorea, ParklnsonTsm, extrapyramidal effects of drugs, for ;-~
example, neuroleptlcs, seTzure disorders associated with eptlepsy, alcohol wTthdrawal, barbiturate wlthdrawal, psychoses assoctated wlth schTzophrenla, depresslon, manlc depression, and hyperkinesTs. Compounds of this 7nvention ! -~
are also useful as hypothermTc agents, myorelaxants, cholInergic agents, antTbacterial agents, anticonvulsant agents, analgesTcs, anorexigenTc agents, antiobeslty agents, tranquTlizers, sedatTves and centra1 nervous system stimu-lants. 0 HC-C-CH-[A']-C-Rz NHR Formula 11 ;
, In the above Formula II the substituent ~roups R and R2 ' -have the meanTngs defined in general Formuta 1, and ~A~] -Ts selected from -CH=CH- and (-CH2-)n whereTn n is an integer of from 1 to 5; and pharmaceutica11y acceptable szlts and individual optlcal isomers; -`

~- '` 10~85t;2 ( ( HC3C-CH-(CH2)n,_,,,C=O

H2N Formula III
In the above Formula III n' is the integer 2 or 3; and pharmaceut;cally acceptable salts and indivTdual optical isomers thereof.
DETAILED DESCR!PTION OF INVENT!ON
As used herein the term lower alkylcarbonyl means the - substituent group -C-(lower)alkyl.
As used herein the term alkoxycarbonyl means the sub-stTtuent group -C-O-(lower)alkyl wherein the lower alkyl moiety may be straTght or branched.
Illustrative examples of straight chain lower alkyl ~ -groups of from 1 to ~ carbon atoms referred to herein are methyl, ethyl, n-propyl and n-butyl, and of branched chaln lower alkyl groups of from 1 to 4 carbon atoms are Isopropyl, isobutyl, and tert-butyl.
Illustratlve examples of straight chain lower alkoxy -groups of from 1 to 4 carbon atoms as used herein are methoxy, ethoxy, n-propoxy and n-butoxyj and of branched chain lower alkoxy groups of from 1 to ~ carbon atoms are isopropoxy, isobutoxy, and tert-butoxy.
Illustrative examples of straight or branched alkoxy groups of from 1 to 8 carbon atoms as used herein are -~ethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-~utoxy, neopentoxy, pentoxy, octyloxy, heptyloxy and hexyloxy.
Illustrative examples of lower alkylamino groups which R2 ~ay represent are methylamino, ethylamino, n-propylamino and n-butylamino Illustrative examples of phanmaceutically acceptable s2l tS of the compounds of this invention include non-tox;c ~EU~5~2 acid addition salts formed with inorganic acids, such as, hydrochloric, hydrobromic, sulfuric and phosphoric acid, and organic acids such as methane su1fonic, salicylic, maleic, malonic, tartar7c, citrtc and ascorbic ac7ds; and non-toxic salts formed with inorganic or organic bases such as those of alkalt metals, for example, sodium, potassium and lTthium, alkaltne earth metals, for example, calcium -and magnesium, light metals of Group lll A, for example, aluminum; organic amines such as primary, secondary or tertlary amines, for example, cyclohexylamlne, ethylamine, pyridlne, methylaminoethanol, ethanolamine, and plperazlne.
The salts can be prepared by conventional means. -The compounds of this inventlon wherein [A~ represents s-the ~roup (-CH-)n can be represented by the following Formula IV~
HC=C-CH-(CH)nC-Rz NHR Formula IY
wherein the substituents R, R~, R2 and n have the meanings defined in general Formula 1. -~
The compounds of thls inventlon wherein ~A] represents -C~=CH- can be represented by the following Formula V: -Hc--c-cH-cH=cH-c-R2 NHR Formula Y
wherein the substituents R and R2 have the meanings defined .
in general Formula 1.
The lactams wh7ch are included within the scope of ' ~5 this invention are represented by the compounds of general Fo~mula lll, described hereinabove.
- Illustrative examples of compounds of this invention are the following:

- ; -5-' ' ~( 3-amino-4-yne-pentanoic acid, 4-amino-5-yne-hexanoic acid, 7-amino-8-yne-nonano!c acid, ;
6-amino-3-ethyl-7-yne-octanoic acid, 4-am7no-2-(p-anlsyl)-5-yne-hexanoic acid, 5-amino-3-(p-anisyl)-6-yne-heptanolc acid, N-methyl-(2-amTno-3-yne-butan-1-yl)carbox-amide, 4-amtno-3-phenyl-5-yne-hexanoic acTd, 4-amino-5-yne-1-oxo-hexan-1-ylaminoacetic aci d, ; . -, 5-methoxycarbonylamino-6-yne-heptanoic acid, ;~
~-amino-4-yne-pentanoic acid methyl ester, 4-amino-2-ene-5-yne-hexanoic acid, 4-acetylamino-5-yne-hexanoTc acid Preferred compounds of this invention are those of general Formula 11. More preferred compounds of this in- ;-~
ventlon are those of general Formula 1I wherein the sub-st1tuent group R2 is hydroxy or alkoxy of from 1 to 8 carbon atoms. Still more preferred compounds of this in-ventTon are those of general Formula ll wherein the substltuent group R2 Is hydroxy, and n Ts the integer 1 or ~- -

2. An even more preferred group of compounds of thls in-ventton are those of general Formu1a l1 wherein the sub-stituent group R2 ts hydroxy, n is an Integer of 1 or 2 and R is hydrogen. Of the preferred compounds of this Tnvention, the (I) isomers are the most preferred compounds.
The compounds of thls invention have a variety of pharmaco10gical utl1itles. The compounds of this inventlon are useful as sedatives. The compounds of general Formula ll are useful as tnhibitors of y-aminobutyric acld trans-aminase result7ng in an increase in brain levels of ~-aminobutyric acid rendering the compounds useful in the treatment of disorders of the central nervous system , , .

~o~ z function consisting of involuntary movement associated with Huntington's chorea, Parkinsonism, extrapyramidal effects of drugs, for example, neuroleptics, seizure disorders associated with epilepsy, alcohol withdrawal, and barbiturate withdrawal, psychoses associated with schizophrenia, de-pression and manic depression and hyperktnesis. Compounds of this invent7On are also useful as hypothermic agents, myorelaxants, cholInergic agents, antTbacterial agents, - , anticonvulsant agents, analgesics, anorexigenTc agents, lQ antiobesTty agents, tran~uilizers, sedati~es, and central -nervous system stimulants.
The sedat7ve properties of the compounds of this in-vention were determlned by measurlng spontaneous motor activity In rodents by the procedure descrlbed by P. Dews~ -BrTt. J. Pharmacol. 8, 46 (1953). For example, admTnTs-tration of between 100-200 mg/kg (mlllTgrams per kllogram) of the compound ~-am1no-5-yne-hexanolc acid by eTther the ~
Intravenous, Intraperitoneal or oral route to mice or rats v -produces a substanttally decreased motor activlty which appears 1 hour after adm;nistration of the compound and Ts still observable 48 hours a~tér adminlstratlon.
The abtltty of the compounds of general Formulas II and - -III to inhlbit y-aminobutyric acid transaminase is determined by in vitro and In vivo measure of y-aminobutyric acld trans-amlnase activity. y-Aminobutyric acid levels are markedly Tn-creased in mice and rat braTns after treatment with compounds of general Formula Il at doses between 25-200 mg/kg by paren-teral and oral routes. ~his ability is further shown by the protective effect of this treatment on audiogenTc seizures in mice of the D8A strain measured by the general _7_ 1(1~8S~;2 method described by Simler et al., Bio~hem. Pharmacol. 22, 1701 (1973), which is currently used to evidence anti-epileptic activity. For example, administration of between 50-200 mg/kg of 4-amino-5-yne-hexanoic acid to mice of the DBA strain whTch are susceptible to audiogenic seizures resulted in complete protection one hour after treatment, such protection lasting for over 16 hours.
The ability of the compounds of this ;nvention at doses ranging from 50 to 200 mg/kg, to alleviate reserpine ptosis has been shown by the classical test of B. Rubin et al., J. Pharmacol. 120, 125 (1957), which is currently used to determine antt-depressant activity. For instance, in intra-peritoneal injection of 50 mg/kg of 4-amino-5-yne-hexanoic acid in-mice, one hour after an intravenous tnjection of 2 mg/kg reserp7ne dissolved in 2% ascorbic acid/water results in a palpebral aperture of 5.5, 3 hours after drug adminis-tratton as compared to 6.5 for control reserplnized animals.
The ability of the compounds of this invention to promote loss of body weight in rats has been demonstrated by weighing animals which were given daily doses ranging from 10-50 mg/kg of these compounds. For instance, rats weighing 190 9, when given for four days, oral doses of 25 mg/kg 4-amino-5-yne-hexanoic acid (which is not a sedative dose) weigh only 170 gms as compared to 250 9 for animals of the same group which were given saline for the same period.
The compounds of this invention can be admtn;stered orally or parenterally to animals, particularly warm ~ -blooded animals and mammals and humans either alone or in the form of pharmaceutical preparations containing as the active ingredient compounds of this invention to achieve the ,,., , . . , .. ~ , , .

desired effect. Pharmaceutical preparations containing compounds of this invention and conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets, pills and capsules or liquid solu-tions, suspensions or elixirs for oral administration or liquid solutions, suspensions and emulsions for parenteral use. The quantity of compounds administered can vary over a wide range to provide from about 0.1 mg/kg to about 300 mg/kg of body weight of the patient per day, Unit doses of these compounds can cohtain, for example, from ~
about 50 mg to 2000 mg of the compounds and may be adminis- ~ -tered, for example, from 1 to 4 times daily. Following are illustrative examples of pharmaceutical preparations con-taining the compounds of this invention: -Per Tablet (a) 3-amino-~-yne-pentanoic acid 100.0 mg ~
(b) wheat starch 15.0 mg - ~-(c) lactose 33.5 mg (d) magnesTum stearate 1.5 mg A portion of the wheat starch is used to make a granulated starch paste which together with the remainder of the wheat starch and the lactose is granulated, screened and mixed with the active ingredient (a) and the magnesium stearate.
The mixture is compressed into tablets weighing 150 mg each. ;
An illustrative composition for a parenteral injection is the following, wherein the quantities are on a weight to volume basis: `
Amount (a) (I)4-amino-5-yne-hexanoic acid 100.0 mg ~30 (b) sodium chloride q.s.

g 5~2 ount (c) water for injection to make 20 ml The composition is prepared by dissolving the active Tn-gredient (a) and sufficient sodium chloride in water for injection to render the solution isotonic. The composition may be dispensed in a s7ngle ampule containing 100 mg of the active ingredient for multiple dosage or in 20 ampules for single dosage.
An illustrative composition for hard gelat7n capsules iS as follows:
Amount (a) ~-amino-4-yne-pentanoic acid 200.0 mg (b) talc 35.0 mg The composition is prepared by passing the dry powders of (a) and (b) through a fTne mesh screen and mixing them well.
The powder is then filled into No. O hard gelatin capsules at a net fill of 235 mg per capsule.
The compounds of general Formula I wherein R is hydro- `~
gen, and Rz ts other than -NH-CH-COOH are prepared by ~4 reacting a suitably protected propargylamine derivative, as represented by compound I below, with an alkylat7ng reagent in the presence of a base and subsequently unmasking the protected groups by treatment with acid or base as repre-sented by the following reaction:
(Rs)- Si-CaC-CH2 N=IC;R~ compound 1 BASE
. ~ ~

.

c - lO~Z

_ 1 ,~.' (Rs)- Si-C--C-CH( ) N=C-R~

1. alkylating reagent 2. acid or base -O
HC-(:-CH-~A3-C-R8 NHz --~
Formula VI
In the above reaction sequencé, ~A] has the meaning --defined in general Formula I; R~ ts selected from hydroxy, a straight or branched lower alkoxy of from 1 to 8 carbon atoms and a lower alkylamino group whereln the alkyl moiety contains from 1 to 4 carbon atoms; Rs ts selected from a lower alkyl group havlng from 1 to 4 carbon atoms, such as methyl, ethyl and n-propyl; R~ 7s selected from hydrogen and phenyl; and R7 is selected from phenyl, tert-butyl and - -tr7ethylmethyl In the above reaction, the protected propargylamine derivatlve compound I, Is treated with a strong base to form the carbanion intermedlate. Suitable strong bases are those which will abstract a proton from the carbon adjacent -to the acetylene moiety, such as, alkyl lithium, for example,-butyl lithium, or phenyl lithium, lithium dl-alkylamlde, , -for example, lithium diisopropylamide, llthium amTde, -~
tertiary potassium butylate, sodium amide and sodium ~ `~
hydroxide. ---~20 Following addition of the base, the alkylatlng reagent is added. The alkylating- reagents emp10yed in the above ~' ., ~ -11-~, ;

1~5~;Z

reaction are selected from derivatives having the struc-tures: Rl :
(A) when [A] is -(CH)- and n is equal to 2, Rl :
(HCIC)-z ~.

(B) when [A] is -(CH)- and n is equal to 1 or 3 to ~, Rl halo-(CH)- Z, or - .
Rl ,:
halo-(CH~mhalo and ~-(C) when [A] is -CH=CH-, haloCH=CHCOR~, or HC-C-C~R~
wherein Rl has the meaning defined in general Formula l; Z
O
is selected from cyano or -C-R~ ; R~ Is selected from .;.
a straight or branched alkoxy group of from 1 to 8 carbon .
atoms; m is the inte~er 1 or ~ to 5; and halo is iodine or bromtne.
When the alkylating reagent employed is the di-halo- -alkyl derivative as set.forth in ~8), subsequent to the alkylation reaction the w-halogen is displaced with cyanide, -and as when Z is cyano the reaction mixture is treated with an acid or base to hydrolyze the nitrile to the correspond-ing acid or amide derivative as represented by Formula Yl by procedures well known ir. the art. Similarly, the pro- ~.
tecting groups, that is, the acetylene and the amino protecting groups and the ester or amide functions, if desired, can be removed with aqueous acid, for example, hydrochloric or toluene sulfonic acid or a~ueous base, for lO~S~;Z

example, sodium hydroxide or potassTum hydroxide. The pro-tecting groups can also be removed by using hydrazine or -phenylhydrazine.
The alkylation reaction is carried out in an aprotic solventJ for example, benzeneJ toluene, ethersJ tetrahydro-furan, dimethylsulfoxide, dimethyl formamide, dimethyl acetamlde, hexamethyl phosphoramide and hexamethyl phosphor- r ~:
triamlde. The reaction temperature varies from -120C to ~`
about 25C, and a preferred reaction temperature is about --70C. The reaction time var7es from 1/2 hour to 24 hours. -The protected propargylamine derivatives, compound 1, are prepared by the addition of protectTng groups on the ~
acetylene function and the nitrogen function of propargyl- --amine.Protection ofthe nitrogen function of propargylamine is accomplished by forming in a known manner a Schiff's base with a non-enolizable carbonyl bearing compound, such as benzaldehyde, benzophenone, or trlalkylacetaldehyde.
Protectton of the acetylenlc function is accompllshed by reactlng the above described Schiff's base with trimethyl-sllylchloride, triethylsilylchloride or higher trialkyl-stlylchloride forming in a known manner (E.J, Corey and H.A. Kirst, Tetrahedron Letters, 1968, 5041) the corres-ponding trialkylsilyl derivatives.
The alkylating reagents employed in the above reaction are known in the art or can be prepared by procedures well ~- -known in the art. .
-`~ Compounds of this invention wherein R represents alkyl-~`~ carbony! are prepared ~rom the corresponding acid whereln R represents hydrogen us;ng the appropriate acid anhydride or halide of acetic ac;d, prop;onic acid, butyric acid or -, .

Sf~

valeric acid. ~he amide derivatTves can be isolated as the acid or a derivative thereof, for example, the ester by converting the acid to the acid halide, for example, by treating with thionyl chloride followed by alcoholysis, to give the appropriate ester by procedures generally known in the art.
Compounds of this invention wherein R represents ;
alkoxycarbonyl are prepared from the corresponding acid wherein R represents hydrogen using an appropriate alkyl chloroformate, for example, methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, n-butylchloroformate, isobutyl chloroformate or tert-butyl chloroformate, in the presence of a base by procedures well known in the art. -Compounds of general Formula I wherein R is - --C-CH-R1o are prepared by treating an ester of a compound of Formula i, wherein R is hydrogen wlth a protected acid of the formula HOOC-CH-RIo whereTn the amino functlon is protected with a suttable blocking group, such as, benzyloxycarbonyl or tert-butoxy-carbonyl. Either the free acid or a reactive der;vatiye thereof, for example, an actd anhydride may be employed.
When the free acid is used, a dehydrating agent such as N, N~-dicyclohexylcarbodiimide is used. The substituent 2~ R1O-has the meaning defined in general Formula 1.
Compounds of this invention wherein R2 represents -NH-CH-COOH are prepared from the corresponding acid deriva-R
. .

( ( 1(~885~;Z

tive wherein the amino function is protected with a suitable blocking group, such as, benzyloxycarbonyl or tert-butoxy- -carbonyl. The amino protected de;ivatives either as the free acid, in wh7ch case a dehydrating agent such as ~ ~-N, N'-dicyclohexylcarbodiimide is used, or a reactive derlva-tTve of the acid, such as, an acid anhydride, is reacted with a compound of the structure NH2-CH-COOR~ wherein R~ ~ -R~
has the meaning deflned in general Formula 1, and R~ is a lower alkyl group, for example, methyl, or ethyl, followed by base hydrolysis to remove the protectTng group by pro- - -cedures well known in the art.
The lactams of this invention, as described by general Formula lll, are prepared from the corresponding amino acld, that jSJ a compound of the formula --~
HC-C-CH-(CH2)n-~COOH
Htb ", or ester thereof wheretn n' is the 7nteger 2 or 3, by pro- ~ -cedures generally known in the art, for example, by treating .the amino acid with a dehydrating agent such as dicyclo-hexylcarbodiimide or by heating the appropriate ester derivative. ~ -~
;` The optical tsomers of the compounds of this invention may be separated by using a (+) or (-) binaphthylphosphoric acid derivative or a salt of said derivatlve and an optically active base by the method described by R. Yiterbo --~?5 et al., in Tetrahedron Letters 48, 4617-4620 (1971) and in U.S. patent 3,848,030.
"~. , The followlng spectfic examples are illustrative of - the compounds of this invention.

. . ' ' - ' , Example 1 PROPAN-1-YNE-3-I~INOBENZYL
A solution of propargylamine (26.~ 9, 0.47 M) and benzalde-hyde (52 9, 49 M) in benzene (150 ml) is treated with MgS04 (20 9). The reaction mixture is stirred at room tempera- ;
ture for 30 minutes, then filtered. Excess water is removed by way of azeotropic distillation, the solution concentrated, and the residue distilled to give propan-1-yne-3-imlnobenzy1 (55.5 9, 82%) b.p. 107-110C (10 mm Hg).
Example 2 To a mechanically-stirred solution of propan-1-yne-3-imino-benzyl (4~.5 9, 0.30 M) in tetrahydrofuran (400 ml) at 0C
is added, during 30 minutes, ethyl magnes7um bromide (285 ml of a 1.12 M solutionJ 0.316 M). After 30 minutes at 0C, the resultlng solution is treated wTth a solution of tri-methylsllylchloride (~2.4 9, 0.30 M) In tetrahydrofuran (100 ml)J the additlon taklng 45 mTnutes. After stlrring at 0C for an addltional 1-1/2 hoursJ the solution is treated wtth brine (8 x 100 ml)J then dried and concentrated on a rotorvapor. The resldue Ts distilled to afford a liquid (52.2 9J 80%) b.p. 92-11OOCJ o.6 mm Hg. An a1Iquot was redistilled to give 1-trimethylsilyl-1-propynyl-3- -~
iminobenzyl.
Example 3 ~- To 11.25 y (50 mM) of 1-trimethylsilyl-1-propynyl-3-imino- --benzyl in 500 ml of tetrahydrofuran is added n-butyllithlum (25 ml of a 2 M solutionJ 50 mM) at -70C. After 20 minutes ~o at -70C, feeshly distilled methyl acrylate (4.3 9, 50 mM) ~0885~Z

is added. After 30 minutes at -70C, 10 ml of water is added and the reaction mixture is allowed to come to room temperature. The tetrahydrofuran is then evaporated and concentrated HCl (20 ml) in water (150 ml) is added and the mixture heated at reflux overnight. On coo1ing, the aqueous solution is washed with methylene chloride, adjusted to a -pH of 8 and reextracted with methylene chloride. The - ~;
aqueous base is adjusted to a pH of 6. The product is ~-isolated by ion exchange chromatography on an acid resin followed by recrystallization from ethanol-water.
Example 4 ~-AMINO-4-YNE-PENTANOIC ACID
In 250 ml of tetrahydrofuran is dissolved 3.8 9 (17.75 mM) of 1-trimethylsilylpropan-1-yne-3-tminobenzyl and the solu-tion is cooled at -78C. To the solution, 9 ml of tetra-methylethylenediamine and 9 ml o~ 2-molar n-butyilithium are added successtvely. After a few minutes, stirring ~-2.98 9 (17.75 mM) of ethylbromoacetate dissolved In 20 ml tetrahydrofuran is added. The reaction mixture is stlrred for 5 mTnutes, cooling is stopped and 100 ml NaCl saturated water is added. The reaction mixture Is extracted with ether and the organ7c phase is drled and concentrated and 6.5 9 of an oily residue is obtained.
One-half of the above res;due is dissolved in 30 mt tetra-hydrofuran and 30 ml 6N HCl is added. The reaction mlxture ;s refluxed overnight and the neutral components of the . reaction mixture are extracted with methy1enechloride in basic and acid conditions. The organic phase Is evaporated to dryness and applied on a column of Amberlite i.R. 120 H.
Fractions eiuted with 1 N NH40H are collected, evaporated - . .

;Z
to dryness and recrystallized from EtOH/H20 1 1 to give 50 mg of 3-amino-4-yne-pentanoic acid.
C5H7NO2 Calculated: C: ~3.o8 H: 6.25 N: 12.38 Found: C: 53.23 H: 6.40 N: 12.19 I.R. (film) 32 cm 1 (C CH) 2150 cm 1 (C C, N~Hz) 1570 cm I (COO~) Example 5 (-) 4-AMINO-5-YNE-HEXANOIC ACID AND (+) 4-AMINO-5-YNE-HEXANOIC ACID
300 mg of the racemic compound 4-amTno-5-yne-hexanoic acid 7s dissolved in 5 ml of absolute methanol, and 900 mg of t+) binaphthylphosphoric acid (BNPA) is added. After the solut;on is almost clear and an eventual solid residue has been filtered off, the solvent is evaporated and the dry residue dlssolved at about 80C in EtOH/H20 1:1. On coollng, 440 mg of the crystallized enantiomer A is collected. the mother ltquor is treated with HCl 1/ N to pH 1 and filtered.
The pH of the filtrate is adjusted to 6 and filtered through a column of Amberlite I.R, 120. The amino acid ts eluted with lM NH40H. After evaporation to dryness, the residue is recrystallized in EtOH/H20 9:1 and 40 mg of (-) 4-amino- --5-yne hexanoic acid is obtained: (a)DZ~ = -29 (H20 C: 1.3~).
The ~40 mg of enantiomer A are processed in the same way as the corresponding mother liquor. After recrystalli-zation in ethanol water (9:1), 30 mg of (~) 4-amino-5-yne- , -- hexanoic acid are obtained. [~]2D0 = +30 (H20 C = 1.05).
Example 6 A suspension of 1.27 9 (10 mM) of 4-amino-5-yne-hexanoic .

lO~S~;~

acid in 25 ml of acetic anhydride in 10 ml of water is heated in an oil bath for 1 hour. The acetic anhydride is evaporated under vacuum, the residual syrup taken up in ~- -chloroform, and the solution is evaporated to dryness. This process is repeated several times to remove the acetic acid.
The syrup ts dissolved in 10 ml of chloroform, the solution cooled in ice water and under moisture exclusion 0.9 ml of thionyl chloride is added. The solution is stirred in the cold for 30 mlnutes and 2 ml of methanol is added while the coolTng bath is removed. Stirring 7s continued for 1 hour.
The evaporation of the solvent yields the product as an oTl.
Example 7 5-AMIN0^6-YNE-HEPTANOIC ACID
To 1-trimethylsilyl-1-propynyl-3-iminobenzyl (10 mM) in 200 ml of tetrahydrofuran at -70C was added n-butylllthium (10 mM) followed by ~-Jodobutanoic acid methyl ester (10 mM) in 200 ml of tetrahydrofuran. The temperature was allowed to rise to -20C and maintained at this temperature for 10 hours. The reaction product was extracted Into ether to 2n afford an oil. This oil was hydrolyzed in acid in the same manner as described in Example 3. The product is isolated by ion exchange chromotography and purified by recrystalli-zation ~rom ethanol-water.
Alternatively, 5-amino-6-yne-heptanolc acid may be prepared by the following procedure.
1-Trimethylsilyl-1-propynyl-3-im;nobenzyl (10 mM) in 200 ml of tetrahydro~uran at -70C was treated w7th n-butyl-lithium (10 mM), then with 1-iodo-3-chloropropane (10 mM) in 10 ml o' tetrahydrofuran. After 10 hours at -70C, the tetrahydrofuran was removed by evaporation at room tempera-.~ -19 -~0~i2 -' ture, and replaced by 20 ml of dimethylformamide. To the reaction mixture were added sodium iodide (10 mM) and sodium cyanide (20 mM), and the solution was maintained at 50C
ovçrnight. On cooling, the mixture was poured into ~00 ml of water and extracted with ether. The ether solution was washed with water, dried over magnesium sulfate and concen-trated. The resulting oil was treated with HCl (6 N, 200 ml) ; `-znd ref1uxed for 2~ hours. On cooling, the mixture was ex-tracted with methylene chloride, the aqueous base was adjusted to pH 9 using sodium carbonate and washed again ;;
with ~ethylene chloride. The aqueous base was concentrated to about ~0 ml, adjusted to a pH of 5, and the product isolated by ;on exchange chromotography and purified by recrystallization from ethanol-water.
Example ô
4-AMINO-3-PHENYL-5-YNE-HEXAN~I~ ACID HYDROCHLORIDE
: .:
To a solution of 2:15 9 of 1-trimethylsilyl-1-propynyl-~-tmlno~enzyl (10 mM) ;n ?50 ml of tetrahydrofuran cooled to `~
-78C is added 10 m moles of n-butyllithium. After 10 to 15 ~inutes, a solution of 1.65 9 of trans-cinnamic acid methyl ester (10 ~M) is added. The solution is stirred at -78C
for ~5 minutes and treated with brine. The product of the reaction is extracted by ether. The solution is dried over ~agnesium sulfate and evaporated to dryness leaving an oil ?5 which is treated with 6 N~Cl for 2~ hours. Upon evaporation t~ dryness, the remainTng syrup is dissolved in water, The -product is ;solated by ion exchange chromotography on an acid resin and purified by recrystallization from ethanol-ether.

1o~B5~ 2 Example 9 -1-Trimethylsilyl-1-propynyl-3-iminobenzyl (10 mM) in 100 ml of tetrahydrofuran at -70C was treated with n-butyllithium (10 mM). To the reactfon mixture was added 2-yne-propionic acid methyl ester (10 mM) in 10 ml of tetrahydrofuran.
After 20 minutes at -70C, 10 ml of water was added. On warming to room temperature, 6 NHCl (100 ml) was added and the mixture was refluxed overnight. On cooling, the aqueous solutton was washed with methylene chloride, adjusted to a pH of 8 and reextracted with methylene chlorlde. The aqueous base was adjusted to a pH of 6. The product was isolated by ion exchange chromotography on an acid resin and purified by recrystallJzation from methanol-water.
lS Alternattvely, 4-am7no-5-yne-2-ene-hexanoic acld may be prepared by the followlng process.
1-Trtmethylsllyl-1-propynyl-3-lminobenzyl (10 mM) In 100 ml of tetrahydrofuran at -70C was treated wlth n-butyllithJum (10 mM). To the reactlon mixture was added methyl trans-3-chloroacrylate (10 mM) in 10 ml of tetra-hydrofuran. After 1 hour at -70C, 10 ml of water was added. On warming to room temperature, 6 NHC1 (100 ml) was added and the mixture was refluxed overnight The product was isolated in the same manner as described above.
Example 10 ~-(2-AMINOPROPRIONAMIDO)-5-YNE-HEXANOIC ACID
4-Amino-5-yne-hexanoic acid methyl ester is prepared by refluxing a suspension of 1.27 g of ~-amino-5-yne-hexanotc acid in 20 ml of methanol with continuous anhydrous HCl bubbling through the reaction mixture for 3 hours followed 1 08 8 5 ~ 2 by eva~oration of ~he solvent, dissolution in water, neutralization with aqueous NaOH in the cold and ether extraction. The ether solution is dried over magnesium sulfat~, filtered, and cooled to 0C. Under moisture -~
exclusion a solution of 10 mMoles of ~-alanine where7n the am;no function is protected with benzyloxycarbonyl and the -acid function is activated with ethoxycarbonyl, prepared by the ~ethods known in the art, in ether is added slowly ~- -with stirring. When addition is complete, the cooling bath is re~oved and stirring continued overnight. The 5 solution is evaporatet, leaving a syrupy residue which is taken up in 2 ml of methanol and 10 ml of 2 N aqueous a~monia added. The suspension is stirred at 50C for 1 day, then extracted with ether. The product is isolated by ion ;~
exchange chro~otography on an acid resin. -Example 11 N-(2-PROPIONlC AClD)-3-AMiNO-4-YNE-PENTAN-1-YL CARBOXAMIDE
rO a solutlon of 1.27 9 of 4-amino-5-yne-hexanoic acid (10 ~M) in 10 ml of water was added 10.0 ml of 2 N NaOH.
Thls solution was cooled in ice water and 1.87 9 (11 mM) cf benzylchloroformate was added slowly with stirring.
When the addition was complete, stirring was contlnued for 1 hour. The solution is acidified to a pH of 4 by atdltlon cf aqusous HCl and the oily prec7pitate is extracted into 2~ ether. The ether solution is dried over magnesium sulfate, f71ter^d and cooled. After addition of 700 mg of triethyl-: amine~ an etkereal solution of 11 9 of freshly distilled ethylch10ro.~ormate is added slowly over 1 hour with stlrr7ng. The precipitate is filtered off and to the ether solution a solution of alanine methyl ester in çther is ~ -22-... .. _ .... , . ... . . _ .. _ . _ .. _ . ~ . .

9~5~2 3dded at once. The solution is kept overn;ght and then -eva?orated to dryness. The residue is taken up in 2 ml of ~ethanol and 20 ml of 2 N aqueous NaOH is adted. The sus~ension is stirred for 1 day at 50C, then the solution is extracted with ether and adjusted to a pH of 7. The ~`
product is isolated by ion exchange chromotography on an acid resin.
, .

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Claims (2)

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

1. A process for preparing (+) 4-amino-5-yne-hexanoic acid or a pharmaceutically acceptable salt thereof which comprises the process wherein 4-amino-5-yne-hexanoic acid is reacted with (+) binaphthylphosphoric acid to provide the compound (+) 4-amino-5-yne-hexanoic acid and if desired, reacting said compound with an acid or base to provide a pharmaceutically acceptable salt of said compound.

2. (+) 4-Amino-5-yne-hexanoic acid or a pharmaceutically acceptable salt thereof when prepared by the process of claim 1.