IE46911B1 - Di- and tri-substituted thiazoles,their preparation,their use in pharmaceuticals and intermediate compounds - Google Patents

Abstract

Thiazole derivs. of formula (I) and their salts are new: (R is H or 2-12C acyl; R1 is 1-12C alkyl; R2 is H, CF3, 6-12C carbocyclic aryl, 6-membered N-heteroaryl, thienyl, furfuryl, 1-6C alkyl, alkylthio, alkylsulphinyl or alkylsulphonyl; R3 is 1-6C alkyl, COOX, CN, 6-12C carbocyclic aryl, CF3 or CONR4R5; X is 1-6c alkyl or 6-2C carbocyclic aryl; R4 and R5 are H or 1-6C alkyl, or NR4R5 is morpholino, piperazino or 4-methylpiperazino. Provided that when R2 is Ph, R3 is not 1-6C alkyl or COOX with X being 1-6C alkyl). Corresp. cpds. having a 4-substit. of formula (II) are new: (R6 is H, 1-12C alkyl or 6-12C carbocyclic aryl; and R1-3 are as defined above except that when R3 is COOet, R2 is 1-6C alkylthio). (I) are beta-adrenergic blocking agents; some cpds. have immediate onset of antihypertensive effect and/or vasodilator activity. Dose is 1.5-3,000 mg. daily in man. Cpds. with gp. (II) are intermediates for (I).

Description

The present invention involves novel diand tri- substituted thiazoles having pharmaceutical activity as β-adrenergic blocking agents.

Thiazoles having an aminohydroxypropoxy 5 substituent in the 2-position with or without a specific additional substituent in the 4 or 5position, are known and are taught to have βadrenergic stimulating activity (U.S. 3,850,945). Thiazoles having an aminohydroxypropoxy substituent in the 4 or 5-position with no additional substitution are also known and are taught to have βadrenergio stimulating activity (U.S. 3,850,947, U.S. 3,850,946). Thiazoles having the aminohydroxypropoxy substituent in the 2-position with an amino15 carbonyl, formamido, substituted oxycarbonyl amino group in the 4 or 5-position, are known and taught to have β-adrenergic blocking activity (U.S.3,897,411) Thiazoles having the following formula are known and are taught to be β-adrenergic blocking agents. (U.S. 3,897,442). Thiazoles of the formula Λβύίΐ are known and are taught to block β-adrenergic receptors (U.S. 3,932,400).

Novel di- and tri-substituted thiazoles having a 4(3amino-2-0R-propoxy) substituent have been discovered. The thiazoles are active as β-adrenergic blocking agents.

An embodiment of the present invention is compounds having the formula .R.

R. ‘2 ^0-CH2-CH0R-CH2-NHR1 and pharmaceutically acceptable salts thereof or 0. '3 H CH.

N-R.

R. '1 '6 wherein R is hydrogen, C2-C^2acyl, or C^-C^ aroyl, R^ is c1-c12 alkY-1R2 is hydrogen, CF3, Cg-Cj2 carbocyclic aryl, monosubstituted aryl, 6-membered-N-heteroaryl, C^-Cg alkyl, C1“Cg alkylthio, C^-Cg alkyl-sulfinyl, C-^Cg alkylsulfonyl, thienyl or furfuryl, R^ is Cj_-Cg alkyl, -COO^-Cg alkyl, rCOOCg-C12 aryl, cyano, Cg-C^2 carbocyclic aryl, CF^ or -C-NR^R^ wherein R4 and Rc are independently selected from H and C^-Cg alkyl or are joined forming together with the nitrogen atom N-H or Z~\ -N_J-CH3 . provided that when Rj is phenyl, Rj is other than Cj-Cg alkyl or COOC^-Cg alkyl? and Rg in formula VI is hydrogen, Cj-C12 alkyl or C6-C12 carbocyclic aryl, such that when R3 is —COOCj,H5,R2 must be -S-Cj-Cg alkyl.

The pharmaceutically acceptable salts are the acid addition salts of the formula I free base. Suitable acids include organic as well as inorganic acids. Examples of useful organic acids are carboxylic acids such as acetic acid 2,2'-dihydroxy-1,l‘-dinaphthylmethane-3,3'-dicarboxylic acid, maleic acid, succinic acid, citric acid, tartaric acid, oxalic acid, malic acid, piValic acid, heptanoic acid, lauric acid, propanoic acid, pelargonic acid, oleic acid, and non15 carboxylic acids. such as isethionic acid. Examples of useful inorganic acids are the hydrogen halides i.e., HCl, HBr and HI phosphoric acid, sulfuric acid. The hydrohalide salts especially.the hydrochlorides and maleic acid salts, especially the hydrogen maleate, are preferred.

R may be hydrogen, C2~C12 acyl or C7_C12 “θΥ1· The ^2“C12 SiouPs include alkanoyl groups such as acetyl, pivaloyl, dodecanoyl, hexanoyl, sucoinoyl; carbocyclic aroyl groups include groups such as benzoyl, 1- or 2- naphthoyl, p-methylberizoyl, p-phenylbenzoyl. The C2c6 alkanoyl and benzoyl groups are preferred acyl groups and aroyl groups, respectively. Hydrogen is the most preferred R group.

The R^ substituent comprises ci”c^2 a^Y1 groups and preferably the C^-Cg alkyl groups. The alkyl groups are exemplified by methyl, C^2H25, hexyl, 2-ethylhexyl, isopropyl, sec-butyl, heptyl. The C3_4 branched chain alkyl R^ groups are more preferred, with t-butyl being the most preferred group.

R2 includes H, CF3, Cg-C^2 carbocyclic aryl such as phenyl, monosubstituted phenyl e.g. p-tolyl, o-halophenyl, p-nitrophenyl, p-methoxyphenyl and p-halophenyl; indanyl; 146911 or 2-naphthyl, 6-membered-N-hetercaryl such as 2-, 3- or 4-pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thienyl, furfuryl, C^-Cgalkyl, e.g. methyl, n-hexyl, isopropyl, sec-butyl, ethyl, C^-Cg thio, and the sulfinyl and sulfonyl derivatives exemplified by C2H5~S, CjHg-SO, Cg-H13-SO2, CH(CHg)2~SO2, CH^-SO, t-butyl-S. Preferred R2 groups are hydrogen, C,-Chalky! and C^-Cgalkylthio, especially CHg-S.

The R3 substituent includes CF., C^-Cg alkyl, CN, Cg-Cj_2carixjcYclic a*7l such as phenyl, carboxylic acid esters and amides. The C^-Cg alkyl groups are exemplified by CHg, isopropyl, The ester grup is C^-Cg alkylester exemplified by -COOCH3, “COOCgH13, -COOCH(CH3)2, -COOC2H5 and Cg-C12 arylester, preferably carbocyclic aryl, exemplified by CgHg-OOC, p-CHg-CgH^-OOC-, p-C,Hr-CcH -OOC-, CoHq-00C-. The amide 6 5 6 4 9 9 group includes -CONHg, C^-Cg substituted amide groups such as -CON(CH3)2, -CON(CgH13)2, -CONHCgHg, -CON (sec. butyl)2 and carbonyl Heterocyclic g ,ps such as O (or -CH,) and v_y 3 vy of the R3 groups, CN, CFg and amide, especially CONH2, are preferred.

The formula I compounds have a chiral center (at the 2 carbon in the propoxy substituent) which confers optical activity. The optical isomers are designated conventionally as L and D, 1 and d, + and -, S and R or by combinations of these symbols.

Where the formula or compound name herein carries no specific designation, the formula or name includes the individuvl isomers, the mixtures thereof and racemates.

The thiazole compounds which are preferred ' 6 have the formula Formula II compounds where R2 is H, C^-Cg alkylthio, preferably' CH3«S-, or said heteroaryl groups, 10 especially pyridyl, R3 is CN, CFj, amide, C^-Cg alkyl or said ester groups and R^ is C^-Cg alkyl especially C3-C4 branched alkyl are more preferred, in the most preferred fcnrula II compounds, R^ is said alkylthio or heteroaryl, R3 is CN, c?3, C0nh2, 15 C^-CgSlkylor said ester groups and Rj-.is.C3*C4 branched alkyl. ?5 where R2 is H, Cj-Cg alkyl, C^-Cg alkylthio or pyridyl, R3 is CN, CF3, C^-Cg alkyl or CONB2. In more preferred formula III thiazoles, said branched alkyl is tert.-butyl, Rj is H, CHy CHjS or pyridyl, and R3 is CN, CB3, CONH2 or CFj and the thiazoles where said branched alkyl is tert,-butyl, Rj is 8, CHjS or pyridyl and R3 is CN or C0HH2 are particcularly preferred.

Of the optical isomers those having the S-isomer configuration are preferred.

The thiazoles of the present invention have β-adrenergic blocking activity. This was determined in an in-vivo test using dogs as the test animals.

In this test, representative thiazole compounds, were found to counteract the β-adrenergic stimulating effect of isoproterenol.

Certain of the present thiazoles also exhibit an antihypertensive effect of immediate onset when administered to a spontaneously hypertensive (SH) rat. Representative of such compounds are those having the formula CN i-ch2-chok-ch2-nhc(ch3)3 and CH \—X xH__iL-D-CH2-CHOH-CH2-NHC (CH3) The present thiazoles also show random vasodilator activity.

The present thiazole compounds will effect β-adrenergic blockade in humans. This β-adrenergic blocking effect is useful in the therapeutic treatment of various cardiovascular conditions such as angina pectoris, arrhythmia etc. In administering these formula I compounds for their β-adrenergic blocking effect, the daily dosage may range from about 1.5 mg. to about 3000 mg. Preferred daily dosages are about 6.5 mg. to about 200 mg. Conventional dosage forms suitable for oral as well as parenteral, e.g. intravenous, intraperitoneal etc., administration are used. Oral dosage forms include tablets, capsules, troches, liquid formulations e.g. solutions, emulsions, elixirs, etc. - parenteral dosage forms include liquid formulations especially solutions. The compositions are prepared using conventional procedures and compounding ingredients such as starch, sterile water, flavoring additivies, antioxidants, binders, vegetable oils, sweetening - \r-.* - i agents, glycerine.

Thiazoles which exhibit the immediate onset antihypertensive activity are useful for treating hypertensive humans at daily dosages ranging from about 100 to about 3000 mg. administered in oral or parenteral dosage forms.

The present thiazoles can be prepared by any convenient process.

One such process involves the coupling of a suitably substituted thiazole with a suitably substituted oxazolidine and hydrolyzing the reaction product obtained. This process is illustrated hy the following set of reaction equations! sulfonyl groups are CHj-SOj-, CgHg-so^-» NOj-CgH^SOj·, p-CHg-CgH^-SOj-, mesityiene-S02~, CS^O-CgH^SOg-, trichlorobenzene-SOj-, C15a33*SO2'· Suitable bases are alkali metal bases such as R2GO3» K-o-ciCHjig» NaH, organolithiuma e.g. phenyl* lithium, n-butyllithiua, lithium diisopropyl amide.

Rg is hydrogen or a C^-C^ or Cg-C^ carbocyclic aryl residue of any suitable aldehyde Rg-C^ . Examples of suitable aldehydes are the aryl aldehydes such as benzaldehyde, naphthaldehyde,4-phenylbenzaldehyde, furfural, bromobenzaldehyde, tolualdehyde, mesitaldehyde or an alkanal such as acetaldehyde, butyraldehyde, · 7he process for preparing oxazolidines where z is hydrogen (and a related coupling reaction) is disclosed in U.S. 3,718,647 and U.S. 3,657,237.

The coupling reaction can be carried out at temperatures ranging from 0°C. to 130eC. A temperature range of 50°c. to 130°C is preferred. The reaction is generally carried out in a solvent. Any suitable solvent may be used. Examples of useful solvents are dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tert, butanol, dioxane, toluene, acetone.

The hydrolysis is carried out using a conventional acid system e.g. by treatment with a solution of any suitable acid such as HCl, H2SO4, CH-COOH.

The hydrolysis product can be directly obtained as the salt of the acid used for the hydrolysis. Ordinarily, the product IA is recovered as the free base after conventional neutralization of the salt.

The coupling reaction is ordinarily carried out at atmospheric pressure. Higher pressures may be used if desired.

When a racemic oxazolidine (formula V) is used as a reactant, the product is obtained as a racemate. The racemate may be separated into its individual enantiomers by conventional resolution techniques.

' When Rg in the oxazolidine (e.g. formula V or VI) is other than hydrogen, in addition to the chiral center at oxazolidine position 5 there is a second chiral center at position 2. However, when5 ever an oxazolidine is designated e.g. as (S), (R) or (R,S), this designation refers only to the optical configuration around the carbon atom at the 5 position.

By using a single optical isomer of the 10 formula V oxazolidine in the above reaction the thiazole product (IA) may be obtained directly as a single 'enaiitiomer. This provides a convenient way for directly preparing individual isomers of the present thiazoles.

Thiazoles represented by formula I wherein R is other than hydrogen are conveniently prepared by treating the corresponding thiazole where R is hydrogen with an appropriate acylating agent such as an acyl halide, e.g. undecanoyl chloride, pivaloyl chloride, benzoylchloride, p-methoxybenzoyl chloride, an anhydride e.g. acetic anhydride. The reaction is illustrated by the following equation: The compounds of the present invention also include the pharmaceutically acceptable salts of the novel thiazoles. These salts are conveniently prepared e.g. by treating the thiazole with an appropriate amount of a useful acid, generally in a suitable solvent.

Additional processes for preparing thiazoles with certain other substituents are illustrated by 469 11 the following equation sequences. Conventional reaction conditions are employed. The symbol L represents the -CH^-CHOR-d^-NR^ group.

Sequence 1 dehydration CH ,S '''N Sequence 2 S ON 0-L jCONH2 33-L I «(, Zn/HCl CONH2 0-L dehydration .

CN 0-L The thiazoles having an alkylsulfinyl or alkylsulfonyl substituent are prepared by oxidizing the corresponding alkylthio containing compound.

Any suitable oxidizing agent, e.g. H2O2, may be used. The following equation illustrates the reaction it -r ihe 4-0H substituted thiazole intermediates used in the oxazolidine coupling reaction described above are prepared using conventional processes illustrated by the following equations: Reaction A Reaction B fi CH3-C-NH2 r BrCH(COOC2H5)2 /COOC2H5 Tie following examples illustrate preparation of representative thiazoles of the present invention. All temperatures are in ®C.

Preparation of the tolysate of (S) 2-phssnyl-3-tert. butylamino-5hydroxyroethyloxazolldine.

To a stirred solution of (S) 2-phenyl-3tert.butylamino-5-hydroxymethyloxazolidine (2.5 g., 0.01m) and dry pyridine (5 ml.) is added portionwise p-toluenesulfdnyl chloride (2.0 g., 0.011 m), while maintaining the temperature of the reaction below 30°C. After the addition, the mixture is stirred at room temperature for 3 hours. To the solid mixture is added a solution of K2C03 (1.4g., 0.01 m) in HjO (10 ml.) and the solution extracted with CHC13 (3 x 25 ml.). The organic layer is dried over Na„SO., filtered and concentrated to dryness below 50eC to yield the tosylate of (S) 2-phenyl-3-tert, butyl25 681 amino-5-hydroxymethyloxazolidine which is used in the next step without further purification.

EXAMPLE 1 (S) 5-Carbamoyl-2-phenyl-4-(3-tert.butylamino-2-hydroxy5 propoxy) thiazole hydrogen maleate salt.______ A. Into a dry flask under is added ethyl 4-hydroxy2-phenylthiazole-5-carboxylate ¢2.5 g., 0.01 m), DMF (20 ml.) and NaH (50% mineral oil, 0,5 g., 0.01 m). After stirring for 15 minutes, a solution of the tosylate of (Ξ) 2-phenyl1° 3-tert,-butylamino-5-hydroxymethyloxazolidine (0.01 m) in DMF (15 ml.) is added at 0-4°C. and the solution heated with stirring at 100°C. After 15 hours, the solution is cooled to 0-10°C., poured into i^O (100 ml.) and extracted with ether (3 x 100 ml.).

The organic layer is extracted with IN HCl (2 x 50 ml.) and the acid layer added to NaOAc (8.2 g., 0.1 m). After 5 hours, the solution is extracted with ether (2 x 50 ml.). The agueous layer is neutralized with saturated Na2CO3 and extracted with CHCl^ (3 x 100 ml.). The organic layer is dried over NajSO^, filtered and concentrated to dryness. The residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with 25% hexane 10 CHCl^. The crude product is crystallized with maleic acid in CH^CN - ether to yield 0.7 g. (14%) of (S) ethyl-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate hydrogen maleate, m.p. 165-7eC.

B. A mixture of (S) ethyl-2-phenyl-4-(3tert. butylamino-2-hydroxypropoxy)thiazole-5carboxylate, obtained by neutralizing the product from A., (4.7 g., 0.012 m), MeOH (90 ml.) and liquid NH3 (22 g.) is heated at 100°C. in a sealed tube.

After 24 hours, the reaction mixture is concentrated to dryness. The residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with CHC13· The crude product is crystallized with maleic acid in IPA to yield 1.65 g, (30%) of (S) 5-carbamoyl-2-phenyl-4-(3-tert,butylamino-2 hydroxypropoxy) thiazole hydrogen maleate salt, m.p. 184-5’C.

EXAMPLE 2 (S) 5-Cyano-2-phenyl-4-(3-tert.butylamino-2-hydroxy30 propoxy)thiazole hydrogen maleate salt hemihydrate To. triphenylphosphine oxide (2.25 g., 0.008 m) in CH2C12 (20 ml.) is added dropwise at O-4°C. a solution, of trifluoranethanesulphonic anhydride (1.4 g., 0.0089 m) in CH2C12 (15 ml.). After 15 minutes, (S) -carbamoyl-2-phenyl-4-(3-terfa.butylamino-2-hydroxypropoxy)thiazole (1.4 g., 0.004 m) is added and the solution allowed to warm to room temperature. After 4691 stirring overnight at room temperature, the mixture is poured into saturated Na2CO3 (100 ml.) and the solution extracted with CH2C12 (3 x 400 ml.). The organic layer is dried over Na^O^, filtered and concentrated to dryness. The residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with CHClj. The crude product is crystallized with maleic acid in IPA to yield 0.3 g. (16%) of (S) 5-cyano-2-phenyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maieace salt hemihydrate, m.p. 204-6°C.

EXAMPLE 3 (S) Ethyl-2-methylthio-4-(3-tert.butylamino-2-hydroxy propoxy)thiazole-5-carboxylate hydrogen maleate salt Into a dry flask under N2 is added ethyl-4hydroxy-2-methylthiazole-5-carboxylate (20 g., 0.091 m), DMP (200 ml.) and NaH (50% mineral oil, 5.0 g., 0.104 m). After stirring for 15 minutes, a solution of the tosylate of (S)-2-phenyl-3-tert.butylamino-5hydroxymethyloxazolidine (0.106 m) in DMP (150 ml.) is added at room temperature and the solution heated on a steam bath with stirring. After 15 hours, the solution is cooled to 0-10’C., poured into H2O (1 1.) and extracted with ether (3 x 300 ml.). The organic layer is washed with H2O (2 x 150 ml.) and IN HCl (3 x 233 ml.). The acid layer is added to NaOAc· 3H2O (95 g., 0.7 m). After 5 hours, the solution is extracted with ether (2 x 200 ml.)., neutralized with saturated Na2CO3 and extracted with CHCl^ (3 x 300 ml.). The organic layer is dried over Na2SO^, filtered and concentrated to dryness. Tne residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with CHClg· The crude product is crystallized with maleic acid in IPA-Et2O to yield 8.8 g. (21%) of (S) ethyl 2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy) thiazole-5-carboxylate hydrogen maleate salt, m.p. 114-116eC.

EXAMPLE 4 (S) 5-Carbaraoyl-2-methylthio-4-(3-tert.butylamino-2hydroxypropoxy)thiazole hydrogen maleate Balt_ Using the same procedure described in Example 2B (S) ethyl 2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate (5.2 g., 0.015 m) MeOH (90 ml.) and liquid ammonia (33 g.) are heated to yield 0.9 g. (14%) of (S) 5-oarbamoyl10 2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt, m.p. 180-2eC.

EXAMPLE 5 Carbamoyl-2-methyl-4-(3-tert.butylamino-2-hvdroxypropoxy)thiazole hydrogen maleate salt hemihydrate 15 A. . Using the procedure of Example IA, ethyl 4-hydroxy-2-methylthiazole-5-carboxylate (9.35 g., 0.05 m), DMF (100 ml.), NaH (57% mineral oil, 2.5 g., 0.052 m) and the tosylate of 2-phenyl-3-tert.butylamino-2-Kydroxymethyloxazolidine (0.053 m) in DMF 20 (100 ml.) are reacted to yield 4.7 g. (30%) of ethyl 2-fflethyl-4-(3-tert.butylamino-2-hydroxypropoxy) thiazole‘-5-oarboxylate.

B. Using the procedure of Example IB, ethyl 2-methyl-4(3-tert.-butylamino-2-hydroxypropoxy)25 thiazole-5-carboxylate (4 g., 0.014 m), MeOH (90 ml.) and liquid NH^ ,(33 g.) are heated to yield 1.3 g. (22%) of 5-carbamoyl-2-methyl-4-(3-tert. butylamino2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate, m.p. 177-78*c. Λ631 1 EXAMPLE 6 Carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate A. Using the procedure of Example IA, ethyl 4- hydroxy-2-*methylthiazole-5-d:arboxylate (28 g., 0.15 m), DM^ (500 ml.), NaH (50% mineral oil, 7»5 g., 0.16 m) and the tosylate of'(S) 2-pheny1-3-tert.butylamino-5-hydroxymethyloxazolidine (0.15 m) in DMF (100 ml.) are reacted to yield 9.8 g. (20%) of (S) ethyl 2-methyl-4-(3-tert. butylamino-2-hydroxypropoxy)thiazole-5-carboxylate.

B. Using the procedure described in Example ib, (S) ethyl 2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)-thiazole-5-carboxylate (9.8 g., 0.034 m), methanol (185 ml.) and liquid NH3 (8.5 g.) are heated to yield 3.6 g. (29%) of (S) 5-carbamoyl-2-methyl-4(3-tert.butylamino-2-hydroxypropoxy) thiazole hydrogen maleate salt, m.p. 161-163“C.

EXAMPLE 7 (S) 5-Cyano-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy) thiazole hydrogen maleate salt._.

Using the procedure described in Example 2, triphenylphosphine oxide (2.78 g., 0.01 m) in CH^Cl^ (20 ml.), and (S) 5-carbimoyl-2-methyl-4-(3tert.butylamino-2-hydroxypropoxy) thiazole (1.4 g.» 0,005 m) are reacted to yield 0.9 g. (47% of (S) - cyano-2-methyl-4-(3-tert.butylaiaino-2-hydfoxypropoxy)thiazole hydrogen maleate salt, m.p. 172174‘C.

I 469 11 EXAMPLE 8 (S) 5-Methyl-2-(4'-pyridyl)-4-(3-tert.butylamino-25 hydroxypropoxy)thiazole._ Using the procedure in Example IA, 4-hydoxy 5-methyl-2-(4'-pyridyl)thiazole (3.65 g., 0.019 m), DMF (50 ml.), NaH (57% mineral oil, 0.95 g., 0.02 m) and the tosylate of (S) 2-phenyl-3-tert.butylamino10 5-hydroxymethyloxazolidine (0.02 m) in DMF (20 ml.) are reacted to yield 0.6 g. (10%) of (S) 5-methyl-2(41-pyridyl)-4-(3-tert. butylamino-2-hydroxypropoxy)thiazole, m.p. 102-104.

EXAMPLE 9 (S) Ethyl 4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate hydrogen maleate salt hemihydrate_ To a solution of (S) ethyl 2-methylthio-4(3-tert. butylamino-2-hydroxypropoxy)thiazole-520 carboxylate (3.6 g., 0.01 m) in 3N HCl (20 ml.) is added portionwise with stirring zinc dust (2.6 g.). After 3.5 hours at room temperature, the mixture is poured into saturated Na2CO3« The suspension is filtered and the filter pad washed wall with CHC13.

The aqueous layer is extracted with CHC13 (3 x 75 ml.). The combined CHCl3 extracts are dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel and the product eluted with CHC13 saturated with aqueous ammonia. The* crude product is crystallized with maleic acid in EtOH-EtjO to yield 0.4 g. (9%) of (S) ethyl 4-(3-tert. butylamino-2-hydroxypropoxy)thiazole-5-carboxylate hydrogen maleate salt hemihydrate, m.p. 103-105’C.

EXAMPLE 10 (S) 5-Carbamoyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole_____ Using the procedure described in Example 5 9, (S) 5-carbamoy1-2-methylthio-4- (3-tert.butylamino-2-hydroxypropoxy)thiazole (1.7 g., 0.005 m), 3N HCl (10 ml.) and zinc dust (0.94 g.) are reacted. Extraction of the aqueous layer with ether yielded unreacted starting material while extraction next with CHClg yielded 0.7 g. (48%) of 5-carbamoyl-4(3-tert. butylamino-2-hydroxypropoxy)thiazole.

EXAMPLE 11 (S) 5-Cyano-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt__ Using the procedure described in Example 2, triphenylphosphine oxide (1.42 g., 0.005m) in CHgClg (10 ml.), trifluorcmathane sulphonic anhydride (0.78 ml., 0.005 m) in CH^Cl^ (10 ml.) and (S) 5-carbamoyl4-(3-tert. butylamino-2-hydroxypropoxy) thiazole (0.7 g., 0.0026 m) are reacted to yield 0.18 g. (19%) of (S) 5-cyano-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt, m.p. 168-170°c.

Claims (17)

1. CLAIMS:1. Compounds having the formula o-ch 2 -chor-ch 2 -nhr 1 £ and pharmaceutically acceptable salts thereof 5 or wherein R is hydrogen, C 2 —c 12 acyl, or C ? —C 12 aroyl, Rj_ is Cj—C^ 2 alkyl, 10 Rj is hydrogen, CF 3 , C g —C^ 2 carbocyclic aryl, monosubstituted aryl, 6-membered-N-heteroaryl, -C g alkyl Cj——C g alkylthio, Cj——C g alkyl-sulfinyl, Cj——C g alkylsulfonyl, thienyl or furfuryl, C^—-C g alkyl, C^-C g alkylthio, Cj——C g alkyl-sulfinyl, 15 c r·^ alkylsulfonyl, thienyl or furfuryl, R 3 is C^-C g alkyl, -COOC^-c e alkyl, -—COOC g —C^2 «yl, cyai»r. Cg—<^2 carbocyclic aryl, CT 3 or I -—-C-NR 4 R 5 2. ί 46311 wherein R^ and Rg are independently selected from H and Cj.—Cg alkyl or are joined forming together with the nitrogen atom _l i~) /O’ , Vi H or _ L.5“ CK 3 provided that when Rg is phenyl, Rg is other than -Cg 5 alkyl or —COOC^—Cg alkyl; and Rg in formula VI is hydrogen, Cg-Cg 2 alkyl or C,—C,- carbocyclic aryl, such that when R, is —COCC„K..k„ O J.Z J Ζ ο Z must be —S-Cg-Cg alkyl.

2. Compounds of Claim 1 wherein R is hydrogen and Rg 10 is Cg—branched chain alkyl.

3. Compounds of Claim 2 wherein Rg is Cg-Cg alkyl.

4. Compounds of Claim 2 wherein R 2 is Cg-Cg 2 carbocyclic aryl.

5. Compounds of Claim 2 wherein R 2 is Cg-Cg alkyl15 thio.

6. Compounds of Claim 5 wherein Rg is -COOCgHg.

7. Compounds of Claim 2 wherein Rg is CN, 4 R 5 4 6911 or C^-—Cg alkyl.

8. Compounds of Claim 7 wherein is —CONH^.

9. Compounds of Claim 2 wherein R^ is t-butyl, R 2 is phenyl and R 3 is -C-NH 2 or —CN

10. . The compounds of Claim 2 wherein R^ is t-butyl, R 2 is CHj—S- and R 3 is —COOCjHg or -nh 2 .

11. The compounds of Claim 2 wherein is t-butyl, R 2 10 is -CHj and Rj is -NH 2 or —CN.

12. The compounds of Claim 2 wherein R^ is t-butyl, R 2 Is H and R 3 is —CN.

13. Compounds of Claim 1 having the S-isomer config15 uration.

14. A pharmaceutical composition for effecting fiadrenergic blockade containing an effective amount of a compound 1 or Claim 1.

15. Compounds of Claim 1, formula VI, wherein is branched chain alkyl and Rg is H or phenyl.

16. A process for preparing compounds of Claim 1, formula 1, wherein R is hydrogen which comprises hydrolyzing 5 an oxazolidine of the formula wherein R., R» and R. are defined as in Claim 1 and R_ is 12 3 6 hydrogen, C^-C^ 2 alkyl or C g -C 12 carbocyclic aryl.

17. A process for preparing compounds of Claim 1, 10 formula 1, wherein R is C 2 -C^ 2 acyl which comprises acylating a compound having the formula . N---— Ο-CH» -CH-CH- -NHR, R,-A I 2 gh 2 1 z x s—U R, wherein R^, R 2 and R^ are defined as in Claim 1.