CA1039287A - Thiazole cardiovascular agents ii - Google Patents

Abstract

Abstract of the Disclosure 1-Amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and/or substituted amino derivatives thereof: 3-(4-or 5-substituted thiazon-2-oxy)-1,2-epoxypropane and 5-(4-or 5-substituted thiazol-2-oxy)-1,2-epoxypropane and 5-(4-or 5-substituted thiazol-2-oxymethylene)-oxazolidine and/or N- and/or -substituted oxazolidine derivatives thereof, generally represented by comound formulas:

(I) (II) (III) wherein R1, R2, R5, R6, R7 and Z are the various substituents and methods of making such compounds. The compounds are characterized by an aminocarbonyl or carbonylamino type substituent at the 5- or 4-position on the thiazole ring.
The above 1-amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and derivatives exhibit cardiovascular activity and are useful in the treatment of abnormal heart conditions in mammals. The 3-(4- or 5-substituted thiazol-2-oxy)-1,2-epoxypropanes are useful as intermediates for the aforementioned cardiovascular agents. The 5-(4- or 5-substituted thiazol-2-oxymethylene)-oxazolidine and derivatives are intermediates for the aforementioned cardiovascular agents and further exhibit cardiovascular activity and thus are useful in the treatment of abnormal heart conditions in mammals. The 1-amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and derivatives can be prepared by base or acid hydrolysis of the corresponding 5-(4- or 5-aminocarbonylthiazol-2-oxymethylene)-oxazolidine or derivative; or by treatment of the corresponding 3-(4- or 5-substituted thiazol-2-oxy)-2, 3-epoxypropane or derivative with the desired amine or amine derivative.

Description

~3~ 7 1. Field of the Invention This invention relates to 3-(4- or 5-substituted thia-zol-2-oxy)-propane derivatives and 4'- or 5'-substituted thiazol-2-oxymethylene-oxazolidine derivatives and to methods of preparing such componuds. In a further aspect this in-veition relates to l-amino-3-(4- or 5-substituted thiazol-

2-oxy)-2-propanol and l-(substituted amino)- and/or 4'-or 5'- substituted thiazole derivatives thereof and to methods of preparing such compounds. In a still further aspect this invention relates to 3-(4- or 5-substituted thiazol-2-oxy)-1, 2-epoxypropane derivatives and to methods of preparing and using such compounds. In another aspect this invention relates to 4'- or 5'-substituted thiazol-2'-oxy-methylene-oxazolidine derivatives and/or substituted oxazolidine derivatives thereof and to methods of preparing and uslng such compounds. This invention also relates to pharmaceutical compositions comprising the l-amino-3-(4- or 5-substituted thiazol-2-oxy)-2-propanol and derivatives, of the invention, and/or the 4'- or 5'-substituted thiazol-2'-oxy-methylene-; 20 oxazolidine and derivatives, of the invention, and to methods of applying such compositions for the treatment of mammals.

.:
'' .

`,`' :' .. ' " ' . ` .: '`''` ~ ` ` ` , . ';'` ~ ,. .' ,' . , 2. The Prior Art ~ t ~he pre~ent time, the compouna ~requantly u~ed in th~ united State~ for the treatment of sev~ral cardlac arrhythmia~ i~ propranolol (i.e. l-(isopropyla~ino)-3-~
naphthyloxy)-2-propanol). This compound primarily achieve~
its therapeutic action by blocking cardiac ~-~drenergi~
r~ceptor sites and i3 a general p-adrenergi.c blockar which ~:
: blocks the peripheral ~-adrenergic receptor site3, ~uch a~
those in the lung, as well as the ~-adrenergic recsptor 10 8ite8 in the heart. Propranolol i~ contraindicated in patients ; who suffer from a~thma or chronic ob~tructive lung disease, because following it~ administration to such patient~, an lncrease in airway resi~tance and bronchial con~trictlon ha3 been observed. Accordingly, I have now di~covered potent 15 cardiac ~elective ~-adrenergic blocking agents which are effective for the treatment or palliation of caxdiac arrhythmîa, and which further can safely be used by pati~h~ su~fering from a~thma or chronic obstr~ctive lung di~ease. ~he compo~nd3 are further effective for the treatment or palliation of angina pectori~ and again can be safely applied to patient~
who also suffer ~rom asthma or chronic lung disease.

DESCRIPl~ION OF THE Il~VE~TION
A~D PREPERRED EMBODIMENl!S
The compounds of the in~ention can be represented by the following ~ub-generic formula~:
~ 25 i :
.
: ~ .. .
. ~,.. . .
,: : .

~39~7 Z ~ O-CII -CHON Cll N~R

(I) Z ~O-C}12-c~7~u2 (II) Z ~ ~ 2 ~ 7 (III) ~ 6 wherein Rl and R2 are independently selected from .~ the group of hydrogen, lower alkyl, cycloalkyl having . rom three through seven ring atoms, lower alkenyl, ' . àryl, arylalkyl, lower alkylaryl, hydroxy lower alkyl, .. S (lower alkoxy) lower alkyl, lower alkyl (N-heterocyclic `; haviny from five through seven ring atoms including one : or two heteroatoms selected from the group of nitrogen, oxygen and sulfur and wherein at least one of said heteroatoms is nitrogen) and groups having the formulas ~(CH2)n-N~ 12 or (CH2)2 ~ ~NRllR12 wherein ' n is a whole integer of from oAe through four; and R
;~ and R12 are independently hydrogen or lower alkyl; or ~, Rl and R2 togetheî with the nitrogen atom to , . 14 which they are joined form a nitrogen heterocycle ~ .

3-having from five through seven r:ing atoms having one or two heteroatoms s~lected from the group consisting of nitrogen, oxygen and sulfur and wherein at least one of said heteroatoms is nitrogen or Rl and R2 form S a substituted nitrogen heterocycle having from five through seven ring atoms including one or two hetero-atoms selected from the group of nitrogen, oxygen and sulfur and wherein at leas~ one of said heteroatoms is ni~rogen and having one or two substituents inde-pendently selected from the group of lower alkyl, and hydroxy(lower alkyl);
Z is a substituent on the thiazole ring at either the 4- or S-position selected from the group having the formulas:
. ~ . .
. lS R4R3N~- ; R4~NR- ; or R ~ - wherein .one of R3 or R4 is independently selected from the ; group of alkyl having from seven through 12 carbon atoms; cycloalkyl having from three through 12 carbon atoms; terminally substituted alkyl group having from two through 12 carbon atoms having one substituted terminal carbon atom having a substituent selected from the group of hydroxy, acyloxy having from two through 12 carbon atoms and alkoxy having from one through six c~rb~ a~oms; and groups having.the formulas -(CH2)nNR8R9 or -(CH2)nR10 wherein n is a whole integer of from one through four, R8 . and R~ are independently selected from the group 28 of hydrogen and alkyl groups having from one through

-4-,~ .

.
~::

~3~

four carbon atoms and R10 is cycloaklyl having from three through eight carbon atoms; an~ the other i8 s~lected from the group of hydrogen: alkyl having from one through 12 carbon atoms; cycloalkyl having from threl3 through 12 carbon

5 atoms s phenyl, lower phenyl alkyl wharein ~aid alkyl ha~ one through six carbon atom~ or sub~tituted phenyl or substituted lower phenylalkyl wherein said phenyl ha~ one ox two ~ubsti~
tuents independently selected from the group of hydroxy, lower alkyl, lower alkoxy and halo; terminally ~ubstituted alkyl group having from two through 12 carbon atoms having one substit~ted terminal ~arbon atom having from one through three sub~ituents independently selected from the group of hydroxy, acyloxy having ~rom two through 12 carbon ato~s and alkoxy having from one through ~ix carbon atoms: and group~ having lS the formulas -(CH ) NR R or -(CH ) R wherein n is a whole 2 n+l 2 n : integar of from one through four, R and ~ are independently selected from the group of hydrogen and alkyl group~ having from one through four carbon atoms and R i3 cy~loalkyl having from thr~e through eight carbon a~om~; and wherein when one of R or R i~ the group.
-(CH2)2-0--~ ~ CNR R then R and R4 can each be independ-ently ~e}ected from the group of hydrogen; alkyl having from one througb 12 carbon atom~: phenyl, lower phenylalkyl wherein ; ::
`: said alkyl has one through ~ix carbon atom~ or sub~titut~d ~ :
phenyl or sub~tituted lower phenylalkyl wherein said phenyl has oneor two substituents independently sele~ted from the group of hydroxy, lower alkyl,lower alkoxy and halo;cycloalkyl ~aving from ,' ~ ~
~ ' ' ,~ . , . :
. .

three through 1~ carbon atomR terminally substituted alkyl group having from two ~hrough 12 carbon atom~ having one ~ubstituted terminal carbon atom having a 3ub8titue~t inde-pendently selected from the group of hydro~y, acyloxy having s from two thxough 12 carbon atoms and alko~r having from one through ~ix carbon atoms; and group~: havim~ the formula~
-(CH2)nN~ R or -(CH2) R wherein n i~ a whole integer of from one through four, ~8 and R9 are independently selected ,~ -~
from the group of hydrogen and alkyl groups having f rom one tbrough four carbon atom~ and * is cycloalkyl having from thrse through eight carbon atoms:
R and R are indepe~d~ntly selected ~rom the group of hydrogen, lower alkyl, arylalkyl or together with the carbon atom to which they are joined form a cy~loalkyl having from five through ~even carbon atoms, R7 i~ hydrogen, lower alkyl, aryl or arylalkyl: and further provided that when Z is R40C~- then R4 ~ cannot be hydrogen .
Al~o encompa~ed within the invention are phar~aceutically ;
acceptable 8alt8 of the above compound of formulas I and III.
The compounds of the invention have an asymmetric carbon atom in the propane side chain and thu~ exi~t as optical isomers. Correspondingly the above ~ormulas are intended to represent the respective individual (+) and (-) optical i~omers a~ well a3 mixtures o~ such isomers and the individual i~omers as well a~ mixtures thereof are encompas~ed within the inven-tion. Where the compounds of the invention have l-positioned substituents, on the propane chain, whicb have asymmetric atom~, the co~npound~ exhibit further optical activity with respect to such asymmetric atoms.

... .

.

1~3~ 7 Defi.n.i.tions As used herein above and below, the following terms shall have the following meaning unless expressly stated to the contrary. The term alkyl, or alkylene, refers to S both strai~ht and bran~hcd chain alkyl. groups. The term : lower alkyl refers to both straight and branched chain alkyl groups having a total. of from one through six carbon atoms and thus includes primary, second~ry, and~-.tertiary alkyl.~groups. ..~ypical.lower alkyls in-clude, for example, methyl, ethyl, n-propyl, isopropyl, . n-bu~yl, t-butyl, n-hexyl and the like. The term cyclo-alkyl refers to cyclic hydrocarbon groups having from three through 12 car~on atoms and preferably three through seven carbon atoms such as, for example, cyclopxopyl, cyclo-pentyl, cycloheptyl, and the like. The term alkenyl refers to monoethylenically unsaturated aliphatic groups and the term lower alkenyl refers to such alkenyl groups having . from two through six carbon atoms and wherein the double bond can be between any two adjacent carbon atoms. Typical ..
. 20 lower alkenyl groups include, for example, vinyl, propenyl, ; and the like. The term alkoxy refers to groups having the ~ormula R'O wherein R' is alkyl and correspondingly the term lower alkoxy reEers to the group having the formula R'O- wherein R' i5 lower alkyl. Typical alkoxy groups include, for example, methoxy, ethoxy, t-butoxy and the like. The term (lower alkoxy) lower alkyl or perhaps more : correctly tlower alkoxy) lower alkylene refers to the group -R'-OR" wherein R' is lower alkylene and OR" is lower ~, alkoxy~ The term hydroxy lower alkyl or hydroxy lower alkylene refers to groups having the formula lIOR'- wherein _7_ .: .
'~

.. ..
: . . . ... . . . .
. . . :
:

R' i~ lower alkylen ~ hydroxyalkyl or hydroxy-alkylene group~ include, for ~xample, ~-hydroxyethylene, ~-hydroxypropylene, hydroxyi~opropylene, and the like.
~he term terminally ~ub~tituted alkyl (or alkylene~ re~r~
s to alkylene group~ having from two through twelve carbon atoms in which the terminal ~arbon atom, or in the ca~e of group~, such a~ t-butyl, which have mora than one term-inal carbon, wh~rein one of ~uch terminal carbon atoms are substituted with from one through three sub~tituents inde-pendently selected from the group of hydroxy, acyloxy, and ~
alXoxy. ~ypical terminally substituted alkyl group~ in ~-clude 2-hydroxy-ethylene, 3 acetoxypropyl, ~-m~thoxyethyl-ene and the like. The term carboxy refers to the group -COOH. The term halo refers to iodo, bromo, chloro and fluoro ~ 15 groups. The term acyl refers to ~oxmyl and acyl groups derived from carboxylic acids having from two through 12 carbon : ~ .
atom~ such as acetyl, propionyl, butyryl, valeryl, i80-valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, undec~
anoyl, lauroyl, benzoyl, phenylacetyl, phenylpropionyl, o-, m-, p-toluoyl, @-~yclopentylpropionyl, and the like.
.~ The term alkoxycarbonyl refers to groups having the .~ ~
formula R30C- wherein R3 is an alkyl group having from one through 11 carbon atoms. Typical alkoxy~arbonyl gro~ps :, :
~ thus include, for example, methoxycarbonyl, propoxycarbonyl, . .
25 isopropoxycar~onyl~ undecanoxycarbonyl, and the like. The term acyloxy refers to groups derived from carboxylic acids having from two through 12 garbon atom~ 8uch a~ acetylo~y, propionyloxy, butyryloxy, valeryloxy, i~ovaleryloxy, hexan-oyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, und~anoyloxy, , .

::
,: . :, - : .: ~ .

~L~339~7 lauroylox~ benzoyloxy, phenyL~cetyloxy, phenylpropionyl~
oxy, o-, m-, p-toluoyloxy, ~-cyclopen-tylpropionyloxy, and the like.
By the term aryl is meAnt A group containing one aro-matic ring having up to ten carbons and preferahly is phenyl.
By the term alkylaryl is meant a substituted phenyl group having one or more alkyl substituents and having 7 throu~h 12 carbon atoms such as o-tolyl, m-tolyl, p-isopropylphenyl, 2,3-dimethylphenyl, 3,5-dimethylphenyl, and the like. By the term arylalkyl is meant a phenyl (or substi~uted phenyl) substituted alkyl group such as benzyl, phenylethyl, ~-(p-hydroxyphenyl)ethyl, and wherein sald allcyl moiety has from one through six carbon atoms. The term substituted phenyl refers to phenyl groups having one or two substituents inde-pendently selected from the group of hydroxy, lower alkyl, lower alkoxy or halo. Substitution can be at any position on the ring and preferably the phenyl ring is only monosubstituted.
~ypical substituted phenyl groups include, for example, p-hy-droxyphenyl, 3,4-dimethoxyphenyl, p-fluorophenyl, p-chloro-phenyl and the corresponding ortho and meta isomers.
The term alkylamino refers to the group having the formula R'IIN- wherein R' is alkyl and the term low~r alkyl-amino refers to such groups wherein R~ is lower alkyl.
The term dialkylamino refers to the group having the form-ula RiR2N- wherein Ri and R2 are independently alkyl.
Typical lower dialkylamino groups include, for example, dimethylamino, N-methyl-N-ethylamino, diethylamino, N-t-; butyl-N-isopropylamino, and the like.
` The term aminocarbonyl or carbamoyl refers to the group having the formula H2N~-. The tcrm substituted amino-carbonyl (e.g. alkylamillocarbonyl) or substituted carbAmoyl . _g .

"~,' " ' . ~ , .:

~3~ 7 refers to the yroup having the formula R HN~- wherein R3 is as defined herein. Typical alkylaminocarbonyl or alkyl-carbamoyl groups include, for example, methylaminocarbonyl or methylcarbamoyl; heptylaminocarbonyl or heptylcarbamoyl;
n nonylaminocarbonyl or n-nonylcarbamoyl; and the like.
The term disubstituted aminocarbonyl or disubstituted car-bamoyl refers to ~roups having the formula R3R4N~- wherein R3 and R4 are as defined herein. Typical dialkylaminocar-bonyl or dialkylcarbamoyl groups include, for example, N-methyl-N-heptylaminocarbonyl or N-methyl-N-heptylcarbamoyl;
diheptylaminocarbonyl or aiheptylcarbamoyl, N-(n-nonyl)-N-~n ocytyl)-aminocarbonyl or N-(n-nony1)-N-(n-ocytyl)-amino-carbamoyl and the like. The term hydroxyalkylaminocarbonyl or hydroxyalkylenaminocarbonyl or hydroxyalkylcclrbamoyl refers to groups having the Eormula HO-R~ - wherein Rl is an alkylene group having from two through ~welve car-bon atoms. The term alkoxyalkylaminocarbonyl or alkoxy-alkylenaminocarbonyl or alkoxyalkylcarbamoyl reEers to groups having the formula R2O-Rl-N~- wherein Rl is as de-fined immediately above and R2 is alkyl. The term acyloxy-alkylaminocarbonyl or acyloxyalkylcarbamoyl reers to groups having the formula ~cO-Rl-N~-, wherein Rl is as de-fined above and ~cO is acyloxy as defined herein above.
The term formamido re~ers to the group having the 2S formula H ~ -. The term N-substitu*ed formamido (e.g. N-alkylformamido) reers to the groups having the formula }~N- wherein R3 is as defined herein. The term substi-tuted amido ~e.g. alk~lamido) or substituted carbonylami-no (e.g. alkylcarbonylamino) or acylamino reer to the group having thc formula R4~N- whereill R4 is as de~ined .

. . ': : ' 3~ 37 herein. The term N-(substituted)-substituked a~ido or N-(substitut~d)-substituted carbonylamino or N-substituted-acylamino re~er to g~oups having the formula R4~N- wherein R3 and R~ is as defined herein above. Typical groups having s the formula R~N- include, for example, N-heptyl-acetamido or N-heptyl acetylamino; or N-heptyl-methylcarbonylamino;
N-methyl-heptylcarbonylamino, and the like.
The term substi~utedoxy carbonylamino (e.g. alkoxy-carbonylamino; phenoxycarbonylamino refers to the group having the formula R40~N- wherein R4 is as defined herein.
- The term N-substituted-substitut~doxy carbonylamino (e.g.
N-alkyl alkoxycarbonylamino; N-alkylphenoxycarbonylamino refers to groups having the formulas R40~N- wherein R3 and R4 are as deined herein. Typical R40~- groups include, for example, N-methyl-heptoxycarbonylamino, N-heptyl-t-; butoxycarbonylamino and the like.
The terms N-heterocycle or nitrogenheterocycle refer to both saturated and unsaturated heterocyclics having from five through seven ring atoms, one of which is nitrogen and ....
which can optionally also contain a second heterocycle ring atom selected from the group o nitrogen, sulfur and oxygen.
Also encompassed within the term are substituted N-hetero-cyclics having one or two substituents independently selected from the group of lower alkyl, hydroxylower alkyl, and halo. Typical N-heterocycles include, for example, those having the formulas:
. . .

~ ~N /--N-C33 ; _N~ ;

,... .
, ~ , .
i, . . . .

~3 CH3 .

~ ~2C1120~

¢~ 3 r ~

....
and th~ like.
The term N-heterocycle alkyl or ~-heterocycle alkyl-ene refers to a lower alkylene group having an N-heterocyclic substituent a~ deined herein above. ~uch group~ can be represented by the formula XR' - wherein X i3 N-heterocyclic and ~' i8 lowex a}kylene.
~he t~rm pharmaceutically accaptable ~alt~ refers to ~`~
pharmaceutical}y acceptable hydrog~n-anion addition salt~ ;~
which donot adver3ely affect the pharmaceutical propertie~
of the parent compound~. With re~pect to the addition 3alts, suitable inorganic anions include, for example, chloride, bromide, iodide, sulfate, phosphate, carbonate, nitrate, hydrocarbonate, ~ulfate and the like. Suitable organic anioras include, for exan~le, acetate, b~nzoate, lactate, pic~at~, propionate, butyrate, valerate, tartrate, maleat~, fu~arate, citrate, ~uccinate, to~ylate, aæcorbate, pamoate, ni::otinat0, :
adipate, glyconate, and the likb.
Typical illu~tration~ of the compounds of formula I
can ~e had, for exan~le, herein below by referen~e to - ~.- . . .. .: .

~39~ 7 :*** Examples 4-7, 9, 11, 12, 15-18. The pref~rred Rl and R2 subs-tituents are those wherein one of Rl or R2 is hydrogen and the other is selected from the group of isopropyl; sec-butyl; t-butyli cyclopropyl; cyclopentyl; a-phenylethyl;
~-hydroxyethyl; a-phenylpropyl; ~-(3,4-dimethoxyphenyl)-ethyl;
~-(4-hydroxyphenyl)-ethyl; a-methyl ~--(4-hydroxyphenyl)-ethyl;
- y-(4-hydroxyphenyl)-propyl; a-methyl-y-(4-hydroxyphenyl)-propyl;
a-methyl-y-phenylpropyl; and ~-(4-aminocarbollylphenoxy)-ethyl. The preferred R3 and R4 substituent compounds of ; formula I are those wherein R3 is hydrogen and R4 is selected from the group of 3'-methylhexyl, 4'-ethylhexyl, 3'-propyl-hexyl, n-heptyl; n-octyl; cycloheptyl, cyclohexyl, ~-cyclo-pentylethyl, y-cyclopentylpropyl, 4'-cyclopenkylbutyl, ~-cyclohexylpropyl, ~-methoxyethyl, and y-dimethylaminopropyl and especially 5'-methylhexyl and 4'-methylhexyl. The particularly preferred compounds of formula I are:
l-t-butylamino-3-(5-3'-methylhexylaminocarbonylthia-zol-2-oxy)-2-propanol;
l-isopropylamino-3~(5-3'-methylhexylaminocarbonyl-thiazoi-2-oxy)-2-propanol;
1-[~-~4-aminocarbonylphenoxy)~ethylamino]-3-(5--3'-. methylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-4'-methylhexylaminocarbonylthia-zol 2-oxy)-2-propanol;
1-isopropylamino-3-~5-4'-methylhexylaminocarbonyl-thiazol-2-oxy)-2-propanol;
1-[~-~4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-5'-methylhexylaminocarbonylthia~
zol-2-oxy)-2-propanol;
. ' .
;:

39~

l-isopropylamillo-3-(5-5'-methylh~xylaminocarbonylthia zol-2-oxy)-2-propanol;
1- E~- (4-aminocarbonylphenoxy)-ethylamino]-3- (s-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
1-t-butylamino-3-(5-4'-ethylhexylaminocarbonylthiazol-`, . 2-oxy)-2-propanol;
l-isopropylamino-3-(5-4'-ethylhexylaminocarbonylthia-zol-2-oxy)-2-propanol;
-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-, 10 ethylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-3'-propylhexylaminocarbonylthia-, zol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-3'-propylh'exylaminocarbonyl- '.
thiazol-2-oxy)-2-propanol;
;~ 15 1~ 4-aminocarbonylphenoxy)-ethylamino]-3-~5-3'-. propylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
, l-t-butylamino-3-(5-n-heptylaminocarbonylthiazol-2-', oxy)-2-propanol;
, l-isopropylamino-3-(5-n-heptylaminocarbonylthiazol-.. ..
2-oxy)-2-propanol;
1- L ~- (4-aminocarbony:Lphenoxy)-ethylamino]-3-(5-n-heptylaminocarbonylthiazol-2-oxy)-2-propanol;
, l-t-butylamino-3-.(5-~-cyclopentylethylaminocarbonyl-thiazol-2-oxy)-2-propanol;
1-isopropylamino-3-(S-~-cyclopentylethylaminocarbonyl-thiazol-2-oxy)-2-propanol;
(4-aminocarbo3lylphenoxy)-ethylamino]-3-(5-~-cyclo-. : pentylethylaminocarbonylthiazol-2-oxy)-2-propanol;
; ' l-t-butylamino-3-(5-y-cyclop~ntylpropylaminocarbonyl-thiazol-2-oxy)-2-propanol;
: ', , -14-:

.: , ' :
::.:: :~.
. . .

~3~

l-isopropylamino~3~5-y-cyclopentylpropylaminocarbonyl-thiazol-2-oxy)-2~propanol;
~ 4-~1inocarbonylphenoxy)-etllylamino]-3-(5-y-cyclo-pentylpropylaminocarbonylthiazol-2-oxy)-2-propanol;
S l-t-butylc~nino-3-~5-4'-cyclopcntylbutylaminocarbonyl-~ thiazol-2-oxy)-2-propanol;
; l-isopropylam.ino-3-(5-4'-cyclopentylbutylaminocarbo-nylthiazol-2-oxy)-2-propanol;
1-[~-~4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-cyclopentylbutylaminocarbonylthiazol-2-oxy)-2-propanol;
l-t-butylamlno-3-(5-~-cyclohexylpropylaminocarbonyl-thiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-y-cycloheXylpropylaminocarbonyl-thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylaminol-3-(5-y-: cyclohexylpropylaminocarbonylthiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-3'-methylllexylcarbonylaminothia-zol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-3'-methylhexylcarbonylamino-thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino~-3-(5-3'-me~hylhexylcarbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-4'-methylhexylcarbonylaminothia-zol-2-oxy)-2-propanol;
1-isopropylamino-3-(5-4'-methylhexylcarbonylamino-thiazol-2-oxy)-2-propanol;
1-[~-(4-~minocarbcnylphenoxy)-ethylamino]-3-(5-4'-~ . methylhexylcarbonylamino~hiazol-2-oxy)-2-propanol;
- l-t-butylamino-3-(5-5'-methylhexylcarbonylaminothia-zol-2-oxy)-2-propanol;
,' ' .

.; . - .
' ~'' ' ' ' ' ' - ' :

`:
3~ 37 .` l-isopropylamino-3-(5-5'-methylhexylcarbollylaminothia-zol-2-oxy)-2-propanol;
(4-aminocarbonylphenoxy~-ethylamino~-3-~5-5'-methylllexylcarbonylaminothiazol-2~ox~)-2-propanol;
.j 5 1-t-butylamino-3-(5-4'-ethylhe~ylcarbonylaminothiaæol-. 2-oxy)-2-propanol;
:~` l-isopropylamino-3-(5-4'-ethylhexylcarbonylaminothia-zol-2-oxy)-2-propanol;
~ 1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-- 10 ethylhexylcarbonylaminothiazol-2-oxy)-2-propanol, `~' l-t-butylamino-3-(5-3'-propylhexylcarbonylaminothia-zol-2-oxy~-2-propanol;
l-isopropylamirlo-3-(5-3'-propylhexylcarbonylamino-thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylaminol-3-(5-3'-~ propylhexylcarbonylaminothiazol-2-oxy)-2-propanol;
:~ l-t-butylamino-3-(5-n-heptylcarbonylaminothiazol-2~
: oxy)-2-propanol;
. l-isopropylamino-3-(5-n-heptylcarbohylaminothia :.. 'j .
2-oxy)~2-propanol;
-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-n-heptylcarbonylaminothiazol-2-oxy)~2-propanol;
l-t-butylamino-3-(5-~-cyclopentylethylcarbonylamino-":, thiazol-2-oxy)-2-propanol;
1-isopropylamino-3-(5-~-cyclopentylethylcarbonylamino- .
thiazol-2-oxy)-2-propanol;
-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-~-. ,., ~
: cyclopentylethylcarbonylaminothiazol-2-oxy)-2-propanol;
:.. : l-t-butylamino-3-(5-y-cyclopentylpropylcarbonylamino-.. 30 thiazol-2-oxy)-2-propanol;

.,.; ~ .
'~` ' .
. .~ - . . .. .
::.,.. :... : . :.
. ~`.~ ~' ' ' ' ' ' ', ' 3~ 37 l-isop:ropylam:ino-3-(5-y-cyclopent:ylpropylcarbonylam:irlo-thi.azol-2-oxy)-2-propanol;
~ -aminocarbonylphelloxy~-ethyl~lino]-3-(5-y-cyclo-pentylpropylcarbonylaminothiazol-2-oxy)-2-propanol;
1-t-butylamino-3-(5-4'-cyclopentylbutylcarbonylamino-thiazol-2-oxy)-2-propanol;
l-isopropylamino-3-t5-4'-cycloperltylbutylcarbonyl-aminothiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3 (5-4'-cyclopentylbutylcarbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-y-cyclohexylpropylcarbonylamino-thiazol-2-oxy)-2-propanol;
l-isopropylami.no-3-(5-y-cyclohexylpropylcarbonylamino-thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-y-cyclohexylpropylcarbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-3'-methylhexoxycarbonylaminothia-zol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-3'-methylhexoxycarbonylamino-....
thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-3'-methylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
; l-t-butylamino-3-(5-4'-methylhexoxycarbonylaminothia-. zol-2-oxy)-2-propanol;
1-isopropylamino-3-(5-4'-methylhexoxycarbonylamino-thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-methylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-5'-methylhexoxycarbonylaminothia-zol-2-oxy)-2-propanol;

~17-.

.~ , ; l-isopropylamillo-3-~5-5'-motilylhexoxycclrbony1.lmino-thiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphelloxy)-ethylamino]-3-(5-5'-methylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
1-t-butylamino-3-~5-4'-etllylhexoxycarbonylaminothia-zol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-4'-e~lylhexoxycarbonylaminothia-zol-2--oxy)-2-propanol;
-(4-aminoearbonylphenoxy)-ethylamino]-3-(5-4'-ethylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamlno-3-(5-3'-propylhexoxycarbonylam.inothia-æol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-3'-propylhexoxyearbonylamino-thiazol-2-oxy)-2-propanol;
1-~ -aminoearbonylphenoxy)-ethylamino]-3-(5-3'-propylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-n-heptoxycarbonylaminothiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-n-heptoxycarbonylaminothiazol-` 20 2-oxy)-2-propanol;
-(4-aminoearbonylphenoxy)-ethylamino~-3-(5-n-;~ heptoxyearbonylaminothiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-~-eyelopentylethoxyearbonylamino-thiazol~2-oxy)-2-propanol;
:
~ 25 1-isopropylamino-3-(5-~-cyclopentylethoxycarbonylamino-:, thiazol-2-oxy)-2-pr-opanol;
(4-aminoearbonylphenoxy)-ethylamino]-3-(5-~-eyelo-.pentylethoxycarbonylaminothiazol-2-oxy)-2-propanol;
t-butylamino-3-(5-y-eyelopentylpropoxycarbonylamino-.1 , .: 30 thiazol-2-oxy)-2-propanol;
: . , , .
' -18-':' .. .:..... . ~,, : .
::: . . . - - ~ ; ..... . . :
. ::: . . . - :

~ .

~ . .

- l-isopropy:l.amino-3-(5-y-cyclopentylpropoxycarbonylamino~
thiazol-2-oxy)-2-propanol;
l-[~ aminocarbonylphenoxy)-ethylamino]-3-(5-y-cyclo-pentylpropoxycarbonylamino-thiazol-2-oxy)-2-propanol;
1-t-butylamino-3-(5-4'-cyclopentylbutoxycarbonylamino-`: thiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-4'-cyclopentylbutoxycarbonylamino-thiazol-2-oxy)-2-propanol;
-(4-aminocarhonylphenoxy)-ethylamino~-3-(5-4'-cyclopentylbutoxycarbonylaminothiazol-2-oxy)-2-propanol;
- l-t-butylamino-3-(S-y-cyclohexylpropoxycarbonylamino-thiazol-2-oxy)-2-propanol;
'! l-isopropylami.no-3-(S-y-cyclohexylpropoxycarbonylamino-thiazol-2-oxy)-2-propanol; and 1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-y-cyclohexylpropoxycarbonylaminothiazol-2-oxy)-2-propanol~
Typical illustrations of the compounds of formula II
can be had, for example, herein below by reference to Example 3. Further since the primary use of compounds of formula II is as intermediates for the compounds of form-ula I, the preferred R3 and R4 substituents are the same , as listed above for formula I and the particularly pre-., ferred compounds of formula II are the precursors corres-ponding to the particularly preferred compounds of form-.~ 25 ula I as set forth herein above.
,, :. Typical illustrations of the compounds of formula III
~ can be had, herein below, by reference to Examples 10 and : 13-18~ The preferred R3 ~nd R4 substituents for the com-pounds of formula III are the same as listed above for the .~; 30 compounds as formula I. The preferred R5 and R6 substituents , ,., , --19--' :' , ~, . . . . .
;., ,,.: ,~
.. : . .: . .
,. ,......... , : , . . . ~ .

~,13~7 and the compounds of Eormula III are those whereill R5 and R6 are each hydrogen or each me-thyl. The preferred R7 substituents are methyl, isopropyl, sec-butyl, t-butyl, cyclopropyl, cyclopentyl, a-phenylethyl, y-phenylpropyl, ~-(3,4-dimethoxyphenyl)-ethyl, ~-(4-hydroxyphenyl)-ethyl, a-methyl-~-t4-hydroxyphenyl)-ethyl, y--(4-hydroxyphcnyl)-butyl, a-metl-yl-~-t~-hydroxyphenyl)-p:ropyl, and a-methyl-y-phenylpropyl. The particularly preferxed compounds of formula III are:
5-(5-3'-methylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-t-butyloxazolidine;
5-t5-3'-methylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-isopropyloxazolidine;
5-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-methyl-I lS ene-N-t-butyloxazolidine;
5-t5-4'-methylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-isopropyloxazolidine;
5-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-t-butyloxazolidine;
, 5-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-isopropyloxazolidine;
; 5-(5-4'-ethylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-M-t-butyloxazolidine;
: .
$-(5-4'-ethylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-isopropyloxazolidine;
.5-.(5-3'-propylhexylaminocarbonylthiazol-2-oxy)-methyl-ene-N-t-butyloxazolidine;
5-(5-3'-propylhexylaminocarbonylthiazol-2-oxy)-methyl-29 ene-N-isopropyloxazolidine;

392~37 5-(5-n-hep-tylaminocarbonylthiazol-2-oxy)-methy.l.cne-N-t-butyloxazolidine;
5-(5-n-heptylaminocarbonylthiazol-2-oxy)-methylene-N-isopropyloxazolidine;
5-(5-~-cyclopentyl~thylaminocarbo~ylthiazol-2-oxy)-methylene-N-t-butyloxaæolidine;
5-(5-~-cyclopentylethylaminocar~onylthiazol-2-oxy)- .
methylene-N-isopropyloxazolidine;
., 5-~5-y-cyclopentylpropylaminocarbonylthiazol-2-oxy)-methylene-N-t-butyloxazolidine;
5-(5-~-cyclopentylpropylaminocarbonylthiazol-2-oxy)-methylene-N-isopropyloxazolidine;

:: .
i 5-(5-4'-cyclope~tylbutylaminocarbonylthiazol-2-oxy)-; methylene-N-t-butyloxazolidine;

5-(5-4'-cyclopentylbutylaminocarbonylthiazol-2-oxy)-;l methylene-N-isopropyloxazolidine;

5-(5-y-cyclohexylpropylaminocarbonylthiazol-2-oxy)-:. . . methylene-N-t~butyloxazolidine;
., .
.`. 5-(5-~-cyclohexylpropylaminocarbonylthiazol-2-oxy)-,:~ ... . . .
methylene-N-isopropyloxazolidine;

~ 5-~5-3'-methylhexylcarbonylaminothiazol-2-oxy)-methyl-., ene-N-t-butyloxazolidine;

... . .
5-(5-3'-methylhexylcarbonylaminothiazol-2-oxy) methyl-ene-N-isopropyloxazolidine;

.. 25 5-(5-4'-methylhexylcarbonylaminothiazol-2-oxy)-methyl-~-. ene-N-t-butyloxazolidine;

5-(5-4'-methylhexylcarbonylaminothiazol-2-oxy)-methyl-.:., ;:, ene-N-isopropyloxazolidine;
. . ~ .
5-(5-5'-methylhexylcarbonylaminothiazol-2-oxy)-methyl-3C ene-N-t-butyloxazolidine;

, . .

3~3 37 5-(5-5'-me~hylhexylcarbonylaminothiazol~~-oxy)-1ne-thyl-: ene-N-isopropyloxazolidine;
5-(5-4'-ethylhexylcarbonylaminothiazol-2-oxy)~methyl-ene-N-t-butyloxazolidine;
5-(5-4'-ethylhexylcarbonylaminothiazol-2-oxy]-me-thyl~
ene-N-isopropyloxazolidine;
5~(5-3'-propylhexylcarbonylam~ othiazol-2 oxy)-methyl-ene-N-t-butyloxazolidine;
5-(5-3'-propylhexylcarbonylaminothiazol-2-oxy)-methyl-ene-N-isopropyloxazolidine;
5-(5-n-heptylaarbonylaminothiazol-2-oxy)-methylene-N-, t~butyloxazolidine;
5-(5-n-heptylcarbonylaminothiazol-2-oxy)-metllylelle-N- -isopropyloxazolidine;
.l5 5-(5-~-cyclopentylethylcarbonylaminothiazol-2-oxy)-methylene-N-t-butyloxaæolidine;
5~(5-~-cyclopentylethylcarbonylaminothiazol-2-oxy)-. methylene-N-isopropyloxazolidine;
5-(5-y-cyclopentylpropylcarbonylaminothiazol-2-oxy)-methylene-N-t-butylGxazolidine;
5-(5-~-cyclopentylpropylcaxbonylaminothiazol-2-oxy) methylene-N-isopropyloxazolidine;
5-(5-41-cyclopentylbutylcarbonylamino~hiazol-2-oxy)-methylene-N-t-butyloxazoli~ine;
5-(5-4'-cyclopentylbutylcarbonylaminothiazol-2-oxy)-methylene-N-isopropyloxazolidine;
: 5-t5-y-cyclohexylpropylcarbonylaminothiazol-2-oxy)-- methylene-N-t-butyloxazolidine;
5-(5-y-cyclollexylpropylcarbonylaminothiazol-2-oxy)-3~ methylene-N-isopropyloxazolidine;
~' .

: , . .
:, ,: .
" ~ . ' `

~Q39~8~

5-(5-3'-metllylhexoxycarbonylaminothiazol-2-oxy)-methylene-N-t-butyloxazolidi.ne;
5-(5-3'-methylhexoxycarbonylaminothia~ol-2-oxy)-methylenc-N-isopropyloxazolidine;
S 5-(5-4'-methylhexoxycarbonylaminothiazol-2-oxy)-methylene-N-t-butyloxazolidine;.
5-(5-4'-methylhexoxycarbonylaminothiazol-2-oxy)- -methylene-N-isopropyloxazolidine;
5-(5-S'-methylhexoxycarbonylaminothiazol-2-oxy)-methylene-N-t-bu-tyloxazolidine;
5-(5-5'-methylhexoxycarbonylaminotlliazol-~-oxy)-methylene-N-isopropyloxazolidine;
5-(5-4'-etllylhexoxycarbonylaminothi.azol-2-oxy)-methyl-ene-N-t-butyloxazolidine;
;: 15 5-(5-4'-etllylhexoxycarbonylaminothiazol-2-oxy)-methyl-ene-N-isopropyloxazolidine;
. 5-(5-3'-propylhexoxycarbonylaminothiazol-2-oxy)-methylene-N-t-butyloxazolidine;
5-(5-3'-propy:lhexoxycarbonylaminothiazol-2-oxy)-. .
methylene-N-isopropyloxazolidine;
5-(5-n-heptoxycarbonylaminothiazol-2-oxy)-methylene-N-t-butyloxazolidine;
5-(5-n~heptoxycarbonylaminothiazol-2-oxy)-methylene-N-isopropyloxazol.idine;
; 25 5-(5-~-cyclopentylethoxycarbonylaminothiazol-2-oxy)-methylene-N-t-butyloxazolidine;
5-~5-~-cyclopentylethoxycarbonylaminothiazol-2-oxy)-mathylene-N isopropyloxazolidine;
5-(5-y-cyclopentylpropoxycarbonylaminothiazol-2-oxy)-:~ 30 methylene-N-t-butyloxazolidine;

.:

,, ' : , 5-(5-~~cyclopentylpropoxycalbony:Lami.nothia~ol-2-oxy)- .
methy:Lene-N-isopropyloxazolidine;
5-(4'-cyclopentylbutoxycarbonylarninothiazol~2-oxy)-methylene-N-t-butyloxazolidine;
S (4'-cyclopentylbutoxycarbonylamino-t}lia~ol-2 oxy)-methylene-N-isopropyloxazolidine;
5-(5-y-cyclohexylpropoxycarbonylaminothia~ol-2~oxy)-.~ methylene-N-t-butyloxazolidine; and . 5-(S-y-cyclohexylpropoxycarbonylaminothiazol-2-oxy)-methylene-N-isopropyloxazolidine.
rrhe correspondiny 4'-position substituted thiazole position isomer correspond:Lny to the particularly pre-ferred 5-position compounds enumerated above with respect to ormulas I, II and IIIr are also preferrecl but ~enerally 15 the 5-position isomers have superior properties to the 4-~- position isomers.
The preferred pharmaceutically acceptable salts are ..
hydrogen addition salts of chloride, bromide, sulfate, maleate, lactate, tartrate, succinate and especially -chloride. Thus, the preferred salts are.. the preferred anion addition salts oE formulas I and III and corres-pondingly the particularly preferred salts ax~ the pre-:.~ erred hydroyen anion addition salts of the preferred and particularly preferred compounds of formulas I and III and especially the hydrochloride salts.
The compounds of the invention can be conveniently :~ prepared by the follow.iny process, which can be repre-: sented by the followiny schematic overall reaction equa-29 ti.on s~quence:-~ .

. , .

, , , . : : ' 39~E37 ~- N\
z~ \~o-Cl12~ 2 ~ ' O\ ~p .

~A) C~ \
1~3 C~13 Z ~0~ ~CH/ ~--OI~
~H ( 2 ) (B) . ' ' ':

~2)~ o ~CH~" ~I ~CH \
(C) O-CII -CI-I CH
. (3) S 2 \ / 2 (4) (II) p Z~ \~ O-CH2-CllOH-CII2-N\ 2 wherein Y' is allcyl or phenyl, and Rl, R2 and Zlhave the:same meanings:as set.forth herein :~ above.
Step 1 can be conveniently efected by treating the compound of formula A with a suitable organic or inorganic ::
acid, preferably in a suitable inert solvent. Typically this treatment is conduct2d at temperatures in tho range of about from 0 to 65~C and preerably about 25-30~C, for abou-t from three minutes to 18 ho~lrs and precrably about from one to four hours. Ilowever, temperatures, -2~-: .

: ~
. .. .
.- . , .
. . ~ . :

~L~3~287 eaction times and mole ratios both above and below these ranges can also be used. Suitable inorganic acids which can be used include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. Suitable organic acids which can be used include, for example, formic acid, oxalic acid, acetic acid, propionic acid, and the like. Suitable solvents which can be used include, for example, water, methanol, acetone, monoglyme, ether and the like. Good results are typically obtained by using aqueous formic acid solution.
Step 2 of the above process can be effected by treating the compound of formula B with a suitable phenyl sulfonyl chloride or bromide or alkyl sulfonyl chloride or bromide, in a suitable organic solvent. The particular sulfonyl derivatlve used is largely immaterial since the sulfonyl substituent is split off during the next step. Thus, typically other phenyl sulfonyl chloride or bromide or alkyl sulfonyl chloride or bromide deriva-tives can also be used. Typically this treatment is conducted at temperatures in the range of about from 0 to 60C and preferably about from 0 to 25C for about from five minutes to 18 hours, preferably about from 10 minutes to 45 minutes, using mole ratios in the range of about from 1.0 to 1.1 moles of sulfonyl deriva-~ tives per mole of compound of formula C. ~owever, temperatures, - treatment times, and mole ratios both above and below these ranges can also be used. Suitable phenyl sulfonyl chlorides or bromides, which can be used include, for example, benzene sulonyl chloride, benzene sulfonyl bromide, or p-toluene sulfonyl chloride, p-ethyl benzene sulfonyl bromide, and the like. Suitabl~

: ,_ . .:- . , . -i: -.. : ~, . . ~ ... .
, - ~ ,. ~ : . , , ..-... . . . .
.` ,; ' : "'','"':' ' ' : ' ., .
: .~ , ; :

:~039~37 llkyl sulfonyl chlorides, and bromides, which can be used include, for example, methane sulfonyl chloride, methane sulfonyl bromide and the like. Suitable organic solvents whi~h can be used include, for example, pyridine, triethylamine or other tertiary amines, and the like.
Step 3 can be conveniently effected by treating the compound of formula C with a strong base preferably in an inert organic solvent. Conveniently this treatment is conducted by adding a strong base directly to the product reaction mixture of step 2 without separation of the product of formula C from the reaction mixture.
The treatment, can o~ course, also be applied to the isolated pro-duct of formula C. Typically this treatment is conducted at tem-peratures in the range of about from 0 to 100C, preferably about from 20 to 60C for from l/2 hour to three hours, and preerably about from 1/2 hour to one hour. However, temperatures and reac-tion times both above and below these ranges can also be used.
Suitable strong bases which can be used include, for example, alkali metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide, and the like, and alkali metal alkoxides such as, for example, sodium methoxide, potassium methoxide, and alkyl or aryl lithium such as butyl lithium, octyl lithium, phenyl lithium and the like. Suitable inert organic solvents include, for example, monoylyme, ethyl ether, benzene and the like.
Step 4 can be conducted by treating the intermediate product of formula II, of the invention, with the desired R , R amine or amino derivative or ~-heterocyclic derivative, including amines incorporated in cyclic systems ~

: . . :; :. : . ............. ..
,: ., ...... , , ~. ................... .. .

.:......... ~ . , : . .:.

. . ~ 7 ` `

~335~
For ex~unple hy txcatin~ tlle compourld of fo~mula II with an alcoholic solution oE ammonia, the corresponding compounds of forlnula I wherein each of Rl and r;2 is hydro~en is ob-tained. Similar]y, treatmcnt with a monoalkyl amine will yield the corresponding compound o ormula I wherein one of Rl or R2 is the corresponding alkyl group and the other is hydrogen, and where a dialkyl amine is used, each of R1 and R2 will be an alkyl group. Correspondingly, using a nitrogen heterocyclic such as, for example, piperidine;
pyrrolidine; or morpholine will aford the corresponding Nl-piperidino; Nl-pyrrolidinyl; or N1-morpholino compounds - of formula I, respectively. Further, althoucJh optimum conditions and solvents will vary wi-th ~he particular inter-mediate of formula II and ammonia or amino~type derivatives used, the treatment is typically conducted at temperatures in the range of about from 25 to 100C for about rom 10 minutes to 18 hours. However, temperature ranges both above and below ~lese can also be used. Suitable solvents which can be used include, or example, monoglyme, methanol, . .
ethanol, pyridine and the like.
Also although not specifically stated, it should be understood, as would be apparent to one having ordinary skill in the art, that where the starting material for a yiven step has free hydroxy or free amino groups, which - 25 could interfere with the treatment, suchgroupsare pref-erably protected with convcntional labile ester or etller ; groups by procedures which are well within the scope of the art. For example, with respect to step 2, free hydroxy groups, other than the 1- and 2-hydroxy propane groups, are conveniently protected by ~reatment with acetic anhydride.
, 2~

~L~)39~87 ~he acetatc protectil~ c~roup can -thcn be conveni~lltly re-moved, after the treatment of step 2, via treatment with a mild base.
Preferably, with the exception of step 3 which, as noted above, is conveniently conductecl by direct addition to the product reaction mixture o the preceding step, the respective products of eaeh step are isolated prior to their subsequent use as startiny materials for the next succeeding step. Separation and isolation can be effeeted by any suitable separation or purification procedure such as, for example, evaporation, crystallization, chromato~-raphy, thin-layer chromatography, ete. Specific illustra-tions of typical separation and isolation proeedures can be had by reEerence to khe corresponding examples c~escribed herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Where an isomer mixture of the product of formula I is obtained (for example, where racemie glycerol acetonide mixture has been used in step 1), the respective optically aetive (+) ... ..
and (-) isomers can b~ resolved, if desired, by conventional proeedures. For example, by reacting the compounds of formula I with an opti.cally active acid which will yield pure optical salts of the eompounds of Eormula I and then isolating the respective (~) and (-) optieal salts by re-peated erystallization.
The 5- and 4-aminoearbonyl substituted starting ma*e-rials of ~ormula A ean be eonveniently prepared aecording 28 to either of the following overall reaction sequences:

. .
-2~-:.
:::. .
, .
:

~L~3~

R ' O~-¢ \~--X ~ ~ ~ o~o-cll 2 -fH i ll 2 A ' A \C

.; ' ~ wherein R' is lower alkyl ana preferably is - ethyl and X is chloro or bromo.
Steps a and.a' of the above process can be effected by treating the respective khiazole compound of formula ~' : S or A" with glycerol acetonide in a suitable inert solve~lt, in the presence o~ an al~ali metal hydride. Typic.ally, this treat~ent i.s conducted at temperatures in the range : of about from 20C to reflux for about from a few minutes .. to 20 hours, using mole ratios in the range of about 1 to .:, .
100 moles of glycerol acetonide per mole. of compound Al : or A". .. However, temperatures, react.ion times, and mole ~ ratios both above and below can also be used. Suitable alkali metal hydrides which can be used include, for example, sodium hydride, potassium hydride, calcium hy-.. 15 dride, lithium hydride and the like. Suitable inert organic solvents which can be used include, for example, : . monoglyme, tetrahydrofuran, diglyme, dimethylormamide, : and the like. Also an excess of glycerol acetonide can be used as the solvent. Further by using the optically pure ~) glycerol acetonide isomer (see J. Biol. Chem., v. 128, p. 463 (1939)) or the optically pure (-) glycerol . acatoni.de isomer (see J. Am. Chem Soc., v. 67, p. 944 ., ,, . ,,, , . . ............. - .
.;:: ' .

~ ~3~%~

(19~5)), the corresponding (t) or (-) optically ac-tive i.so-mer oE formula ~ or ~"' i5 obtained. Correspondin~ly, wher~in a (~) or (-) isomer mlxture of the glycerol acetonide i5 used, the p~oduct will similarly be a mixture of isomers.
This optically active isomer relationship between the starting materials and products exist throughout all the steps of various processes described herein. Also typi~
cally and conveniently, a racemic glycerol acetonide isomer mixture will be used and thus typically the product will correspondingly be a racemic mixture. The starting mate-rials of formula A" can be prepared according to known procedures such as, ~or example, described in Helv. Chim.
Acta., p. 2057 (1954) and Helv. Chim. ~c ~., p. 1073 (1942).
The starti~g materials of formula A' and also the starting materials of ~ormula ~" can be prepared according to the procedures set forth in the respective prepa~ations des-cribed herein below or by obvious moclifications o~ such procedures.
Step a" can be conveniently effected by treating the compound of ~ormula ~"' with an amine derivative having the desired R3,~4 groups. Typically, this treatment is conducted in a suita~le inert organic solvent at temper-atures in the range of about from 0 to 100C, preferably about from 20 to 50C for about from one to 48 hours, pre~-erably about ~rom two to 10 hours. Typically, a 10-50 molar excess of the desired amine is used. Suitable amines which can be used include, Eor example, 4'-methylhexylamine, N-methyl-N-4'-methylhexylamine, 5'-methylhexylamine, n-do-decylamine, cycloheptylamine, 12'-hydroxydodecylamine, - 30 heptylamine, N-heptyl-N-methylamine, y-cyclopentyLpropylamine, .
.~ ~, . . ., ~.
.. ~

.:: . .
. . .

~0392~37 `.-cyclopentylethylamine, 4-cyclopentylbutylamine, dicyclohep-tyl-amine and the like. Suitable inert organic solvents which can be used include, for example, methanol, ethanol, glyme, and the like.
The starting materials of formula A wherein Z is R OCN- series can also be prepared according to the following procedure repre-sented by the following schematic overall reaction equation se-quence:

2~ ~ ~ C~2cl~l 2 b ~2~ 0CH2CIHI~2 10 A** H C-C-CM / A* H3C-C-C~3 .; ~
.

15~40lc~ 0c~2c~ 2 As shown above, the 4- or 5-amino compounds of formula A** can be prepared from the corresponding 4- or 5-nitro compounds of formula A** via hydrogenation. This can be conveniently effected by treating the nitro compound of formula A** in a suitable inert organic solvent with gaseous hydrogen in the presence of a suitable ~ catalyst such as, for example, Raney nickel. This treatment is : typically conducted at temperatures in the range of about from -30 to +30C, preferably about from 25 to 30C for about from 15 minutes to 16 hours and preferablY ~-:
'' , . . .

: ~ :: :. . : , : : : , :, :- , , , :, - :: , :

. :. : . , -^:: : ~ : :: ....... :. .. : . , : :: : ~ .

3~ 7 a]~out from one to three hour~. '.ui.table .~olvents wh.ich can be used incluc1c, for example, e~hanol, metllanol~ ~thyl acetate, tetrahydrofuran, and the ].ilce. Suitable hydrogen-ation catalysts which can be used include~ for example, Raney nickel, l~alladium, and tlle li]ce. The 5- or 4-nitro-. thiazole starting materials can be prepared by treating the correspondi.n-~ 2-chloro or 2~bromo ox 5- or 4-~itrothiazole (Helv. Chim. Acta., v. 33, p. 306 (1950)) with ylycerol acetonide as described above. Step b"of tl~e above reac-; 10 tion sequence can be efected in two phases. Xn the first phase the 4- or 5-amino compoullcl of formula ~* is treated with sodium hydr.ide in an inert oryan.ic ~olvent corltai.lling a catalytic amount of t-butanol. Typically, this treat- -ment is conducted at temperatures .in the range of about from 0to 20C, for about from one to 24 hours and prefer-ably about from seven to eight hours. Best results are obtained by conductiny th.is treatment under anhydrous con-. ditions and preferably under an inert gaseous atmosphere.
In the seconcl phase the desired R4-substituted chlorofor-mate is then conveniently added to the reaction mixture without separation of the intermediate product, and the .~ mixture maintained at from about -10 to 80C, preferably at reflux, for from about 1/2 hour to 16 hou.rs. Suitable alkyl chloroormates which can be used include, for example, . 25 4'-methylhexyl chloroformate, 5'-methylhexyl chloroformate, :; y-cycl.opentylpropyl chloroformate, ~-cyclohexylethyl cl~loro-~ormate, n-heptyl chloroformate, and the like. A:Lterna-tively, step b"can be e~fected by treatin(3 the ~ or S-amino compound of Eorn~ula A* wi-th the desired R~--substitu~ed chloro-formate in an inert oryanic basic solvent. Typically t.his , . : .
, .
.~ , ,. . . . ,~

3s~7 treatment i~ conducted at tempsratures in the ranqe o about from 0 to 30C for about from onQ to 24 hours. The same range of alkyl chloroformates can be u~ed ~n thi~
treatment as above. Suitable ba~ic ~olvent~ include, for S example, pyridine, triethylamine and the l.ike.
The R4O~- starting material~ o~ formula A can al80 ~: be prepared starting from the known R3-carboxylic acid ethyl e~ter ( alv. chim. Acta., vO 29, p. 1230 (1946) ) accord~ng to the sequence represented by the following : 10 schematic reaction equations:

N~ NH ~H ~ ~0 R ~-C - ~ ~ Cl ~ -(c) -? H2N N ~ ~ ~ Cl _ ~ 2_~
, ., ~*.~,* ";~*
. :j .
: 15 C~ Cl ~ _ ~ R40~ t ~ Cl A* A' ; wherein R' is lower alkyl, aryl or arylalkyl.
Step c o:E the above reaction sesluence can be effected by treating the above 2-chloro-4- or 5-carbo~ylic acid or ester compound of formula ~**~ with hydrazine hydrate. ~ypically, this treatment i~ conveniently conducted at temperature~
in the range of about from ~ to 100C, for about from one .~ 25 to six hours. ~uitabla ~ner~ organic solvenks which can be used include, for example, methanol, ethanol, monoglyme, dimeth~rlformamide and th13 like. Step c ' is effected in two ~tep~, fi~t by treating the 4- or 5-hydrazide . ~ .

)39~37 roduct of step c (formula A**) with nitrous acid. The nitrous acid can be conveniently prepared by reacting sodium nitrite an~
conc. hydrochloric acid. The treatment~step c'~l)) is conveniently conducted at ambient temperatures although temperatures both above and below ambient can also be used. The resulting 4- or 5-azido-2-chlorothiazole is then heated ~step c'(2)) at temperatures in the range of about from 60C to 150C under anhydrous conditions in a suitable inert organic solvent; to give the 4- or 5-isoc~an-ate of formula A*. Suitable inert organic solvents which can be used include, for example3 benzene, toluene, xylene, diglyme, tri-glyme, and the like, and mixtures of such solvents.
Step c can be efected by treating the compounds of formula A* with an alcohol of the desired R group. Typically, and pre-ferably, this treatment is conducted at temperatures in the range of about the reflux temperature of the system, for about from 1/2 hour to 5 hours. Suitable alcohols which can be used include, for example, heptanol, 5'-methylhexanol, 4'-methylhexanol, ~-cyclo-hexylethanol, ~ -cyclohexylpropanol and the like. Alternatively, the treatment can be conducted in an inert organic solvent such as~
Eor example, monoglyme, dioxane, benzene, and the like.
The starting material of formula A can then be prepared by ~I treating the 2-chloro compounds of formula A with glycerol aceto-.:j -1 nide as described above-.,.,~

~, c :;:;: .: . ,. : ;. : ~ , . . ,:

~- .. ~ . .~ . . -:: . . . : ; . :.
. -~ . . - , . . ~ .
.: ~ .. . . . ; - . .
', :~ ' ',` . . : ., , . .,-: . : ~ : :

~35~Z~3~
Tll~ st~lrti~g materi.als of formula ~ wllerein z .is Rq~N- can ~)e advanta~ously prepa~-ed according to the 3 ollowin~ overall reaction se~fuence:

sr~3r ~ Br---¢~ O-CEl2~~CH 1112 (2") S S O\ /0 ( D ) 3 Ll --C~o C}12 ICI 111~. (3"~

~13) /1 ~

--~ Li O-C C~---CN2-b~l bH2 (4 i (F) / \
. CEI3 CH3 :' .

CE13C112o~o~ o CH2 Cb}l ICH2 (5"~

(G) / \

5--")> N3C--~ -CH2-lH ICIi2 (6") .

.
.
.

' . ~ . ' . `' .
, . . ~ . ;
. .: ~, . . .
1' ` . . . ..
:, ;,-. , , ~ :
., ~ . . . .

2 ::
~--N\ R Msx ~
r~ O=C~ o-CH2 ~ ~H2 ~7'~
~J) > R4gN - 1+ ~ CH2 ~n ~H2 ( 8 ~

(A) (~"~ R ~ ~ 0-CH2 ~ CH ~

: 3 3 ' wherein X' i9 chloro, bromo or iodo; and R3 and R4 are a~ de~ined above.
Step 1~ of the above proces~ can be conveni~ntly effected by treating th~ 2,4-d~bromothiazole or 2,5-dibromo-: 5 thiazole 3tarting makerial with glycerol acetonide, in a : suitable inert organic so}vent in the pre~ence of an alkali metal hydride in the ~me manner as described herein above :-with respect to the preparation of other 4'- or 5'-position `~
~ub3tituted thiazo}-2-oxy-propanediol 1,2-acatonide~. The -2,5-dibromothia201e and 2,4-dibromothiazole are known com-pound~ and can be prepared according to procedure~ described in Recueil des Travaux Chimioues de~ ~a~s Ba~e, volume 73, ~.
page 325 ~1964) and the 2, 4-dibro~othiazole in Bulletin de ;
.

' ', 3~2~37 `a Societe Chimique de France, page 1735 (1962), respectively.
Step 2" can be effected by treating the compound of formula E
with an alkyl lithium reagent (preferably t-or n-butyllithium) in a suitable inert organic solvent. Typically this treatment is con-ducted at tempera-tures in the range of about ~rom -10C to -150C~
preferably about from -60C to -80C for about from 10 minutes to two hours, and preferably about from 15 minutes to one hour, using mole ratios in the range of about from two to three moles of alkyl lithium per mole of the compound of formula E. Best results are typically obtained by conducting the treatment under anhydrous con-ditions and preferably in the absence of air, e.g. by conclucting the treatment under an inert gas such as nitrogen. Suitable inert organic solvents which can be used include, for e~ample, tetrahydro-; furan, hexane, diethyl ether, monoglyme, and mixtures of such sol-vents and the like.
Step 3" can be conveniently conducted in situ by bubbling anhydrous carbon dioxide through the reaction product solution of the compound of formula E. The carbon dio~ide reaction is typically conducted at temperatures in the range of about from -78C to room temperature and since the rate of reaction will vary with the flow rate of carbon dioxide, the reaction is preferably monitored by thin-layer chromatography and allowed to proceed until the thin-layer chromatography reveals that thiazol-2-yloxypropanediol aceto-.,.,.
nide derived from the starting material of formula E has been consumed.

Step 4" is also conveniently conducted in situ by adding an : alkyl chloroformate directly to the reaction medium. Typically this step is conducted at temperatures in the range of about from -78C to room temperature for about from one hour to six hours.

Suitable alkyl chloroformates which can be used include, for ., . . , . - .

: , . .

~l~3~2~7 ?xample3 methyl chloroformate, ethyl chlor~formate, isopropyl chloroformate, t-butyl chloroformate, n-butyl chloroformate and the like. Best results are typically obtained u9ing ethyl chloro-formate. Accordingly the above reaction sequence has been shown using ethyl chloroformate although other alkyl chloroformates could also be used. Also typically about from 1.1 to l.S moles of alkyl chloroformate is used per mole of compound of formula F.
Step 5" is also conveniently conducted in situ by adding sodium azide, preferably as an aqueous solution, directly to the ` 10 product reaction mixture of formula G. Typically this step is conducted at temperatures in the range of about rom 0C to room temperature, preferably about from 10 to 25C, for about from 1/2 hour to six hours, preEerably about from 1/2 hour to two hours.
Step 6" is conveniently effected by adding the compound of formula H to an inert aromatic solvent, such as toluene and heating the mixture at temperatures in the range of about from 100 to 110C, preferably about from 105-108C, for about from 1/2 hour to two hours. Also while best results are obtained using these conditions, temperatures and reaction times, both above and below these ranges could also be used. Also other inert solvents such as, for example xylene and diglyme could also be used.

.'' ~.
., .

: :: . . , . . ~
. .:, . . . ~ ~ .~ , , . -~l~3~2~9~

Step 7" can be con~enient]Ly e~fected by a Grignard type reaction by treating th0 isocyanate produ~t o~ formula J
with a Grignard reagent having the de~ired R -substituent~.
~ypically thi~ treatment i8 conducted at temperatures in the S range o~ about from -78 to -100C, prefer~ly about -78C, for about from one minute to 1/2 hour and preferably about from one minute to 15 minutes. T~pi~ally the tr~atment i8 conducted in an inert solvent ~uch a~, for example, toluene, : ether (diethyl), tetrahydrofuran, monoglyme and th~ like, or mixtures thereof. Suitable Grignard reagents which can be used are tho~e having the general formula R4MgX' whereir X' i~ ~hloro, bromo or iodo and R is as defined herein, #uch .~ Grignard reagents $nclude, for example, 0'-methylhexyl~agnesium bromide~ 4'-methylhexyl-magne~ium bromide; methylmagnesium iodide, butylmagnesium chloride: r-cy~lopentylpropylmagne~ium bromide; dodecylmagne~ium bromide and the like. The Grignard reagent can be prepared according to known procedure~, or obviou~ modification~ thereof such as, for example, descrlbed in .:: Pieser & Fieser, Rea~ents for Organic Synthe~is, pages 415-424 (1967) John Wiley & Sons, Inc.
Where the compounds wherein R3 i8 oth~r than hydrogen are de~ired, ~tep 8" can be conveniently conducted in two phases by fir~t treating the R3-sUbstituted compound of formula A
with a strong alkali ~uch as butyllith~um, sodium me~hoxidç~, sodilDn hydride, or potassium t-butoxide, in an inert organic ~olvent under anhydrous conditions. ~ypical}y thi3 treatment i8 conducted at tempsratures in the rang~ of ~out ~rom -70 to -85C for about from five minutes to two hour~, u~ing about from 1 to 1. 5 moles of base per mole of ~... ,.. ~, .
' ', ' ' ~ '. ~ ` ' ' ' ` ' , ~3Y3~197 compound o~ formula A. Suitable inert organic ~olvent3 whioh can be u~ed include, fo~ example, tetrahydro*uran, diethyl ether and the like. The ~econd pha~e i~ conducted in situ by adding the de~ired reagent having the for~ula R3X' wherein R3 and X' are as defined above!, preferably in cln aprotic solvent (e.g. ether, tetrahydrof.uran, mo~oglyme, dimethylformc~mide) to the product reaction mixture and then allowing the resulting mixture to warm to about room t~sm-perature. Thi~ phase i8 typically conduct~d at temperature~ :;
Of about from -78 to 25C, conveniently room t~mp~ratur0, for about from 1/2 hour to two hours. suitable R3X' rea-gents in~lude, for example, methyl chloride, ethyl bxomide, phenyl chlor~de, propyl iodide, 5l-methylhexyl chlor~de and the like. The R3X' reagents can be prepared according to conventional procedure~, well Xnown to the art, or by obvious modification~ o~ such procedures.
The ~tarting materials of formula A wherein Z i8 R40~N- can be advantageously prepared according to tha ~ollowing overall reaction sequence:

,,N 4 ' O~C~ 0-CH~ 2 _ OH >
- S O~

~ ~ CEI
`' ' :' ,~? R OC~ O-CN g~N ;~

.
.
(~) ..... . . .
~ . ~ . . .

~ ~Q3~

' 2~ R4~8~3~ o -~ c CH

(K) ,C~ :
CH CH

wherein R3 and R are a~ de:Eined h~rein ~ove.
Step 1' can be effectsd by tr6~at:ing the compound oi~
for~nula J with an al~:ohol havi~g the desir6~d R4 group -i.e. R40H. Although th~ treatment can be ~!onductad wi~hout a ~olvent, the treatment i8 typically conducted in an inert organic solvent such as, for exampl~, tolue~e, since this ~impli~ies isolation of the resulting product. The treatment is typically conducted at temperatures in the range of about from 95 to 120C for about from 1/2 to four hours, pre~erably about one to two hours. Typically a ~toichiom~trical exce~s of alcohol is u3edl for example, a 10-20 mole equivalent exce~s ~an b0 conveniently used. suitable ~ OH alcohol~ w~ich can b~ used include, for exampl~, 5-methyl~axyl alcohol: 4-methylhexyl alcohols methanol: phenol: r-cyclophenylpropyl al~ohol; dode~yl alcohol and the like. `;
Where the co~pounds wherein R3 i~ other than hydrogen ~: .
are desired, step 2~' can be ~onveniently donducted in two ~ -pha~es by first treat~ng the R3-substit~ted compound of formula A with a ætrong alkali such a~ butyllithium, Yodiu~ methoxide, or ~odium hydride, in an inert organic solvs~t under anhydrous ;~
condition. Typically thi3 treatment is conducted at tem-perature~ in the range of about from -70 to -85~C for about from 1/2 hour to two hours, using ~bout rom 1 to 1~5 mole~ ~

- 42 `
. ' .

. . .
.. . ~ .

~39%~37 :~
of strong alkali p~r mole of compound of ~ormula ~. Sult-able inert organic solvents which can be used include, for example, tetrahydrofuran, diethyl ether ancl the like. The second phas~ is conduc~ed in situ by allowing the product reaction mixture to warm to about roorn tcm~erature and then adding the de~ired rea~.~ent having tl~e formula R3X' wherein R3 and X' are as defined above, preferably in an aprotic solvent (e.g. ether, tetrahydrofuran, dime~hylformamide, monoglyme, etc.). Thi.s phase is typically conducted at temperatures of about from 15to 30C, conveniently room .; temperature, for about from 1/2 to two hours. Suitabl~
R3X' reagents include, ~or example, methyl chloride, ethyl brom.ide, phcnyl chloride, propyl iodo, S'-methylhexyl chloride and the like. The R3X' reacJents can be prepared according to conventional procedure~, well ]cnown to the art, or by obvious modifications of such proceclures.

. ! ~
" .,, . 1 .

. . , .

' ',"; ' ' ~,' . ",, . , ,' ' " ' ' ';, "' ' '. ' ' . ' : '', . ' ' ' : ' '`': ' "' " .' ' ' . . ' ' ' : ., `' ~ ' '' ,`''~ '' ' ' ' : ' ' '`, '' , ' . . . , ' ' .' '.'.':, -., ' ' ' . ', ' ;' ,,'; ' , ' ' ''.. ' ' , ', ' ,`,;' ' , ' . .' "..... '.' ' ' , . . . :
' ,. " ' . ' ' . ' ~ ' ' ' ' ` '' ' ' . ' ' :: .'. '.:' '. ' ' . . :.'.: ' : ' .. ' ' ' ' ' ~`~ ''~ '. . , ': ' ` . ': ' "' "'.'. "; ; ' '. ' " ' ' . ' 3~3~2~37 The compounds vf ~ormula III can be prepared direc~ly from the corre~ponding compounds of formula I:

S ~ ~ 2 ~ 2 ~ \ ~ > z ~ ~ -0-CN2-C~-CD2 I' III \ /
; R~ \R6 ~ wherein R5, ~ , R and z are a~ clefined herein above.
This trea~ment can be ~onveni2ntly efPected by treating the corresponding compound of formula I' with a ketone or aldehyde having the de3ired RS and R6 ~ub~tituent~, and aluminum isopropoxide. Typically this treatment i8 conducted at temperatures in the range of about from 20 to 100C for lS about fxom one to 48 hours u3ing mole ratios în the range of ~bout from one to 150 mole~ of ketone and one o 10 moles of alwminum isopropoxids per mole of co~pound of formula I. : -Typically a substantial CXC~5 of ketone or aldehyds ~ .
is used a~ th~ excess u~ually will function a~ an inert organic solvent. Suitable ketone~ whi~h can be used include, for example, formaldehyde, acetone, cyclohexanone, cyclopentanone, cycloheptanone, and the like. A180 aluminum t-butoxida can be used in place of aluminum isopropoxide. :, Alternatively the above tre~tment can be effected in : 25 the case o~ the 2-spirocycloalkyloxazolidine compounds, of ~;
formula III ~i.e. R5 and R together with the ~arbon atom to which they are ~oined form a cycloa~kyl ) , by :;

:, ' ' ' :~

,~
., . . .. : . ~
.
:

~3~ '7 reating the corresponding compound of formula I ' with a cycloal-kanone having the desired cycloalkyl group, in an inert organic solvent in the presence of potassium carbonate. Typically this treatment is conducted at temperatures in the range of about from 20 to 100C for about from 48 to 72 hours, using mole ratios in the range of about from one to 150 moles of cycloalkanone per mole ;.
of compounds of formula I'. Suitable cycloalkanones which can be used include, for example, cyclohexanone, cyclopentanone, cyclo-heptanone, and the like. In place of potassium carbonate, the fol-lowing compounds can also be used; sodium carbonate, lithium carbo-: nate, and the like.
The compounds of formula III, and of formula I, wherein Z is ~.
the group R R N~- and one of R or R is hydrogen and the other is hydrogen, lower alkyl, or arylalkyl, can also be prepared via 15 the process of the invention~ represented by the following schema- .
tic overall reaction equations~
,',.' .~' fH2 C\ CH2 + 2 ( 1 ) fH2 CH ICH2 OH / OH OH NHR " ' (glycidol) / (A') (2') R NC _~ ~X 4 3 li ~
f 2 f 1 2 , R R NC ~ ~ O-CH2 IcH I 2 .

2 5 OH o NR / O ~NR 7 R/6 \R 5 ~ ( I I I ) R R
(B~ ) : o N
4 3 ~ o-cH2-cH-cH2-NR
--S OH H

3 0 ( I ) .' .
... .
: `- :: : ' :: : . :

~39~37 whexein R"' is hydrogen, lower alkyl, aryl, or arylalkyl, X is chloro or bromo, and R , R , R , R and R are as defined herein above.
Step (1') of the above process can be effected by treating glycidol with ammonia or the desired monosubstituted amine. Typi~
callyJ this treatment is conducted at temperatures in the range of about from 20C to reflux and preferably at reflux, for about from 0.5 to five hours. Frequently, as the reaction is exothermic and typically will occur at ambient temperature, the reaction can be conducted at reflux without supplying external heat. Also wherein anhydrous ammonia or volatile amines are used, the reaction is typically conducted by passing the gaseous ammonia or substituted amine through a solution of glycidol. Alternatively, suitable inert organic solvents can be used but, typically are unnecessary as glycidol itself is a liquid at room temperature in which the respective substituted amines are usually soluble. Suitable sub- -stituted amines which can be used include, for example, methylamine, ~`
ethylamine, propylamine, isopropylamine, n-butylamine, t-butyl-amine, phenylethylamine, p-methylbenzylamine and the like.
Step (2') can be effected by treating the product of step (1'), of formula A', with an aldehyde or ketone in a suitable inert -organic solvent such as, for example, ethanol. Typically, this `;~

treatment is conducted at temperatures in the range of about from .
20C below reflux to reflux and preferably at reflux about from eight to 18 hours. Typically, formaldehyde is used in the form of ` an aqueous solution.

Step (3') is preferably conducted in two steps. In the ini-tial phase the 5-hydroxymethyl-3-oxazolidine or 5-hydroxymethyl--~ substituted oxazolidine product of step (2') (i.e. formula s') is treated with an alkaline metal hydride, e.g. sodium hydride, in a ' ' ' - , . . . .
:

~3~37 ;uitable inert organic solvent. Typically, this treatment is con~
ducted at temperatures in the range of about from 20 to 80C for about from 15 minutes to five hours. Preferably this treatment is ~-conducted under anhydrous conditions and praferably conducted in the absence of air, e.g. under an inert gas, e.g. nitrogen. Inert organic solvents which can be used include, for example, dimethyl-formamide, monoglyme, diglyme, and the like. The second phase of step (3') is conducted by treating the initial product reaction :: ~
mixture with either 2-chloro or 2-bromothiazole or the desired sub-stituted-2-chloro or 2-bromothiazole. Typically, this treatment is conducted at temperatures in the range of about from 60 to 140C
for about from one to 24 hours. Typically, the 2-halothiazole reagent is added to the reaction mixture in the form of a solution in a suitable inert organic solvent. Suitable inert organic sol-vents which can be used include, for example, dimethylformamide,monoglyme, diglyme, and the like. Also an excess of the oxazoli-dine reagent can typically be used as the solvent. Again prefer-ably the second phase will also be conducted under anhydrous con-ditions and preferably conducted in an inert gas such as, for example, nitrogen.
Step (4') can be convenient:Ly effected by simple acidic or ; basic hydrolysis of the intermediate of formula III. Thus, acid hydrolysis can be conveniently effected by treating th0 compound of formula III with a suitable organic acid such as, for example, acetic, formic, oxalic acid and the like or suitable acids such as, for example, hydrochloric, sulfuric, and the like. Preferably the hydrolysis is conducted under mildly acidic conditions. Similarly, basic hydrolysis can be conducted by treating the compound of for-mula III with a suitable base such as, for example, dilute sodium hydroxide, potassium hydroxide and the like. Preferably the .~ , ~39~X37 ydrolysis can be conducted under mildly alkaline conditions.
Alternatively, the hydrolysis can be conducted via exchange with a suitable ion exchange resin in either the H or OH form.
Again, as noted previously with respect to the first described process of the invention, it should be understood that in each of the aforedescribed preparation and process steps, that where starting materials having free amino or free hydroxy groups which could interfere with the desired treatment are used, such starting materials are first protected with cGnventional labile ester or ether groups. And again, unless noted to the contrary, it is pre-ferred that the respective products of each process step or prep-aration step, described herein above, be separated and/or isolated prior to its use as starting material for subsequent steps.
Separation and isolation can be effected by any suitable purifica-tion procedure such as, for example, evaporation, crystallization, column chromatography, thin-layer chromatography, distillation, `;
etc. Specific illustrations of typical separation and isolation ~
.....
procedures can be had by reference to the appropriate examples described herein below. However, other e~uivalent separation pro-cedures could, of course, also be used. Also where an isomer mix~ture of the product of formula I or III is obtained (for example, ; wherein an isomeric mixture of glycerol acetonide or glycerol has been used in steps 1 and 1', respectively), the respective optically ;~ active (~) and (-) isomers can be resolved by known procedures.
Optimum resolution procedures can be obtained by routine trial and ~ ;
error procedures well within the scope of those skilled in the art.
The pharmaceutically acceptable acid addition salts of the :: :
~- compounds of formulas I and III can be prepared via neutralization ~

: :
of the parent compound, typically via neutralization of an amino moiety, with the desired acid. Other pharmaceutically acceptable -48- `
.,,, ' :, . . ~ - , .. . . .

ddition salts can then be conveniently prepared from the neutrali-zation addition salt~ via anion exchange with a suitable ion ex-change resin in the desired anion form.
The compounds of formulas I and III, of the invention, are useful in the treatment and palliation of cardiovascular abnormali- -ties in mammals. These compounds primarily achieve their thera-peutic action by selectively blocking the cardiac ~-adrenergic ~;
receptor sites and accordingly, because they are cardiac selective, they can also be applied to treat cardiac abnormalities in patients suffering from asthma or chronic obstructive lung disease. The compounds are especially useful in the treatment or palliation of cardiac arrhythmias, angina pectoris, hypertrophic subaortic steno-sis, pheochromocytoma, thyrotoxicosis, hyperkinetic syndromes, tetralogy of Fallot, mitral stenosis with tachycardia, general ischemic conditions, and hypertension founded on elevated cardiac outputs due to a hyperadrenergic state. The compounds are active, both in the treatment or palliation of acute attacks of such car-diac disorders, and further can be applied prophylactically to prevent or reduce the frequency of such attacks. This prophylac-tic action is particularly desirable in reducing the frequency ofattacks of angina pectoris, since the medication (i.e nitroglycerin) presently commonly used in the treatment of angina pectoris has no recognized prophylactic action.
Additional information concerning the use, action and deter-mination of ~-blockers can be obtained by reference to the litera-ture such as, for example, Dotlery et al, Clinical Pharmacology and Therapeutics, volume 10~ ~o. 6, 765-797 and the references cited therein.
The compounds of formulas I and III can be administered in a wide variety of dosage forms, either alone or in combination with : ;

~3~8~
~ther pharmaceutically compatible medicaments, in the form of pharmaceutical compositions suited for oral or parenteral adminis-tration. The compounds are typically administered as pharmaceuti-cal compositions consisting essentially of the pharmaceutically acceptable salts of the compounds of formula I and/ox III and a pharmaceutical carrier. The pharmaceutical carrier can be either a solid material or liquid, in which the compound is dissolved, dispersed or suspended, and can optionally contain small amounts of preservatives and/or pH-bufering agents. Suitable preserva-tives which can be used include, for example benzyl alcohol andthe like. Suitable buffering agents include, for example, sodium acetate and pharmaceutical phosphate salts and the like.
The liquid compositions can, for example, be in the form of solutions, emulsions, suspensions, syrups or elixirs.

. ..:

~33~

and optionally can c~nt~in small quantitie~ of pre~ervatives and/or buffering agent~
The solid compo~ition~ can take the form of tablets, powder~J cap~ules, pills or the like, preflerably in unit do~ags form3 for simpla administrat~on or pre~ise dosage~.
Suitable solid ~arriers include, for example, pharma~eutical :
grade8 of ~tarch, lactose, ~odium saccharin, sodium bi~ul-fite and ths liks.
- The compounds of thi~ invention are typically admin~
~ 10 stered i~ do~ages of about from 0.01 to 5 mg. per kg. oi body weight. The preci8e effective do~age will, of cour~e, vary depending upon the mode of admini~tration, the condition being treated and the ho~. Preferably, the compounds are administered orally, either as solid compositions, e.g. tablet~, or liquids a~ described herein above.

.
Also the primed numerical terms designated branched : alkyl groups are believed clear on their face, it is noted, that a8 u~ed h~rein above and below, that branched alkyl terms such a~, for example, 4'-methylhexyl, refer to group~
having the ~ormula:

. ~H3 .: CH3-CH2-- H2-C~I2 -CH2-CH2-: 6' 5' 4' 3' 2' 1' A further understanding of the invention can be had from the following non-limiting Preparations and Example~
Al~o as u~ed herein above and below unls~s expressly ~tated to the contrary, all temperatures and temperature ranges refer to the Centigrad~ ~yst~m and the term~ a~bient or room te~perature refer to about 20 C. The term perceslt :: :

~1~3~:32~

or ~) refers to weight percen-t. The tcrm e~uival.ent reers to a quantity of rea~en-t equal in moles to the moles of the preceding or succeeding reactant recited in thclt Preparation or Example in terms oE moles or finite weight or volume. ~lso unless expressly stated to the cont:rary, racemic mixtures are used as sta.rting matcrials and correspondingly racemic mixtures are obtained as products and where necessary, preparations and examples are repeated to provide sufficient quantities o starting 1~ mnterials for suLsequent prepnrations nnd exnmples.

, .

-5~-. . . . . .

-:
~ ~Q392~37 PR~:P~ 'rION
2-Bromo-5 alk~ car~onyltllicl~ole A mixture containin~ 272 g. of methyl chloroacetate and 158 g. o methyl aceta~e in 600 ml. of toluene is S cooled to 0C. A total o~ 143 g. of sodium methoxide is ; added portionwise, maintaining the temperature of the mix-ture below 5C, with rapid stirrin~ -The mixturc is then s~irred for an additional four hours at 0C and one liter of water ~hen added yielding a two phase liquid~ uid mixture. The toluene layer is decanted oEf and the aqueous layer is then washed with ethyl ether and neutralized wi~h dilute a~ueous h~drochloric acid and extracted with ethyl ether. The ethyl ether extracts are comb:ined, dried over ,:
magnes.ium sulfate and then evaporated yielding the oil resi~
due o~ methyl ~hloroeormyl acetate. 210 Grams o thiourea in 1500 ml. oE ethanol is then added to the residue an~
refluxed for 18 hours. The ethanol solvent is then dis-tilled off and one liter of water added to the concentrate.
The aqueous mixture is then filtered and the iltrate made ' slightly basic by the addition of dilute aqueous ammonium hydroxide ~ielding a precipitate which is then recovered by filtration, washed with water, and dried, under vacuum, for 18 hours at 70C yielcling 2-amino-5-methoxycarbonyl-thiazole.
A mixture containing 100 g. of amyl nitrate and 600 ml.
of bromoform is warmed to 70C and then a total of 100 g.
of 2-amino-S-methoxycarbonylthiazole i5 ~dded portionwise with rapid stirring while maintaining the temperature at about 95-100C. The mixture is then stirred for an addi-tional ten minutes at this tcmperature and then tle bromoform .

~39~37 s distilled off under vacuum. The residue is chromatographed on silica gel yielding 2-bromo-5-methoxycarbonylthiazole.
Similarly, 2-bromo-5-ethoxycarbonyLthiazole is prepared by following the same procedure but using ethyl chloroacetate and sodium ethoxide in place of methylchloroacetate and sodium methox-ide.
2-Bromo-4-methoxycarbonylthiazol and 2-bromo-4-ethoxycarbonyl- -thiazole are respectively prepared by following the procedure described in Helv. Chim. Acta., v. 25, p. 1432 (1942); ibid., v.
10 28, 362 (1945) and ibid., v. 27, p. 1432 (1944).

,:

2-Bromo-5-substituted aminocarbonylthiazole A mixture containing 10 g. o~ 2-bromo-5-methoxycarbonylthia-15 zole, 10 ml. of 5'-methylhexylamine, 12 ml. of water and 50 ml. of methanol is stirred for 18 hours at room temperature. The mixture is then evaporated to remove methanol and poured into 50~ ml. of ethyl acetate, which is then washed three times with water, then dried over magnesium sulfate and evaporated to dryness. The resi-2Q due is then redissolved and recrystallized from ethyl acetate aff-ording 2 bromo-5-(5'-methylhexylaminocarbonyl)thiazole.
- Similarly, by following the same procedure but respectively .
replacing 5'-methylhexylamine with 4'-methylhexylamine, 3'-methyl-~- hexylamine, 4' ethylhexylamine, 3'-propylhexyl, cyclopentylamine, ~-cyclopentylethyl, ~-cyclopentylpropyl, 4'-cyclopentylbutylamine, ; ~ -cyclohexylpropyl, . . , . : . `. :

. :: . . . ~ :: ~: : .
:, . . . . , ,, ~ ::
. ~: . .: ,: :
- . -. ~ ..

~1~3~ 7 Il-heptyla~oine, cycloheptylamine, n-octylamine, n-nonylamine, n-dod~cylamine, 7 '-hydroxy-n-heptylamine, 9 '-acetoxy-n-nonylamine, ~-methoxyethylamine, di(r-cyelopantylpropyl) amine, di(n-dodecyl)a~ine, l'-methylhexylamine; 6'-acetylbexyl-s amine: 6'-dimethylaminohexylamine; 6'-methoxyhexylaminet ~-pro-po~ypropylamine: and 6'-aminohexylamine, the following compounds are r~spectively prepared:
2-bro~o-5-(4'-~thylhe~ylaminocarbonyl)-thiazol~
2-bromo-5-(3'-~ethylhexylaminocarbonyl)-thiazole:
2-~romo-5-~4'-ethylh~xylaminocarbonyl)-thiazole 2-bromo-5-(3'-propylhexylaminocarbonyl)-thiazoles 2-bromo~S-~yclopenkylaminocarbonylthiazole:
2-bromo-S-(~-cyclopentylethylaminocarbonyl)-thiazole;
2-bromo-5-(r ~yclopsntylpropylaminocarbonyl)-thiazole;
1 2-bromo-S-n-h~ptylaminocarbonylthiazol~;
2-bro~o-5-(4'-cyclopentylbutylaminocarbonyl)-thiazol~;
2-bromo-5-(r cyclohexylpropylaminocarbonyl)-thiazole: ~ -2-bromo-5 cycloheptyl2minocarbonylthiazole;
2-bromo-5-octylaJninocarbOrlylthiazoles 2-bro~o-S-nonylaminocar~onylthiazole;
2-bromo-5-dodecylaminocarbonylthiazole, 2-bromo-5-(7'-hydroxyheptylaminocarbonyl)-thiazol~:
2-bromo-5-(9'-acetoxynonylaminocarbonyl)-thiazole:
2-bromo-5-(~ thoxy~thyla~inocar~onyl~-thiazole: :
2-bromo-S-di-(r-cy~lopentylpropyl)-aminocarbonylthia-zol~;
:.~ 2-bromo 5- (l-me~hylhexylaminocarbonyl)-thiazole;
2-bromo-5-(6-acetylhexylaminocarbonyl)-thiazole;
2-bromo-5- (6-dimethylaminohexylamino ::arbonyl ) -thialzole;

~' ~ ~ .

:la~39~37 2-~romo-5~ methoxyaminocarbo~yl)-thiazol~;
2-bromo-5~ propoxypropylaminocarbonyl)-thiazole, 2-bromo-5-~6-ami~ohexylaminocar~onyl)-thiazole; and 2-bromo-5-di-~n-dod~cyl)-aminooarbonylthiazole.
. 5 similarly, by ~ollowing the same procedure but u~ing 2-bro~o-4-methoxycarbonylthiazole in place of 2-bromo-5-~ethoxycarbc~ylthiaz~le, the corr0æponding ~-positior; i50-mer~ of each of ~he z~o~r~ product3 is respecti~ely prepar~d.
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~03~37 2-Bromo-5-carboxythiazole A mixture containing 10 g. of 2-bromo-5-methoxycarbonylthia-zole, 100 ml. of 10~/o aqueous sodium hydroxide and 200 ml. of methanol is stirred at 0C for five minutes. The methanol is dis-tilled off in vacuo and the resulting concentrate extracted twice with ethyl acetate. The remaining aqueous phase is acidified by the careful addition of dilute aqueous hydrochloric acid resulting in the formation of a precipitate which is then recovered by fil- ~;
tration and dried under vacuum yielding 2-bromo-5-carboxy-thiazole.
Similarly, 2-bromo-4-carboxythiazole is prepared according to the same procedure but using 2-bromo-4-methoxycarbonylthiazole in place of 2-bromo-5-methoxycarbonylthiazole.
,' ~ .

2-Bromo-5-substituted aminocarbonylthiazole A mixture containing 6 g. of 2-bromo-5-carboxythiazole, 3 ml.
thionyl chloride, and 0.5 ml. of dimethylformamide in 150 ml. of ethyl acetate is refluxed for 30 minutes and then evaporated to remove the ethyl acetate solvent. The resulting residue is dis-solved in 100 ml. of chloroform, then cooled to about 0C. A mix-ture containing 10 ml. of 5'-methylhexyl in 100 ml. of chloroform is then added with stirring and the ensuing mixture warmed to 0C
washed twice with water and then dried over magnesium sulfate and evaporated to dryness affording a solid residue of 2-bromo-5-5'-methylhexylaminocarbonylthiazole.
Similarly, 2-bromo-4-t-butylaminocarbonylthiazole is prepared by following the same procedure but using 2-bromo-4-carboxythiazole in place of the 5-position isomer.
Similarly by replacing 5'-methylhexylamine with the amine :, . . . :

~eagents set forth in Preparation 2, the correspondin~ 2-bromo-4-and 5-substituted aminocarbonylthiazoles are respectively pre-pared.

3-(5-sromothiazol-2-oxy)-propanediol acetonide In this preparation sodium hydride (18 g., 56 wt. /O dispersion in oil) is washed with n-hexane, and the hexane is replaced with ~ -monoglyme (100 ml.). To this mixture is added a solution of gly- ; ~;
cerol acetonide (44.5 g.) in monoglyme (200 ml.) under an atmos-phere of nitrogen. After 15 minutes, 2,5-dibromothiazole (32 g.) is added~ and the mixture is refluxed for 1.25 hours. The reaction :;
mixture is then cooled, diluted with ether and ~iltered. The fil trate is washed with saturated a~ueous sodium chloride twiceJ dried ;
15 and concentrated by evaporation. Fractional distillation yields ~
3-(5-bromothiazol-2-oxy)-propanediol 1,2-acetonide. ~`
Similarly 3-(4-bromothiazol-2-oxy)-propanediol 1,2-acetonide is prepared by following the same procedure but replacing 2,5-dibromothiazole with 2,4-dibromothiazole.
EXAMPLE A
3-(5-Azidocarbonylthiazol-2-oxy)-propanediol 1 2-acetonide In this example 150 ml. of a butyllithium, in hexane, solu-tion (each ml. of solution contains 100 mg. of butyllithium) is cooled to -78C and then added to a solution containing 60 g. of 3-(5-bromothiazol-2-oxy)-propanediol 1,2-acetonide in 200 ml. o~
anhydrous tetrahydrofuran at -78C under a nitrogen atmosphere.
The resultant mixture is maintained at -78C for 15 minutes affor-ding 3-~5-lithiumthiazol-2-oxy)-propanediol 1,2-acetonicle. A
stream of anhydrous carbon dioxide is then passed throuclh the pro-~uct solution. The mixture is periodically sampled and monitored :~3~2~3~
.y thin-layer chromatOgraphy and the carbon dioxide treatment con-tinued until all of the starting material is consumed ~about two hours). ~hirty grams of ethyl chloroformate is then added to the reaction mixture and the temperature o~ the resulting mixture allowed to rise to room temperature and a:Llowed to stand at room temperature for three hours. An aqueous solution containing 50 g.
of sodium azide in 100 ml. of water is then added and the resulting mixture stirred vigorously for 50 minutes. The tetrahydrofuran solvent is then distilled off at 50C and the resulting residue is then washed with diethyl ether and then with water affording a ; crude residue of 3-(5-azidocarbonylthiazol-2-oxy)-propanediol 1,2-acetonide. The crude residue is then further purified by chroma-tography over aluminum oxide (neutral, activity III) eluting with a gradient system of 3,000 ml. of hexane and 3,000 ml. of benzene.
Similarly by following the same procedure but using 3-(4-bromothiazol-2-oxy)-propanediol 1,2-acetonide as the starting ; material, the corresponding 3-(5-azidocarbonylthiazol-2-oxy)-pro-:
panediol l,2-acetonide is prepared.
;

EXAMPLE B
3-~5-r-Cyclopentyl~ropylcarbonylaminothiazol-2-oxyl-propanediol 1,2-acetonide.
In this example a Grignard reagent is prepared by adding 5 g.
of ~-cyclopentylpropyl bromide to a suspension of 700 mg.

: ~ - . . ; -. . . :

.. ~ . ~ : : . :., :::

~(~39~2~7 o ma~nesi.~n in 100 ml. of anllydrous etl~yl ether at room temperature unde.~- an argon atmosphere. Tll~ resulting exo~
tilermic reaction is allo~ed to cJo to coMpletion affording a liqu:id mixture containin~ the Griynard rea~ent y-cyclo-S pen~ylpropylmagllesium bromide, wllich .is then cooled and . maintained at -78C.
. 3-(5-Isocyanato-tlliazol-2-oxy)-propanediol 1,2-acetonide is prepared by adding 5.5 g. oE 3-(5 az:i.docarbonylthiazol-2-oxy)-propanediol 1,2-acetonide to 100 ml. oE anhydrous ]0 toluene. The mixture .is then heated, under an argon abmos-phere, at 108C :Eor ~0 minutes. rJ.'he re~sultin~ mixture is then coole(l to -7~C and addccl to the ~-cyclopellty.1.L)ropyl-magnesium brc,mide die~thyl ether soluti.on previously pre-pared. The combined reaction mixture is allowed to react 15 for one minute and then 2 ml. of water is added and the temperature o:E the mixture allowed to rise to room temper-ature. The resulting product mixture is then filtered, dri.ed over sodium sulate, filtered, and evaporated to dryness affording a residue whi.ch is then further purified , 20 by pla~e chromatography eluting wi.th a sys-tem of 5~ meth-anol-95% chloroform yieldiny 3-(5-y-cyclopentylpropylcar-bonylaminothiazol-2-oxy)-propanediol 1,2-acetonide.
Similarly by followin~ the same procedure but substi-tutin~ the app.ropriate Grignard reagents, the following 25 compounds are re.spectively prepare~:
3-[5-5'-methylhexylcarbonylaminothiazol-2-oxy)-propane-diol 1,2-acetonide;
3~~5-3'-methylh~xylcarbollyl.-~ninothiazol-2-oxy)-propane-2~ diol 1,2-acetonide;
.
.; .

; ~
';.:: , ' :

3~2~3~
3-(5-~'-methylhexylcarbonylaminotllia~:ol 2-oxy)-propane-diol 1,2-acctonidc;
3-~5-4' e-tllylhexylcarbonylaminothiazol-2-oxy)--propane-diol 1,2-acetonide;
3-(5-3~-propylhexylcarbonylaminothiazol-2-oxy)-propane-diol 1,2-acetonide;
3-(5-n-heptylcarbonylaminothiazol-2-oxy)-propanediol 1,2-acetonide;
3-(5-~-cyclo~entyletllylcarbonylaminotlliazol.-2-oxy)-propancdiol 1,2-acetollide;
3-(5-4'-cyclopentylbutylcarbonylaminothiazol-2-oxy)~.
propanediol 1,2-acetoniclei and ; 3-(5-y-cyclohexylp.ropylcarbony:Lalliinotll.ia~oi.-2-oxy)-:~ propanediol 1,2-aceton:i.cle.
., lS Similarly by Eollowing the same procedure but usingthe correspondlllg 4-position isomers, the corresponding 4-position isomer is respecti.vely prepared.

EXAMPLE C
3 _ -N'-methyl-y-c~__opentylprol~l.carbonylami.nothiazol-2-oxy]-~ro~anediol 1 r 2-acetonide.
___ :' In this example 1.1 e~uivaleIIts of butyllithium in- 25 ml. of hexane is added to a solution containing 0.5 g.
of 3-[5-y-cyclopentylpropylcarbonylaminothiazol-2-oxy]-propanediol 1,2-acetonide in 25 ml. o tetrahydrofuran at -78C. Ten equival~nts of methyl iodide is then added .`, and the resulti.n~ mix~ure allo~ed to stand for 50 minutes and ~ thell r~fluxed 5 hours. The ~ixture is tllen filtered, dried :~. over sodium sul.fate and evaporated to dryness afford.ing A crude ;: 29 residue of 3-[5-N'-methyl-y-cyclo~entylpropylcarbonylamino--j:, ~ , .,.. ~ ~ . .. .
-:
,: ~ ~ . , , ., , - , , ~g~35~7 thlazol-2-oxy]-propal-ec~iol l,2-acetonide which i~ ~hen further puri~ied by t:hi.n-layer chromato~raphy.
SimilarJ.y by ol1.ow.ing the same procedure u~ing the products o Exampl~ l3 as ~tartirlc3 materials, the corres-ponding N'-methyl clerivatives o~ the products o~ Example B
are respectively prepared.
Similarly by following ~he same procedure but using in place of methyl chlor.ide, the following compounds 5'-methylhexyl chloride, 4'-methylhexylbromide, phenyl bromide, ~-cyclopentylpropyl bromide, and ethyl :ioclo, the corres-pondincJ N'-meth~ e~y.l., N'-phen,yl, N-~-cyclopent:y:l}?ropyl, and N-ethy:L d~r:lvative.s are rec;pect:ively preparecl, EXAMPLE D
3-(5-y-cyc].o~entylpropoxycarbonylaminoth propanediol-l/2-acetonide.
In this example 5.2 g. of 3--(5-az.idocarbonylthiazol-2-oxy)-propanedlol l,2-acetonide is added to a mixture of lO0 ml. of anhydrous toluene and 4 ml. o:E y-cyclopelltyl-propanol. The resulting mixturc is hea-ted for one hour at 107C and then the solvent distilled o~ under reduced pressure aording a crude resicluc of 3-(5-y-cyclopentyl-propoxycarbonylamillothiazol-2-oxy)-propanediol l,2-aceto-nide which is then urther puri~ied by chromatography.
Simila.rly by fo].lowing the same procedures using the corresponding substituted a.lcollol starting materials, the following compounds are respectively prepared:
3-(5~ methylhexoxycarbollylaminothiazol-2-oxy)-pro-panediol l,2-acetonidc;
3 (5-5'-metllylllexoxycarbolly:laminot:lliazol-2-oxy) pro-panediol l,2-acetonicle;

.. , .. . . . :

. .

1~3~
3-(S~ ethylhoxoxycarbonylamlnothiazol-2-oxy3-propane-diol 1,2-acetonide, 3-(5-3'-propylhexoxycarbonylaminothiazol-2-oxy)-pro-panedlol 1,2-acetonide 3-(5-n-heptoxycarbonylaminothiazsl-2-oxy)-propanediol 1,2-acetonide 3-(5-~-~yclopentylethoxycarbonylaminothiazol 2-o~y1-propanediol 1,2-a~etonide; and 3-(5-4'-cyclopentylbutoxycarbonylaminothiazol-2-oxy)-propanediol 1,2-acetonide; and 3-(S-y-cyclohexylpropoxycarbonylaminothiazol-2-oxy)-propanediol 1,2-acoto~ide.
similarly by ~ollowing the 8ame procedure but u~ing th2 4-poaition azidocarbo~ylthia201e i80mer a~ ~tarting material, the corresponding 4-position isomer~ of the above compounds are re8pectively ~ed~ .
EXAMPLE E
: 5-(N'-methyl-Y-cyclopentylp~eoxYcarbonyla~inothiazol-2-oxy) -propanediol 1, 2-acetonide : 20 In this example 1.1 equivalent~ o butyllithium in hexane i~ added to a solu~ion containing 500 mg. o~ 3- (5-r-cyclopentylpropoxycarbonylaminothiazol-2-oxy)-propanediol 1,2-acetonide in 25 ml. of tetrahydrofuran at -78C. Ten equivalents of methyl iodide is then added and the re~ulting mixture allowed to 3tand for 50 minutes and h~ated at re~x ~or 5 hour~. The mixture i~ then filtered, dried over ~odium sul~ate and ~vaporated to dryns~3 affording a crude ::

., ~
.~
'"``' , ........................ . . .

1~39%87 ::

residue oE 5-(N'-metllyl-y-cyclop~nt~lpropoxycarbonylamino-thiazol-2-oxy)-L~rop~nediol 1,2-~cetonide which is then urther purifie~ by chromato~raphy~
Similarly by ollot~ y the samc procedur~ using the products o Example D as st~rting m~terials, the corres-ponding N'-methyl deri~atives of the products o Example D
are respectively prepared.
Similarly by ~ollowin-~ the same procedure but usin~
in place of methyl chloride, ~he following compounds 5~
methylhexyl chloride, 4-methylllexyl bromide, phenyl bro-mide, ~-cyclop~ntylpropyl bromide, and ethyl iodo, the corresponding N'-methylhc~yl, N'-pheny]., N'-~-cyclopen~yl-propyl, and N'-ethyl derivatives aro respoctively pr~pared.

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In this example lO g. of 2-bromo-5-ethoxycarbonylthiazole is stirred in lO0 ml. of anhydrous tetrahydrofuran, under a nitrogen atmosphere, and then 8.4 g. of a glycerol acetonide is added drop-wise with stirring and the stirring continued unti] the solutionis complete. The mixture is then cooled to -5C and then 2.24 g.
of sodium hydride (5~/O dispersion containing 2.24 g. of sodium hydride in mineral oil) in lO0 ml. of anhydrous tetrahydrofuran is added and the resulting mixture allowed to warm to room temperature and allowed to stand for one half hour. The mixture is cooled to -10C, resulting in the formation of a precipitate, and then poured into 200 ml. o~ ethyl acetate. The ethyl acetate mixture is washed three times with water, then dried over magnesium sulfate and eva-porated to an oil which is then chromatographed on silica gel affording 3-(5-ethoxycarbonylthiazol-2-oxy)-propanediol 1,2-aceto-nide.
., Similarly, by following the same procedure using the corres-ponding 2-bromo-4- or 5-alkoxycarbonylthiazole starting material, the corresponding compounds are respectively prepared:
3-(~-ethoxycarbonylthiazol-2-oxy)-propanediol l,2-acetonide;
3-(5-methoxycarbonylthiazol-2-oxy)-propanediol l,2-acetonide;

~ and :'' :

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~%~

3-(4~methoxycarbonylth.iazol-2-oxy)-propanediol 1,2-aceto~ide.

EX~MPLE lA
This example illustrates methods according to the invention for preparing the .intermediates of formula A
wherein z is R3R4N~- . In this example a methano'l. solu-tion containing 5 g. of 3 (5--ethoxycarbonylthiazcil-2-oxy)-propanediol 1,2-acetonide; 20 ml. of water and 30 ml. o~
4'-methylhexylamine and sufficient methanol to ma]ce the mixture homogeneous i5 stirred at room temperature ~or 18 hours, and then poured inl:o 500 ml. of etllyl acetate.
The ethyl acetate mixture .is washeæL ~hree time~ with wa~er, '~ dried over magnesi.um sulfate and evaporated to c'lryness affordincJ a residue of 3-(5-4'-met1lylhexylamin~carbony]-; 15 thiazol-2-oxy)-propanedio]. 1,2-acetonide which i.s then ~urther purified ~y recrystallization using an ethy.'L-hexane mixture.
Similarly, by following the same procedure but res-pectively replacing 4'-methylhexylamine with the amines en~e!rated in Column A, the corresponc1ing proc1~1cts o~
'~ Column B are respecti~ely prepared:
CO~UMN
3'-methylhexylamine;
5'-methylhexylamine;
; 25 4'-ethylhexylamine;
3'-propylhe.x-ylamine;
'` n-heptylamine;
~-cyclopen*ylethylamine;
29 ~-cyclopentylpropylamine;

.. ..

::, .: . , - . , , .: .
: .. ~ ;, ~ ; . .. .

~3~2~7 4'-cyc:lop~nty]l~utylamille;
y-cyclollexylpropylamin~;
5'-met}l,yl-2'-methylhexylamin~i 4'-met:hyl-1'-methylhexylamine;
r-dim~t}lyl~minopl~opy~.a~nin

6'-metll~lheptylamine;
5'-methy:Lheptylamine;
N-(5'-methylhexyl)-N-methylamine;
N-(4'-methylhexyl)-N-methylamine; and 6'-ethoxy-n-hexylamine.
COLUMN B
3-(5-3'-methylllexylanlinocclrbonylthia~ol-2-ox,y~-propane-diol l,2-acet:onide;
3-(5-5'-~netlly:Lhexylaminocarbonylthiclzol-2-oxy)-propane-diol 1,2-acetonide;
3-(5-4'-ethylhexylaminocarbonylthiazol-2-oxy)-propalle-diol 1,2-acctonide;
3-(5-3'-propylhexylaminocarbonyltlliazol-2-oxy)~propane-- diol 1,2-acetonide;
3-(5-n-heptylaminocarbonylthiazol-2-oxy)-propaIIediol 1,2-acetonide;
3-(5-~~cyclopentylethylaminocarbonylthiazol-2-oxy)-propanediol 1,2-acetonide;
3-(5-y-cyclopentylpropylaminocarborlylthiazol-2-oxy)-propanediol 1/2-acetonide;
3-(5-4'-cyclopentylbutylaminocarbonylthiazol-2-oxy)-propanediol 1,2-acetonide;
3-(5-~-cyclohexylpropylaminocarbon,yll:hiazol-2-oxy)-29 propanediol 1,2-acetonide;
i ,. --~6--,. . ..

~39~
3 (5--5'-metl~yl~2'-1netll.~Ylhcxylalllinocarbony.l.-tll.iaæol-2-oxy)-prop.~nediol l,~-acct~ni.de;
3-(5-~'-metllyl-1'-metllylhexy].amillocar~ollyll:hi.a~ol-2-oxy)-propancdiol 1,2-acetonide;
3-(5-y-dimethylaminopropy:Laminocar~onyltlliazol-2-oxy~-propanediol 1,2-acetonide;
3-(5-6'-m~thylhcptylaminoc~arbon~ltlliazol-2-o~y)-propanedlol 1,2-acetonide;
3-(5-5'-meth~,].heptylam.inocarbonylthiazol-2-oxy)-propanedi.ol 1,2-aceton.ide;
3-(5-N-.(5'-me-thylllexyl)-N-methylaminocarbonylthiazol-2-oxy)-propanediol 1,2.-acetonide;
3-(5~N-(4'-metllylhexyl)-ll-methy:l.am:inocarbonylthiazo].-2-ox~v)-pr(~panediol 1,2-acetonide; and 3-(5-6',et}loxy-n~hexYlam~-ocarbonyl.th:ia~ol-2-oxy)-propanediol 1,2-acetonide.
Sin~ilarly, by following the same procedure but re-placing ~-(5-ethoxycarbonylthiazol-2-oxy)-propallediol 1,2-acetonide with 3~(4-ethoxycarbonylthiazol-2-oxy)-propane diol 1,2-acetonide/ the correspondi.ng 4-position isomers o 3-(.5-aminocarbonylthiazol-2-oxy)-propanediol 1,2-aceto-nidc and of each o:E the proclucts enumerated ,in Col~mln B
is respectively prepared.

, - EX~PLE lB
':.' 25 This example illustrates the preparation 4 and 5-amunocarbonyl starting materials of formula A. In this example sodium hydride (1~ ~., 56 wt. ~ dispersion in oil) is washcd with n-hexane, and the hexane is repla~ed witll 2~ monoglyme (100 ml.). To th.is m.ixture is added a soluti.on :, :;

. ::, : . . . . .

~ 3 ~
of glycerol acetonide ~44.5 g.) in monoglym~ (200 ml.) ~nder an atmo~ph~re of nitrogen. ~ter 15 minute~, 2-bromo-5-5'-methylhexylaminocarbonylthiazole (32 g~ i5 added, and the mixture i8 refluxed for 1.25 hours. ~he reaction mixture i8 then cooled, diluted with ether and filtered. The filtrate is wa~hed with ~aturated aqueou~
sodium chloride ~olution twice, dried and concentrated by evaporation. Fra~tional distillation yields 3-~5-5'-methylhexylaminocarbonylthiazol-2-oxy)-propanedio~ 1,2-acetonide.
Si~il~rly by following the same procedure but re~pectivelyreplacing 2-bromo-5 5'-methylhexylaminocarbonylthiazole with the compounds prepared in Preparation 2, the corre~pond.ing 3-(sub~tituted aminocarbonylthiazol-2-o~y) -propanediol 1,2-acetonide compounds are respectively prepared.
: EXAMPLE 2 Thi~ example illustrates method~ ac~oraing to step 1of the gensric proce~s of the invention. In this example a mixture containing 2 g. of 3-(5-4'-methylhexylaminocar-20 bonylthiazol-2-oxy)-propanediol 1,2-acetonide in 5 ml. o~ .
80~ aqueous formic acid is stirred at room temperature ~or five minutes. The solution i8 then evaporated under vac~um at room temperature afording a residue of 3-(5-4'-methylhexy-lamino~arbonylthiazol-2-oxy)-1,2-propanediol which i~ then further purified by recrystallization using an ethyl acetate-h~xane mixture.
Similarly, by following the same pro~ed~re, the prod-uct~ prepared a~cording to Examplss lA, 1B~ and Example~ B, C, D and E are cleaved to the corre~ponding propanediol compound~.

. . .
~ -l~J~
EX~MPLE 3 This example illustrates steps 3 and 4 of the generic process of the invention and further illustrates preparation of the com-pounds of formula II of the invention. In this exarnple 0.6 g. of 5 methylsulfonyl chloride is added with rapid stirring to a mixture containing 1.2 g. of 3-(5-4'-methylhexy:Laminocarbonylthiazol-2-oxy~-propanediol in 20 ml. of pyridine at -30C. The mixture is then allowed to warm to room temperature and evaporated to dryness affording a residue of 2-hydroxy-l-methylsulfonyloxy-3-(5-4'-methyl-lO hexylaminocarbonylthiazol-2-oxy)-propane. The residue is then dissolved in 50 ml. of anhydrous methanol and cooled to 0C. A
mixture containing 1 g. of sodium metho~ide in lO ml. of anhydrous methanol is added and the resulting mixture stirred for two minutes and then evaporated to remove methanol. lO0 Milliliters of ethyl ; 15 acetate is added and the resulting ethyl acetate mixture washed three times with water, dried over magnesium sulfate, and evapora-ted affording a residue of 1,2-epoxy-3-(5-4'-methylhexylaminocar-bonylthiazol-2-oxy)-propane as an oily residue.
Similarly, by following the same procedure as above, the pro-20 ducts, prepared according to Example 2, are converted to the cor-responding l,2-epoxypropane thiazole compounds of formula II.
" '.

This example illustrates further methods according to the invention of preparing the compounds of formula I to the invention.
In this example 0.6 g. of isopropylamine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonyl-thiazol-2-oxy)-propane in ,'' ,:- .' .:' , -,..: ' ,' :. : ' .. ;. . ~' .: ' .

... ...
- . . . : . : , ::. . . : . -. ........ . - .
. ,:~ : . : : . . . - : , . . .

~0 ml. of anhydrou~ absolult:~ ethanol, and l;hen allowed to ~tand for 12 hours at room temperatureO ~rhe mixture i~ then evapsr-ated to dryness and the resullting re~idue chromato~raphed on silica g~31 yielding 1-isopropylamino-3- (5-4 '-methylhexyl~nino-5 carbonylthlazol-2-oxy~-2-propanolO
Sl~nila~rly, by following the above procedlurel bu~ respect-ively ~sing the! produ~ts prepared accord~ng to Example 3 as starti~g materials, the corre~ponding compound~ om;Dnerated herein below in column C and al~o the corre~pondin5~ N'-deriva-tives corresponding to starting matQrials prepared ln ~xa~]ple~
C and E, are r~pe~tively prepared:
COLUMN ~
l-isopropylamino-3-(5-3'-methylhexylaminocarbonyl-thiazol-2-oxy)-2-propanol:
1-isopropylamino-3-(5-5'-methylhexylamino~arbonyl-thia201-2-oxy)-2-propanol; ~.
l-isopropyla~ino-3-(5-4'-ethylhexylaminocarbonyl-thiazol-2-oxy)-2-propanol:
l-i~opropylamino-3-(5-3'-propylhexylam~nocarbonyl-thiazol-2-oxy)-2-propanol l-isopropylamino--3-(5-n-h~ptylaminocarbonylthiazol ; 2-oxy)-2-propanol, m.p. 93-94 C;
opropylamino-3-(5 ~ -cyclopentylethyla~inocarbo-nylthiazol-2-oxy3-2-propanol:
1-i~opropylamino-3-(S-r-cyclopentylpropylaminocarbo-nylthlazol-2-oxy)-2-propanol:
opropylamino-3-(5-4'-cyclopentylbutylaminocarbo-: nylthiazol-2-oxy)-2-propanol:
~ opropylamino-3-(S-~-cyclohexylpropylaminocarbo-nylthiazol-2-oxy)-2-propanol, :

l-isoprt~pylamino-3- (5-5 '-methyl-2 '-me~hylh~xylamir~o-i . .

. .
.:

,~.. . . , : .. . , : .
. i;. .. . , . . :
.; . ::: . - . . . - , :. :. :: : .. : .-:: . : , : :
. . .

~3~

C~Ll~Olly~ iLI~.01-2-OX,y)-2-proE~clnol;
l-isopropylami.no-3-(5-4' metllyl-].'-methylhexylamino-carbonylthi.azol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-y-dimethy].aminopropylaminoearbo-Snyl~hiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-6'-methylheptylaminocarbonyltlli.a-zol-2-oxy)-Z-propanol;
:- l-isopropylamino-3-(5-5'-methylheptylaminocarbonylthia-zol-2-oxy)-2-propanol;
101-isopropylamlno-3- (S_N (5'~methylhexyl)-N~-methylamino-earbonylthiazol-2-oxy)-2-propanol;
l-isopropylamillo-3-(5-N-(~'-methylllexyl)-N-methylamino-earbonylthiazol-2~oxy)-2-propanol;
l-isopropylami.no-3-(5-eyclopentylaminocarbonylthiazol-152-oxy)-2-propanol;
l-isopropylamino-3-(5-eyeloheptylaminocarbonylthiazol-2-oxyj-2-propanol;
l-isopropylamino-3-(5-n-oetylaminocarbonylthiazol-2-oxy)-2-propanol;
201-isopropylamino-3-(5-n-nonylaminocarbonylthiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-n-dodecylaminocarbonylthiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-7'-hydroxyheptylaminocarbonyl-25thiazol-2-oxy)-2-propanol;
isopropylamino-3-~5-9-aeetoxynonylaminoearbonyl-thiazol-2-oxy)-2-propanol;
l-isopropylamino-3-~5-N,N-di(y-eyelopentylpropyl) aminoearbonylthiazol-2-oxy)-2-propanol;
301-isopropylamino-3-(5-N,N-di(n-dodccyl)aminocarbonyl-thiazol-2 oxy)-2-propanol;

,: ~

~ .. ..... ;:. . -:

~ opropylamino-3-(5-3'-m~thylh~xylcarbonyla~ino-thiazol-2-oxy)-2-propanol:
l-isopropylamino-3-~5-4'-methylh~xylcarbonylæmino-thiazol~2-oxy)-2-propanol 1-isopropylamino-3-(5-5'-methylhexyl~arbonylaminothia zol-2-oxy)-2-propanol:
1-i~opropylamino-3-( 5-4 '-ethylhe~lcarbonyla~ninothia-zol-2-oxy~-2-propanol;
: l-i80propylami~0-3 -(5-3'-propylhexylcarbonylamino- ;~ ~
thiazol-2-oxy)-2-propanol: ~ `
~ opropylamino-3-(5-n-heptylcarbonylaminothiazol- ::
2-oxy)-2-propanol~
l-isopropylamino-3-(5-~-cyclopentylethylcarbonyl-aminothiazol-2 oxy)-2-propanol; . .
1-isopropylamino-3-(5-r-cyclopentylpropylcarbo~yl-aminothiazol-2-oxy~-2-propanol:
: l~isopropylamino-3-~5-4'-cyclopentylbutylc2rbonyl-.' 2~ninothiazol-2-oxy)-2-propanol;
' l-i~opropylamino-3-(S-r-cyclohexylpropylcarbonyl-aminothiazol-2-oxy)-2-propanol;
.
l-i~opropylamino-3-(5-3'-methylhexoxycarbonylamino-thiazol-2-oxy)-2-propanol;
l-i30propylamino-3-(5-4'-methylhexoxycarbonylamino- -~
thiazol-2-oxy)-2-propanol;
1-i~opropylamino-3-(5-5'-methylhexoxycarbonylamin~-.. thiazol-2~oxy)-2-propanol;
opro~pyl~mino-3- (5-4 '-ethylhexoxycarbonylamino-.. ~

... .

,~

... . . ..

~L~)392~37 thiazol-2-oxy)-2 propanol;
l-isopropylarnino-3-~5-3'-propylllexoxycaxbollylamino~
- thi.azol--2-oxy)-2-propanol;
isopropyla1nino-3-(5-n-hepl:oxycarbonylamlnothiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-~-cyclopcntylethoxycarbonyl-am.inothiazol-2-oxy)-2-propanol;
l-isopropylamino-3-(5-~-cyclopentylpropoxycarbony].-aminothiazol-2-oxy)-2-propanol;
1-isopropylamino~3-~5-4'-cyclope~ntylbutoxycarbonyl-aminothia~ol-2-oxy)-2 propanol; and l-isopropylamino-3-(5-y-cyclollexylpropo~ycarbonyl-aminothi.azol-2-oxy)--2-propanol.
Similarly the corresponding N'-substituted compounds of fortn-ula I (Z is R ~- or R OCN-) corresponding to the star-tlng mate-rial prepared according to Examples C and E, are also respect-ively prepared but have not b~en enumerated above or purposes of brevity.
The 4-position isomers are similarly prepared according ~; 20 to the same procedure but usinc3 the corresponding 4-position isomer starting materials.
The hydrochloride adclition salts of each of the a~ove product compounds are then prepared by respectively treating 1 g. of each compound with one molar equivalent and 50 ml.
o~ ethyl ether saturated with anhydrous gassous hydrogen chloride at ~0C for one hour.
Similarly, by following the same procedure as above : but usin~ t-butylamine in place o isopropylamine, the , corresponding l-t-butylamine derivatives of each o~ the : 30 above products and als~ their hydrochloride ad~lition salt3 are respec~ivcly prepared.

':

3~
EX~IPI.E 5 This example illustrates met}lods according l:o the in-vent:ion of conver-ting tl~e compounds o~ formula II to the corresponding compounds of formula I of tlle invention. In thls example, 350 mg. of 1,2~epoxy-3-(5-4'-methylhexylaminocarbonyl-thiazol-2-oxy)-propane is di~solved in G ml. o~ anhydrous ethanol saturated with ammonia and allowed to stand at room temperature for 20 hours. The mixture is then evap-orated to remove ethanol and the result:ing residue puri--fied by thin-layer chromatography on preparative silica plates using a developing system of 1% triethylamine, 1.5~
metllanol an~ the remainder ethyl acetate, yieldin~ l-amino-3-(5~'~mel:hy:Lhexylam:i.nocarbollylthi~zol-2-oxy)--propanol.
Similarly, by ~ollowing the above procedure bu-t res-;, 15 pectively using the products, prepared according to ~xample 3, as starting materials, the corresponcling 1-amino-3-~5-and 4-substituted thiazol-2-oxy)-2-propanol compouncls are respectively prepared.
Similarily by following the same procedure but replacing ammonia with methylamine, dimetllylamine and ethylamine, res-pectively, thc corresponding l-methylamino; l-dimethylamino;
and 1-ethylamino derivatives are respectiveJ.y prepared.
EX~MPLE 6 ~ This example illustrates further methods according to ; 25 the inventic~n of preparinc3 the com~ounds of formula I o~
the invention. In this example 1 g. of morpholine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methyl-hexylaminocarbonylthiazol-2-oxy)-propane in 20 mlD of anhy-drous absolute ethanol at 20C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand ulltil conversion of tl-e 1,2-epoxy-3-(5--aminocar-- -7~-.
..

~`

~33~37 bonylthiazol-2-c)xy)-prop.lne is essentially complete. The mixture is then evaporatccl to dryness yielcling a crude residue of l-(N-morpholino-3-(5-4'-met}lyl}lexylaminocarbo-nylthi.aæol-2-oxy) 2-propanol which is then further puri-fied by thin-layer chromatography Oll silica yel.
Similarly, by following the same procedure asa above but respectively using the products of Example 3 as starting materials, the corresponding l-(N-morpholino)-3-(5-su~sti-tuted aminocarbonylthiazol~2-oxy)--2-propanol derivatives 10 are prepared.
~rhe corresponding hydrochloride add.ition salts of each o~ the above products ar~ respecti.vely prepared by respect-iv~ly tr~ating tll~ corr~spondin~ l-tN-morpholino) deriva-tives, enumerat~d above, with hydrogen chlo.ri.de as described in Example 4.
; Similarly, by following the same procedure but respect-ively using pyrrolidine, piperidine, 4-~-hydroxyethylpiperi-dine, N-~-hyclroxyethylpiper,-~zine, in place of morpholine, the corresponding l-(N-pyrrolidinyl), l-(N-piperidinyl), l-[N-(4-~-hydroxyethyl)-piperid.inyl], and l-[N-(N'-~-hydroxyethylpiper-azinyl~ derivati.ves and their hyclxochloride addition salts are ~ respectively prepared for each of the products of Example 3.
: The 4-position isomers are similarly prepared ac-cording to the same procedure but using the corresponding `. 25 4-posi~ion isomer starting materials.
EXAMPL~ 7 This example illustrates further methods according to the invention of preparing ~urther compounds of formula : I o the invention. In this exampl.e 1 g. o~ ~-(4-amino-carbonylphelloxy)~ethylamine is added to a solution containing 0.4 g. o~ 1,2-epoxy-3-(5~ methyllle~yl~minocarbonyltlliazol-.: -7S-.
.

2-oxy)-propane in 20 ml. of anhydrous ab~olute ethanol at 20 C.
The resulting mixture i8 monitored by thin-layer chromatvgraph-ic analysis and allowed to ~tand until ~onversion of the 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-~xy)-propane i8 essentially complete. The mixturQ is then evaporated to dryne~s y~lding a crude residue which is then further p~urified ;!"
by thin-layer chromatography on silica g~l yielding 1~ (4-aminocarbonylphenoxy)-ethylaminoJ-3-~5-4'-methylh~xylaminocar-: bonylthia~ol-2 oxy)-2-propanol.
similarly, by following the same procedure but using the ; product~ of Example 3 as starting materials and 1,2-epoxy-3-t5-hexylaminocarbonylthiazol-2-oxy)-propane, the correlsponding products enumerated herein below in column E, and also the cox-responding N'-derivatives corresponding to starting material~
prepared in Examples C and E are resp~ctively prepared:
COLUMN ~
~ (4-aminocarbonylphenoxy)-ethylamino] -3-(5-3'- ::
methylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
~ (4-aminocarbonylphenoxy)-ethylamin~ -3-(S-S'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol ~ -(4-aminocarbonylphenoxy)-ethylamino3 -3-(5-4'-: ethylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
4-aminocarbonylphenoxy)-ethylamino3 -3-(5-3'-propylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
1-~-(4-aminocarbonylphenoxy)-ethylamino~ -3-~5-n-heptylaminocarbonylthiazol-2-oxy)-2-propanol, 1-[~-(4-aminocarbonylphenoxy)-ethylamino] -3-(5-~-cyclopentylethylamino~rbonylthiazol-2-oxy)-2-propanol;
1-[~-~4-aminocarbonylphenoxy)-Qthylami~o] -3-(5-r-cyd opentylpropyla~inocarbonylthiazol-2-oxy)-2-propanol;

: . .

~(~3~
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4'-cyclopentyl-butylaminocarbonylthiazol-2-oxy)-2-propanol;
~ -(4-aminocarbonylphenoxy)-ethylaminol-3-(5-~-cyclohexyl-propylaminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-5'-methyl-2'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-4l-methyl-1'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5 ~'-dimethyl-aminopropylaminocarbonylthiazol-2-oxy)-2-propanol;
~ -(4-aminocarbonylphenoxy)-ethylamino]-3-(5-6'-methylheptyl-aminocarbonylthiazol-2-oxy)-2-propanol;
.~ 1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-5'-methylheptyl-aminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-~-(5'-methyl-hexyl)-N-methylaminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-cyclopentyl-aminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-cycloheptyl-aminocarbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-n-octylamino-carbonylthiazol-2-oxy)-2-propanol;
- 1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-n-nonylamino-` carbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-n-dodecylamino-carbonylthiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-7'-hydroxy-heptylaminocarbonylthiazol-2-oxy)-2-propanol;

~n ~ t4-aminocarbonylphenoxy)-ethylamino]-3-~5-N,~-di(n-dodecyl)aminocarbonylthiazol-2-oxy)-2-propanol; ::
1-[~-(4-amino~arbonylphenoxy)-ethyl~mino]-3-(5-4'- ~ ;
cyclopentylbutylaminocarbonylthiazol-2-o~y~-2-propanol~
51-[~-(4-aminoc~rbonylpheno~y)-ethylamino~-3-(5-r-cyclohexylpropylaminocarbonylthiazol-2-oxy)-2-propanol; ~`
1-[~-(4-a~inocarbonylphenoxy~-ethyl2mino3-3-(5-3'-methylhexylcaxbonylaminothiazol-2-oxy)-2-propanol;
~ (4-aminocarbonylphenoxy)-ethyl~mino]-3-(5-4'-10methylhexylcarbonylaminothiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamin~ -3-(5-5'-methylhexylcarbonylaminothiazol-2-oxy)-2-propanol;
-t~- (4-aminocarbonylphenoxy)-~thylamino]-3-(5-4 -ethylhexylcarbonylaminothiazol-2-oxy)-2-propanol;
151-~-(4-aminocarbonylphenoxy)-ethylaminoJ-3-(5-3~- ;
propylhexylcarbonylaminothiazol-2-oxy)-2-propanol;
l-t~-~4-aminocarbonylphenoxy)-ethylamino-3-(5-n-heptylcarbonylaminothiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylphenoxy)-ethylamino]-3-(5-~-20cyclopentylethylcarbonylaminothiazol-2-oxy)-2-propanol;
l-t~-(4-aminocarbonylphenoxy)~ethylamino~-3-(5-y-cyclopentylpropylcarbonylam~nothiazol-2-oxy)-2-propanol;
l-L~- (4-aminocarbonylphenoxy3-~hylæmino3-3-(5-4 -cyclopentylbutylcarbonylaminothiazol-2-propanol;

.

t4-aminocarbonylphenoxy~-ethylamin~ -3-(5-r-cyclohexylpropylcarbonylaminothiazol-2-oxy)-2-propanol;
1-~ -(4-amlnocarbonylphenoxy)-ethylaminc~-3-(5-3' methylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
1- ~ -(4-aminocarbonylphenoxy)-ethylaminc~-3-(5-4'-m~thylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
~ 4-aminocarbonylphenoxy)-ethylaminc~-3-(5-5'-methylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
1-@- (4-aminocarbonylp~enoxy)-ethylamino~-3-~5-4 ethylhexoxycarbonylaminothiazol-2-oxy)-2-propanol;
1-[~-(4-aminocarbonylph~noxy)-ethylamino]-3-(5-3'-propylhexoxycarbonylthiazol-2-oxy)-2-propanol;
l-~ -(4-aminocarbonylphenoxy)-ethylamino~-3-(5-n-heptoxycarbonylaminothiazol-2-oxy)-2-propanol:
1-~ -(4-aminocarbonylphenoxy)-ethylamino]-3-(5 ~-cyclopentylethoxycarbonylaminothiazol-2-oxy3-2-propanol:
1-~ -(4-aminocarbonylphenoxy)-~thylamino -3-(S-~-cyclopentylpropoxycarbonylaminothiazol-2-oxy)-2-propanol:
1-~ -(4-aminocarbonylphenoxy)-ethylamino~-3-(5-4'-cyclopentylbu~oxycarbonylamino~hiazol-2-oxy)-2-propanol~
1-[~-(4-aMinocarbonylphenoxy)~ethylamino]-3-(5~
cyclohexylpropoxycarbonylaminothiazol-2-oxy) 2-propanol: and 1-[~-(4-a~inocarbonylp~enoxy)-ethylamino3-3-~S-hexylaminocarbonylthiazol-2-oxy)-2-propanol, m.p. 156-157C.
similarly tha corre~ponding ~'-sub~tituted ~ompounds of formula I (Z i~ R4~N- or R4 ~ ~-) corre~pondlng to th~ ~tarting : material prepar~d aceording to Examples C and E, are al~D re~-pactively prepared but have ~ot been enu~erated above fo:r purpo~es : of brevity.

i~

. ~ . , similarly, by fo}lowincJ tha ~ame proc~dure de~cr:Lbed a~ iLn ~ca~nple 4, the hydrochloride addition ~alt~ o~ each . .
of the abo-.re compounds ara re~pectively prepar~d.
, .: . ~ . . .
~: - . . . . .
., , ~ , .
~ . :

1~3~

Simllarly, by followinq the sclme procedurc but res-pectively using ethanolami~le; l-amino-l-pllenylethane; ~
(p-hydroxypllenyl)-ethylamlne; a-metllyl-~-(p-hydroxyphenyl)-ethylamine; y~(p-hydroxyphenyl)-propylamine; and a-methyl-y-(~-hydroxypl~enyl)~propylamine in place of ~-(4-amino-carbonylphenoxy)-ethylamine, the correspondin~ -hyclroxy-~ ethy.l.amino)-; l-(a-phene-thylamino)-; l-(~-[p-hydroxyphenyl~-: ethylamino)-; l-(a-methyl-~-[p-hydroxyphenyl]-ethylamino)-;
l-(y-(p-hydroxyphenyl).-propylamino)- and l-(a-methyl-y-[4-10: hydrox~phenyl)-propylamino- deriv~tives of the above enu-merated products and tl~eir hydrochloride addition salts are respectivcly preparcd.
The 4-pos.ition isomers are similarly prepared according to the same procedure but using the correspondlng 4-position .. 15 isomer starting materials.

; EX~PLE 8 .. ~ This example illustrates the preparation of the oxa-zolidine reagent according to steps 1' and 2' of the process of the invention for preparing the 5- or ~-R4R5N~- series 2a of compounds oE ormula III. In this example 25 ml. of racemic glycidol and 50 ml. of t-butylamine are mixed to-l gether at room temperature. After about 30 minutes the .. mixture boils spontaneously and is then allowed to stand .
; at room temperature for an additional 20 hours. The reac-tlon mixture is then concentrated via evaporation to a viscous oil which is then dissolved in a solution con-taining 250 ml. oE ethanol and 50 ml. of 37% (wt.) aqueous formaldehyde. The resulting mixture is refluxed for 18 23 hours and then evaporated, under vacuum, affordin~ 5-,.
:.: ~ . ........ ..
. ,. .... . . ~ . .. . .

hy~roxymetllyl-N~t-butyJoxazolidine which is then further pur.ified }~y distil.lation. Similarly, by following the same procedure but replacincJ t-butylamine with anllydrou5 ammonia, methylamine, isopropylam.ine, b~nzylamine, and ~-methyl-y-phenylpropylamine, respectively, the followin~
compounds are respectively prepared:
5-hydroxymethyloxazolidille;
S-hydroxymethy~ N-metllyloxazolidine;
5-hydroxymethyl-N-isopropyloxazolidine;
5-hydroxymethyl-N-benzyloxazolidine; and 5-hydroxymethyl-N-(~~[a-methyl-~-phenylpropylJ)-oxa-zolidine.
~lso in the ca~e of l:he volatile rea~ents (i.e. ammonia and methylamLne), the procedure is conducted in a closecl system by first bubbling the re~uisite amount of ammonia or methylamine through the glycidol and then sealing the reaction vessel.

. :
; EXAMPLE 9 This example illustrates methods according to the invention of preparing the compounds of formula I oE the invention via the intermediate of formula III of the in-vention~ In this example 20 ml. of 5-hydroxymethyl-N-t-butyloxazolidine is added dropwise, with stirring, to a mixture containing 0.6 g. of sodium hydride ~50% sodium hydride dispersed in mineral oil containing 26 g. sodium hydride) in 20 ml. of anhydrous tetrahydrofuran at room temperature under a nitrogen atmosphere. The mixture is stirred for 30 minutes and then a solution containing 29 3 gO of 2-bromo-5-5'-methylhexylaminocarbonyltll:ia~ol~ in ', ' .

:

~3~ 7 10 ml. of anhydrous tetrahydrofuran is added. The tetra~
hydrofuran is removed by evaporation under vacuum and the --resulting concentrate stirred for 18 hours at room tempera-ture and then poured into 200 ml. of ethyl acetate. The resulting ethyl acetate mixture is washed three times with water, and then dried over magnesium sulfate and evaporated to an oily residue. The oil is then distilled under vacuum to remove excess 5-hydroxymethyl-N-t-butyloxazolidine, and the chromatographed on silica gel yielding l-t-butylamino-3~
(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol, m.p.90-91C.
Similarly, by following the same procedure but respec-tively using the corresponding 2-bromo-thiazole derivatives, prepared according to preparation 2 as starting materials, the following compounds are respectively prepared~
COLUMN F
l-t-butylamino-3-(5-3'-methylhexylaminocarbonylthia-zol-2-oxy)-2-propanol, m.p. 75-76C.
l-t-butylamino-3-(5-4'-methylhexylaminocarbonylthia-zol-2-oxy)-2-propanol, m.p. 103-104QC.
l-t-butylamino-3-(5-4'-ethylhexylaminocarbonylthia-zol-2-oxy-2-propanol, m.p. 105-106.
l-t-butylamino-3-(5-3 -propylhexylaminocarbonylthia-zol-2-oxy~-2-propanol, m.p. 86-87C.
1-t-butylamino-3-(5-n-heptylaminocarbonylthiazo-2-oxy)-2-propanol, m.p. 129-130C.
l-t-butylamino-3-(5-~-cyclopentylethylaminocarbonyl-thiazol-2-oxy)-2-propanol, m.p. 105-106C.
.

:, :

~3~
1 -t -butyl a~ino-3 - ( 5-r-cyclopentylpropyl ar~lnocarbonyl-thlazol-2-oxy~-2-prt)paraol, m.p. 92-g3~C.
l-t-butylamino-3- (~-4 '-cy~lopentylbutylaminocarbonyl-thiazol-2-oxy) -2-pzopanol, m.p. 95-96C.
; 51-t-butylamino-3-(5-~-cyclohexylpropy]Laminocarbonyl-thiazol-2-oxy)-2-propanol, m.p~ 110-111C.
l-t-butylamino-3-(5-5'-methyl-2'-methylhexylamino-carbonylthia~ol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-4'-methyl-1'-methylhexylamino-10carbonylthiazol-2-oxy)-2-propanol;
t-butylamino-3-(5-r-dimethyla~inopropylaminocarbo-nylthiazol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-6'-methylh0ptylaminocarbonylthia-zol-2-oxy)-2-propanol:
l-t-butyla~ino-3-(5-5'-m2thylheptylaminocarbonylthia-zol-2-o~y)-2-pxopanols l-t-butylamino-3-(5-N-(5'-methylhexyl)-N-methylamino-carbonylthiazol-2-oxy)-2-propanol;
l-t-butyl~mino-3-~5-~-~4'-methylhexyl)-~-methylamino-- 20 carbonylthiazol-2-oxy)-2-propanol l-t-butyla~ino-3-(5 cyclopentylaminocarbonylthiazol-2-oxy)-2-propanol:
l-t-butylamino-3-(5-cycloheptylaminocarbonylthiazol- :~
~ 2-oxy)-2-propanol, m.p. 124-125C.
: 25 1-t-butylamino-3-(5-n-octylaminocarbonylthiazol-2-oxy)-2-propanol~ m.p. 78C.
l-t-butylamino- -(5-n-nonylaminocarbo~ylthiazol-2 oxy~-~-propanol, ~p.p ~9-90C.
l-t-butylamino-3-(5-n-dodecylaminocarboDylthiazol-2-oxy)-2-propanol, m.p. 75-76C.

: :

X.,~rC~

l-t-butylamino~3-(5-7'-hydroxyheptylamin~carbonyl-thiazol-2-oxy)-2-propanol;
l-t-butylamino-3- (5-9-acetoxynonyla~inocarbonylthia-zol-2 oxy)-2-propanol:
1-~-butylamino-3-(5~ di (~-cyclopentylpropyl ) æmino-carbonylthiazol-2-oxy)-2 propanol;
l-t-butylamino-3-~5-N,~-di (m-dode~yl)aminocar~onyl- ~:
thiazol-2~oxy)-2-propanol, ~ butyla~ino-3-(5-1'-me~hylhexylaminocarbonyl-thiazol-2-oxy)-2-propanol, m.p. 74-75C;
l-t-butylamino-3-(5-6'-acetylhexylaminocarbonylthia-zo}-2-oxy)-2-propanol, l-t-butylamino-3-(5-6'-dimethylaminohe~ylaminocarbonyl-thiazol-2-oxy)-2-p~opanol;
1-t-butylamino-3-(5-6'-methoxy~exylaminocarbonylthia-zol-2-oxy)-2-propanol;
l-t-butylamino-3-(5-~-propoxypropylaminocar~onylthia-zol_2-oxy)-2-propanol; and l-t-butylamino-3-(5-6'-aminohexylaminocarbonylthia-zol-2-o~y)-2-propanol.
The 4-po~ition ii~omers are si~ilarly prepared according to the same procedure but ui~ing the corre~ponding 4-po~ition ii~omer starting material~.
Similarly, by following the saime procedure but respect-ively using 5-hydroxymethyloxazolidine; 5-hydroxymet~yl-N-'' ,.... .. ., . .. ... ..... . . . , - ..
, , : , ~ . . - :
.:,:: . -, , ,.,, . ~: , . ~ . . . .
, . . 1 ` '', '' ~ , ` `'.. : . ' :
-,:'' ~' - ' . . :' '. .. ' ,. , :.
:' . : ' : : . '' :` ` . ' :~' ` ` `' ' ` . ' `' :~ ` ' :` " ; ' ' ' :
::;''` ':.' i' ` '' - ` ` : :' :;:'` . `' ~ '` ` : `
` . ' , .
~,', . . " ' ~ethyloxazolidineJ 5-hydroxym~thyl-~-isopropyl~xazolidine;
; 5-hydrox~m0thyl-N-benzyloxazolidine; and 5-hydroxymethyl-N~ methyl-~-phenylpropyl~)~oxazolidine in place of 5-hydroxymethyl-~-t-butyloxazolidine a~ s~ar~ing materials~
S the correQponding l-a~ino-; l-methylam~o-~ 30propyl-amlno~ benzylamino-: and l-~C-methyl-~-phenethyl)-amino-derivatives of each of the ~bove products are respectively prepared.

: :: . , . . . .: . . . ... . . .
.,:: .. : : ;. : : , - , . : ~ :

. . . ~ - : . .
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: . . . ,: . . .
:: , , , - :,, EX~MPL~
This ex2~ple illu~trate~ methods according to the invention of preparing the compound~ of formula III of the invention. Thi~ example 3.0 g. of 5-hydroxymethyl-N-(~- ~-methyl-y-phenylpropyl])-oxazolidille in 10 ml. of anhydrous dimethylformamide is added to a ~3u~pen~ion con- ~
taining 0.9 g. of sodium hydride in 8 ml. of dimethylfDrm- ~:
amide under a nitrogen atmospher~. The re~3ulting mix~re i5 heat~d at 80C for 15 minute~ and then cooled to room :
t~mperature and 2.5 g. of 2-bromo-5-5'-~ethylhexylamino-carbonylthiazole in 15 ml. of anhydrou~ dimethylformamicle i~ added. The re~ulting mixtur~ i8 heatad at 80C or two hours, then cool~d to room temperature and evaporated under high vacuum to yield, as a residue, 5-(5-5'-m~thylhexyl-aminocarbonylthiazol-2-oxy~-methylene~ methyl-y-p~enylpropyl)-oxazolidin2.
Similarly, by following the ~ame procedure but re~-pectively replacing 2-bromo-5-5'-methylh~xylaminocarbonyl-thiazole with the corresponding 2-bromo-5-~ubstituted amino-carbonylthiazole compounds, prepared according to Prepara-tion 2, the corresponding oxazolidine derivative~ o form-ula III are re~pectively prepared.
: Similarly, by fol}owing the ~ame proc~dure but re~-pectively replacing 5-hydroæymethyl-N-(~-[~-methyl-r-.
phenylpropyl~)-oxazolidine by 5-hydroxymethyl-~-t-butyloxa-zolidine: 5-hydroxymethyloxazolidine; 5-hydroxymethyl-N-methyloxazol~dina; 5-hydroxymethyl-~ opropy}oxazolidine:
~nd 5-hydroxymethyl-~-benzyloxazolidine, the corre~ponding N-t-butyloxazolidine: oxa~olidine: ~-methyloxazolidine;

N-i~opropyloxazolidine; and N-benzyloxazolidine derivative~
.. ~ 8~ --d ;d :' : ~ ' ' ' . " ' . .

1~3~37 of eacll of the above proclucts are r~spectlvely prepared.
The 4-position isomers are similarly prcpared according to the same procedure but usiny the corresponding 4-position isomer start:ing materials prepared accordin~ to Preparation ; 5 2.

This example illustrates methods of converting the compounds of formula III into the compounds of formula I
of the invention. In this example 1 g. of 5-(5-5'-methyl-hexylaminocarbonyLthiazol-2-oxy)-methylene-N-~a-methyl-y-phenylpropyl)-oxazolicl:lne is disso:Lved in 50 ml. of ethyl acetate and this solut:ion is washed three times witll aqueous 5% sodium hydroxide (20 ml.) at 20C. The mixture is allowed to stand for 0.5 hours, washed with water, dried over mag-nesium sulfate and then evaporated to dryness affording 1-- (a-methyl-~-phenylpropylamino)-3-(5-5'-methylhexylaminocar-bonylthiazol-2-oxy)-2-propanol, which is then further puri-fied by chromatography on silica gel plates.
Similarily, by following the same procedure using the oxazolidine products of formula III of Example 10, are hydrolyzed to the corresponding products of formula I.
, This example illustrates an alternate method for con-; verting compounds of formula III to compouncls of formula I. In this example 1 g. of 5-~5-5'-methylhexylaminocar-bonylthiazol-2-oxy)-methylene-N-t-butyloxazolidine is dis-solved in 20 ml. of methanol containing 4 cc. of 5% aqueous 28 hydrochloric acid at 20C. After 15 minutes, the mixture '` ~ ' ~' ' , " ' :: . . , ~3~7 is neutral.tzed wi-th dilute aqueous socliurn carbollclte solu-tion, poure(l into wa~er and extracted with etlly]. acetate.
The ethyl ac~tate extract is evaporatc~d to dryn~ss yielding l-t~butylamino-3-t5-5'-methy.lhcxylamirlocarbony~lthiazol-2-oxy)-2-propanol.
Similarly, by fo:Llowing the same procedure, the com-pounds of formula III, enumerated in Example 10, are rcs-pectively hydrolyzed to the corresponding compounds of formula I.

~X~MPL~ 13 This example illustrat~s methods, according to the inventiol1, of convert:i.ng compounds of fo.rmula :C :inlo com-pounds o formula III of the invention. In thls example 1 ~. of 1-isopropylamino-3-(5-5'-methylhexylaminocarbonyl-thiazol~2-oxy)-2.-propanol is dissolved in 25 ml. of acetone ; at 20C, and 2 g. of aluminum isopropoxide is then added.
The solution is stirxed for four days at 20C and then 50 ml. of hexane and 5 ml. of water are added and the re-;; sulting mixture is allowed to stand for 15 minutes. The resulting llexane phase i.s separaked and then evaporated ; to dryness yi.elding 5~(5-5'-metllylhexylaminocarbonylthia-zol-2-oxy)-methylene-N-isopropyl-2,2-di.methyloxazolidine.
Similarly, by following the same procedure, the com-: pounds of formula I, prepared in Examples 4 and 5, are respectively converted into the corresponding compounds of formula III.
~ Similarly~ the corresponding thiazol- and ~-- or 5-substituted thiazol-2-oxy~5-mcthylene-N-isopropyl-2-spiro-29 cyclohexyloxazolidine compounds o ormula III are prepared ' ` ' , .

.','' ' .
:.

according ~o the ~ame procedure but using cy~lohexanone in place of acetone.
EXAMP~E 14 Thi~ example illustrate~ further methods, a~cording to the invention, of ~onverting the compound~ of ~orumla I
into th~ corresponding compound~ of formula~ III. In thi~
exa~ple 380 ~g. o 1-t-butylamino-3-(5-5'~methylhexyl~fnino-carbonylthiazol-2-oxy)-2-propanol and a molar equivalent amount of cy~lohexanone are di3~01ved in 15 ml~ of ethyl ether at 20 z and 0.3 g. o* anhy~rou~ pota~ium carbonate i8 then added. The mixture is stirred for 18 hours at room temperature and then filtered. The ~iltrate i8 evaporated to dryness yielding 5-~5-5'-methylhexylamino-carbonylthiazol-2-oxy)-methylene-~-t-butyl-2-~piro-cyclohe~yl oxazolidine.
Similarly, by following the same procedure~ the prod-uct~ of formula I, of Examples 4 and 5, are respectively converted into the corre~ponding 2-~pixo-cyclohexyloxazoli-dine compound3 of formula III.
EX~MP~E 15 Th~ 8 example illu~trates method~ of preparing hydro chloride addition ~alts of the invention. In this example ;~
1 g. of 1-t-butylamino-3-~5-5'-methylhexyla~inocarbonyl-thiazol-2-oxy)-2-propanol i~ di~ olved in 10 ml. of ethyl ether at 20 C. A stream of ga~eous anhydrous hydrog~n chloride is pas~ed over the surace of the solution until the suparnatent liquid becomes colorle~s. The resulting precipitate i~ collected by iltration, washed with ~thyl . ~A,, `;, ;' ' ,~ '' ` ~

ether and then crystalllzed from methanol, containins 1% :~
water and 1% acetone, affording cry~tall~ne l-t-butyl~mino-3~(5-5'-methylhexyl2mi~o~arbonylthiazol-2-oxy)-2-propanol hydrochloride.
S Si~ilarly, by following th0 same pro~e~dure u~ing eac~
of the compounds of for~ula I, prepar~d according to ~xam-ple3 4-~, 9, 11 and 12 and the compound~ of for~ula III.
prepared accordi~g to ~xaMples 10, 13 and 14 a~ start~ng material~, the corresponding hydrochloride addition salt~ of each o~ the~e compound~ i~ re~pectively prepared.

Thie example illu~trate~ methods of prepari~g the maleato addition salts of compoun~ of formula~ I and III~
: In thi~ example one gram of l-t-butylamino-3- ~5-5 '-methyl-hexylaminocaxbonylthiazol-2-oxy)-2-propanol i8 digsolved in a ~olution of 5 ml. of ethyl ether and 5 ml. of ethanol at 20C. To this ~olution i8 added 10 ml. of a saturated 801ut~0n of maleic acid in ethyl ether~ Th~ mixture i8 allowed to ~tand for one hour at room temperature. The ;~
resulting precipitate i~ recovered by filtration, wa~hed three t~mes with ethyl ether and then cry~tallized from a mixture o~ ethyl ether and ~thano~ 1) affording cry~talline 1-t-butylamino-3-~5-5'-methylhexylaminocarbo-nylthiazol-2-oxy~-2-propanol maleate ~alt.
similarly, by ollowin~ the ~me procedure using each of the compounds of for~ula I, prepar~d according to ~m~
p~æ 4.i7, 9, 11 and 12 and the compound~ of formula IIX, enumerated in Examples 10, 13 and 14 as starting matlsrial~, the corresponding maleate addition salts of each of these ~ - 89 -,~
. .

compounds i~ re~pectively prepared, fl3r example;
l-t-butyl~mino-3-(5-cyclopentyl~minocarbo~ylthiazol-2-oxy~-2-propanol maleate, m.p. 183-185C;
l-t-~utylamino-3-(5-6'-acetylhexylaminocarbc~nylthia-zol-2-oxy)-2-propanol maleate, m~p. 131-132C;
l-t-butylamino-3-(5-~' dimethylaminohexylaminocarbonyl-. thiazol-2-oxy)-2-propanol dimaleate, m.p. 76-79 C;
l-t-butylamino-3-(5-6'-methoxyhexylaminocarbonylthia-zol-2-oxy)-2-propanol maleate, m.p. 133-135C;
. 10 1-t-butylamino-3-(5-r-propoxypropylaminocarbonylthia-: zol-2-oxy)-2-propanol maleate, m.p. 163-164C; and l-t-butylamino-3-(5-6'-aminohexylaminocarbonylthia-.. zol-2-oxy)-2-propanol maleate, 146-149C;
similarly by u~ing lactice acid, the corre~ponding lactate salts are prepared O for example:
1-[~-(4-amino~arbonylphenoxy)-ethylamino~-3-(5 5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol lactate, ; m~p. 65-66C.

: ::

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.
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: :
.: :
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Thi~ example il~u~trates the preparation, accordlng to the invention, of the pure ~) optical i30mer of the compounds o~ formula~ I, II and III. In thi~ example, the procadures of Preparation S and Example~ A-E and 1~16 ;-axe repeated but in thi~ in~tance, in place of racemic glycerol ace~Qnidei the pure (~) optical isomer of glyeerol acetonide is used as starting material in Preparation 5 and Examples 1~ and 1B~ and in the ca~e of Example 8, the pure (~) optical isomer of glycidol i~ u~ed in place of racemic glycidol.
EX~MPLE 18 This example illustrates the preparation, according to the ~nvention, o~ the pure (-) optical isomers of the ~;
compound~ o~ formulas I, II and III. In thi~ example, the procedure~ of PXeparation 5 and Example~ A-E and 1-16 are ~`
repeated but in this instancs, in place of racemic glycerol ~:
acetonide, the pure (-) optical isomer of glycarol acetoniae i8 used as starting material in Pr2paration 5 and Examples lA
and 1B~ and in the ca~e Of EX 8 ple 8, the pure (-) optical i~omer of glycidol i8 u~ed in place of racemic glycidol. :~
~XAMP1E 19 DETERMINA~ION OF ~-ADRE~ERGIC BLOCKING
A~FIVITY OF SELECT COMPOUNDS -The ~-blocking activity of certain randomly selected c~mpound3, of the invention, wa~ studied in ~ale mongrel dog~ which were ane~thstiz0d with sodium pentobarbital and respired by a Harvard re~pirator. ~ midline thoracoto~
wa~ performed and tha animals were in~trumenteæ to recor~d 90 ~

, .

~,. !7~;3'r3,, ~;, J

right ventricular contractile force with a walton-Brodie ~train gauge ~utured to the right ventriclllar ~all. Sy~te~ic blood pre~ure wa~ recorded from a cannulated femoral artery and heart rate by a cardiotachograph t:riggered by the R-g wave of a linib lead II EKG signal. A femoral vein wa~
carmulated for drug admini~tratior~ dogs were bilater-ally vagotomized. Th~ data wa~ recorded on a Beclcman typ0 R dynograph or ~ Gra~ model 7 polygraph.
Dose level~ of 0.1, 0.316, 1.0, and 3.16 mg/kg (or the 10 dosages indicated in the ac~ompanying table~-~ of the agent to be studied were admini~tered intravenously LntO the can-nulated femoral vein approximately 60 minute~ apart. I~o-proterenol (0~5 ~g/kg) wa~ admini~ter2d intravenously beore and 20 minutes ater each dbsa l~vel. To determine ~-15 blocking activity, the heart rate respon~e~ to isoprot~renol : ~0.5 pg/kg) in the contro~ state and after each suc~essive dose o test compound wer0 computed. The perc~nt inhibition of the control i~oproterenol heart rate response following each dose of test compound was then computed. The accom-20 panying table li~t~ ~umula~ive do~e~ o tq3t compound and the re~pective percent inhibition of the heart rate re3ponse following ~he li~ted ~umulative do~e. The percent inh~bition as a mea~re of the degree of ~1-blocXing a~tivity; i.e. the greater the % inhibition, the yr2ater ~he ~-blo~king acti-;25 vity.
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Claims (30)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds having the formulas:

(I) (II) (III) wherein R1 and R2 are independently selected from the group of hydrogen, lower alkyl, cycloalkyl having from three through seven ring atoms, lower alkyl, (lower alkoxy) lower alkyl, lower alkyl (N-heterocyclic selected from the group of heterocyclics represented by the formulas:

; ; ;

; ; ; ; ;

and groups having the formulas or wherein n is a whole integer of from one through four; and R11 and R12 are independently hydrogen or lower alkyl; or R1 and R2 together with the nitrogen atom to which they are jointed form a nitrogen heterocycle or substituted nitro-gen heterocycle selected from the group of heterocycles represented by the formulas:

; ; ;

; ; ;

; ; ;

; ; Z is a substituent on the thiazole ring at either the 4-or 5-position selected from the group having the formulas:

; ; or wherein one of R3 or R4 is independently selected from the group of alkyl having from seven through 12 carbon atoms; cycloalkyl having from three through 12 carbon atoms; terminally substituted alkyl group having from two through 12 carbon atoms having one substituted terminal carbon having a sub-stituent selected from the group of hydroxy, acyloxy having from two through 12 carbon atoms and alkoxy having from one through six carbon atoms; and groups having the formulas or -(CH2)nR10 wherein n is a whole integer of from one through four, R8 and R9 are independently selected from the group of hydrogen and alkyl groups having from one through four carbon atoms and R10 is cycloalkyl having from three through eight carbon atoms; and the other of R3 or R4 is selected from the group of hydrogen; alkyl having from one through 12 carbon atoms; cycloalkyl having from three through 12 carbon atoms; phenyl, lower phenylalkyl wherein the alkyl moiety has from one through six carbon atoms, substituted phenyl and substituted lower phenylalkyl wherein said phenyl ring has one or two substituents independently selected from the group of hydroxy, lower alkyl, lower alkoxy and halo; terminally substituted alkyl group having from two through 12 carbon atoms having one substituted terminal carbon atom having a substituent selected from the group of hydroxy, acyloxy having from two through 12 carbon atoms and alkoxy having from one through six carbon atoms; and groups having the formulas or (CH2)nR10 wherein n is a whole integer of from one through four, R8 and R9 are independently selected from the group of hydrogen and alkyl groups having from one through four carbon atoms and R10 is cycloalkyl having from three through eight carbon atoms; and wherein when one of R1 or R2 is the group then R3 and R4 can each be independently selected from the group of hydrogen; alkyl having from one through 12 carbon atoms;
cycloalkyl having from three through 12 carbon atoms; phenyl, lower phenylalkyl, wherein alkyl moiety has from one through six carbon atoms, substituted phenyl and substituted lower phenylalkyl wherein said phenyl ring has one or two substi-tuents independently selected from the group of hydroxy, lower alkyl, lower alkoxy and halo; terminally substituted alkyl group having from two through 12 carbon atoms having one substituted terminal carbon atom having a substituent selected from the group of hydroxy, acyloxy having from two through 12 carbon atoms and alkoxy having from one through six carbon atoms; and groups having the formulas or -(CH2)nR10 wherein n is a whole integer of from one through four, R8 and R9 are independently selected from the group of hydrogen and alkyl groups having from one through four carbon atoms and R10 is cycloalkyl having from three through eight carbon atoms;
R5 and R6 are independently selected from the group of hydrogen, lower alkyl, arylalkyl or together with the carbon atom to which they are joined form a cycloalkyl having from five through seven carbon atoms; R7 is hydrogen, lower alkyl, aryl or arylalkyl; and further provided that when Z is then R4 cannot be hydrogen; and pharmaceutically acceptable salts of formula I and III; which comprises a) reacting the corresponding compound having the formula:

(D) wherein Z is as defined above and Y' is alkyl or phenyl, with a strong base at temperatures in the range of about from 0° to 100°C, thereby yielding the corresponding compound of formula II; or, when it is desired to obtain a compound of formula III, b) reacting the corresponding compound having the formula:

wherein R5, R6 and R7 are defined herein above, with an alkaline metal hydride in an inert organic solvent at temperatures in the range of about from 20 to 80°C, and reacting the reaction product with the desired compound having the formula:

wherein R3 and R4 are as defined herein above and X is bromo or chloro, at temperatures in the range of about from 60° to 140°C, or reacting the cor-responding compound having the formula:

wherein Z and R7 are as defined above, with a ketone or aldehyde having the formula R5R6C=O
wherein R5 and R6 are as defined above, at tem-peratures in the range of about from 20° to 100°C
for about from one to 48 hours, thereby yielding the corresponding compound of formula III; or, when it is desired to obtain a compound of formula I, reacting the corresponding compound having the formula:

(II) wherein z is as defined with an amino- derivative of the formula wherein R1 and R2 are as defined above or N-heterocyclic derivative as defined above and such derivatives having the desired R1 and R2 substituents; or hydrolyzing the corresponding compounds having the formula:

(III) wherein R3, R4, R5, R6 and R7 are as defined herein above under acid or basic conditions, thereby yielding the corresponding compound of formula I; and where pharmaceutically acceptable salts are desired, d) neutralizing the corresponding compound of formula I or III with the desired salt anion or where further salt variation is desired, exchang-ing the salt with the desired anion.

2. The process of Claim 1, steps c) and d) for preparing a compound of formula I.

3. The process of Claim 2 for preparing the respective compound wherein Z has the formula .

4. The process of Claim 2 for preparing a compound having the formula:

wherein R1, R2, R3 and R4 are as therein defined, and the pharmaceutically acceptable salts thereof.

5. The process of Claim 4 for preparing a compound wherein R3 is hydrogen and R is selected from the group consisting of 3'-methylhexyl, 1'-methylhexyl, 4'-ethyl-hexyl, 3'propylhexyl, n-heptyl, n-oxtyl, cycloheptyl, cyclohexyl, .beta.-cyclopentylethyl, ?-cyclopentylpropyl, 4'-cyclopentyl-butyl, ?-cyclohexylpropyl, 4'methylhexyl and 5'-methylhexyl.

6. The process of Claim 5 for preparing a compound wherein R4 is selected from the group consisting a 4' -methylhexyl and 5'-methylexyl..

7. The process of Claim 5 for preparing a compound wherein one or R1 or R2 is hydrogen and the other is selected from the group consisting if isopropyl, t-butyl and .beta.-(4-aminocarbonylphenoxy)-ethyl.

8. The process of Claim 7 for preparing a compound wherein R4 is selected from the group consisting of 5' methylhexyl and 4'-methylhexyl.

9. The process of Claim 2 for preparing 1-t-butyl-amino -3-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol and pharmaceutically acceptable salts thereof, by reaction of the corresponding compound of Formula II with amine or by hydrolysis of the corresponding compound of Formula III, followed by neutralization of the desired compound with salt anion or exchange of salt with anion.

10. The process of Claim 2 for preparing 1-isopropyl-amino-3-(5-5'methylhexylaminocaxbonylthiazol-2-oxy)-2-propanol and pharmaceutically acceptable salts thereof, by reaction of the corresponding compound of Formula II
with amine or by hydrolysis of the corresponding compound of Formula III, followed by neutralization of the desired compound with salt anion or exchange of salt with anion.

11. The process of Claim 2 for preparing 1-[.beta.-(4-amino-carbonylphenoxy)-ethylamino]-3-(5-5'-methylhexyl-aminocar-bonylthiazol-2-oxy)-2-propanol and pharmaceutically accept-able salts thereof, by reaction of the corresponding compound of Formula II with amine or by hydrolysis of the corresponding compound of Formula III, followed by neutralization of the desired compound with salt anion or exchange of salt with anion.

12. The process of Claim 1, step a) for preparing a compound of said formula II.

13. The process of Claim 1, steps b) and d) for pre-paring a compound of said formula III and pharmaceutically acceptable salts thereof.

14. A compound having the formulas:

(I) (II) (III) wherein each of R1, R2, Z, R5, R6 and R7 are as defined in Claim 1, when prepared by the process of Claim 1.

15. The compound of Claim 14 of formula I, when prepared by the process of Claim 2.

16. The compound of Claim 14 of formula I wherein Z has the formula , when prepared by the process of Claim 3.

17. The compound of Claim 14 having the formula:

wherein R1, R2, R3 and R4 are as defined in Claim 1, and the pharmaceutically acceptable salts thereof, when prepared by the process of Claim 4.

18. The compound of Claim 14 of formula I wherein Z is at position C-5, R3 is hydrogen and R4 is selected from the group consisting of 3'-methylhexyl, 1'-methylhexyl, 4'-ethylhexyl, 3'-propylhexyl, n-heptyl, n-octyl, cycloheptyl, cyclohexyl, .beta.-cyclopentylethyl, ?-cyclopentylpropyl, 4'-cyclo-pentylbutyl, ?-cyclohexylpropyl, 4'-methylhexyl and 5'-methylhexyl, when prepared by the process of Claim 5.

19. The compound of Claim 14 of formula I wherein Z
is at position C-5, R3 is hydrogen and wherein R4 is selected from the group consisting of 4'-methylhexyl and 5'-methylhexyl, when prepared by the process of Claim 6.

20. The compound of Claim 14 of formula I wherein Z is at position C-5 wherein R3 is hydrogen R4 is selected from the group consisting of 3'-methylhexyl, 1'-methylhexyl, 4'-ethylhexyl, 3'-propylhexyl, n-heptyl, n-octyl, cycloheptyl, cyclohexyl, .beta.-cyclopentylethyl, ?-cyclopentylpropyl, 4'-cyclo-pentylbutyl, ?-cyclohexylpropyl, 4'-methylhexyl and 5'-methyl-hexyl and one of R1 and R2 is hydrogen and the other is selected from the group consisting of isopropyl, t-butyl and .beta.-(4-amino-carbonylphenoxy)-ethyl, when prepared by the process of Claim 7.

21. The compound of Claim 14 of formula I wherein Z is at position C-5, wherein R3 is hydrogen, R4 is selected from the group consisting of 5'-methylhexyl and 4'-methylhexyl, and one of R1 and R2 is hydrogen and the other is selected from the group consisting of isopropyl, t-butyl and .beta.-(4-amino-carbonylphenoxy)-ethyl, when prepared by the process of Claim 8.

22. The compound 1-t-butylamino-3-(5-5'-methylhexyl-aminocarbonylthiazol-2-oxy)-2-propanol and pharmaceutically acceptable salts thereof, when prepared by the process of Claim 9.

23. The compound 1-isopropylamino-3-(5-5'-methylhexyl-aminocarbonylthiazol-2-oxy)-2-propanol and pharmaceutically acceptable salts thereof, when prepared by the process of Claim 10.

24. The compound 1-[.beta.-(4-aminocarbonylphenoxy)-ethyl-amino]-3-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol and pharmaceutically acceptable salts thereof, when prepared by the process of Claim 11.

25. The compound of Claim 14 of formula II, when prepared by the process of Claim 12.

26. The compound of Claim 14 of formula III and pharma-ceutically acceptable salts thereof, when prepared by the process of Claim 13.

27. A process for preparing 1-t-butylamino-3-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol or a pharmaceutically acceptable salt thereof which comprises hydrolyzing 5-(5-5'-methylhexylaminocarbonylthiazol-2-oxy-methyl)-N-t-butyloxazolidine or reacting 1, 2-epoxy-3-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-propane with t-butyl-amine and when it is desired to obtain a pharmaceutically acceptable salt, neutralizing 1-t-butylamine-3-(5-5'-methyl-hexylaminocarbonylthiazol-2-oxy)-2-propanol with the desired salt anion.

28. A process for preparing 1-t-butylamino-3-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol hydro-chloride which comprises neutralizing 1-t-butylamine-3-(5-5'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol with hydrogen chloride.

29. The compound 1-t-butylamino-3-(5-5'methylhexylamino-carbonylthiazol-2-oxy)-2-propanol or a pharmaceutically accept-able salt thereof, when prepared by the process of Claim 27.

30. The compound 1-t-butylamino-3-(5-5'-methylhexyl-aminocarbonylthiazol-2-oxy)-2-propanol hydrochloride, when prepared by the process of Claim 28.