EP0000032B1

EP0000032B1 - Di- and tri-substituted thiazoles, their preparation, their use in pharmaceuticals and intermediate compounds

Info

Publication number: EP0000032B1
Application number: EP78100053A
Authority: EP
Inventors: John James Baldwin; Gerald Salvatore Ponticello
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1977-06-01
Filing date: 1978-06-01
Publication date: 1982-05-19
Also published as: EP0000032A1; US4260609A; JPS543063A; JPS631308B2

Description

The present invention involves novel di- and tri- substituted thiazoles having pharmaceutical activity and β-adrenergic blocking agents.
Thiazoles having an aminohydroxypropoxy substituent in the 2-position with or without a specific additional substituent in the 4 or 5-position, are known and are taught to have β-adrenergic 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 β-adrenergic stimulating activity (U.S. 3,850,947, U.S. 3,850,946). Thiazoles having the aminohydroxypropoxy substituent in the 2-position with an aminocarbonyl, 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
are known and are taught to block β-adrenergic receptors (U.S. 3,932,400).
Novel di- and tri-substituted thiazoles having a 4(3-amino-2-OR-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
and pharmaceutically acceptable salts thereof
or
wherein

R is hydrogen, C₂―C₁₂ acyl, or C₇―C₁₂ aroyl,
R₁ is C₁―C₁₂ alkyl,
R₂ is hydrogen, CF₃, C₆―C₁₂ carbocyclic aryl, monosubstituted aryl, 6-membered-N-heteroaryl, C₁―C₆ alkyl, C₁―C₆ alkylthio, C₁―C₆ alkyl-sulfinyl, C₁-C₆ alkylsulfonyl, thienyl or furfuryl,
R₃ is C₁―C₆ alkyl, -COOC₁―C₆ alkyl, ―COOC₆―C₁₂ aryl, cyano, C₆―C₁₂ carbocyclic aryl, CF₃ or
wherein R₄ and R₅ are independently selected from H and C₁―C₆ alkyl or are joined forming together with the nitrogen atom
provided that when R₂ is phenyl, R₃ is other than C₁―C₆ alkyl or COOC₁―C₆ alkyl; and
R₆ in formula VI is hydrogen, C₁―C₁₂ alkyl or C₆―C₁₂ carbocyclic aryl, such that when R₃ is ―COOC₂H₅ R₂ must be ―S―C,―C₆ 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-1,1'-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 non-carboxylic acids such as isethionic acid. Examples of useful inorganic acids are the hydrogen halides i.e., HCI, 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, C_2―C₁₂ acyl or C₇―C₁₂ aroyl. The C₂―C₁₂ groups include alkanoyl groups such as acetyl, pivaloyl, dodecanoyl, hexanoyl, succinoyl; carbocyclic aroyl groups include groups such as benzoyl, 1- or 2- naphthoyl, p-methylbenzoyl, p-phenylbenzoyl. The C₂―C₆ alkanoyl and benzoyl groups are preferred acyl groups and aroyl groups, respectively. Hydrogen is the most preferred R group.
The R_i substituent comprises C₁―C₁₂ alkyl groups and preferably the C₁―C₆ alkyl groups. The alkyl groups are exemplified by methyl, C₁₂H₂₅, hexyl, 2-ethylhexyl, isopropyl, sec-butyl,, heptyl. The C_3-4 branched chain alkyl R₁ groups are more preferred, with t-butyl being the most preferred group.
R₂ includes H, CF₃, C₆―C₁₂ carbocyclic aryl such as phenyl, monosubstituted phenyl e.g. p-tolyl, o-halophenyl, p-nitrophenyl, p-methoxyphenyl and p-halophenyl; indanyl; 1- or 2-naphthyl, 6- membered-N-heteroaryl such as 2-, 3- or 4-pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, thienyl, furfuryl, C₁―C₆ alkyl, e.g. methyl, n-hexyl, isopropyl, sec-butyl, ethyl, C₁―C₆ alkylthio, and the sulfinyl and sulfonyl derivatives exemplified by C₂H₅―S, C₄H₉―SO, C₆―H₁₃―SO₂, CH(CH₃)₂―SO₂, CH₃―SO, t-butyl-S. Preferred R₂ groups are hydrogen, C₁―C₆alkyl and C₁―C₆alkylthio, especially CH₃―S.
The R₃ substituent includes CF₃, C₁―C₆alkyl, CN, C₆―C₁₂ carbocyclic aryl such as phenyl, carboxylic acid esters and amides. The C₁―C₆ alkyl groups are exemplified by CH₃, isopropyl. The ester group is C₁―C₆ alkylester exemplified by ―COOCH₃, ―COOC₆H₁₃, ―COOCH(CH₃)₂, ―COOC₂H₅ and C₆―C₁₂ arylester, preferably carbocyclic aryl, exemplified by C₆H₅―OOC―, p―CH₃―C₆H₄―OOC―, p―C₆H₅―C₆H₄―OOC―, C₉H₉―OOC―. The amide group includes -CONH₂, C₁―C₆ substituted amide groups such as ―CON(CH₃)₂, ―CON(C₆H₁₃)₂, ―CONHC₂H₅, -CON (sec. butyl)₂ and carbonyl heterocyclic groups such as
of the R₃ groups, CN, CF₃ 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 individual isomers, the mixtures thereof and racemates.
The thiazole compounds which are preferred have the formula
Formula II. compounds where R₂ is H, C₁―C₆ alkylthio, preferably CH₃―S―, or said heteroaryl groups, especially pyridyl, R₃ is CN, CF₃, amide, C₁―C₆alkyl or said ester groups and R₁ is C₁―C₆ alkyl especially C₃―C₄ branched alkyl are more preferred. In the most preferred formula II compounds, R₂ is said alkylthio or heteroaryl, R₃ is CN, CF₃, CONH₂, C₁―C₆alkyl or said ester groups and R₁ is C₃―C₄ branched alkyl.
Another preferred group of thiazoles has the formula
where R₂ is H, C₁―C₆ alkyl, C₁―C₆ alkylthio or pyridyl, R₃ is CN, CF₃, C₁―C₆ alkyl or CONH₂. In more preferred formula III thiazoles, said branched alkyl is tert.-butyl, R₂ is H, CH₃, CH₃S or pyridyl, and R₃ is CN, CH₃, CONH₂ or CF₃ and the thiazoles where said branched alkyl is tert.-butyl, R₂ is H, CH₃S or pyridyl and R₃ is CN or CONH₂ are particularly 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
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 /3-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 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 by the following set of reaction equations:
Z is an alkyl sulfonyl or arylsulfonyl group. Examples of sulfonyl groups are CH₃―SO₂, C₆H₅―SO₂, NO₂―C₆H₄SO₂―, p―CH₃―C₆H₄―SO₂―, mesitylene―SO₂―, CH₃O―C₆H₄―SO₂―, trichlorobenzene―SO₂―; C₁₆H₃₃―SO₂―. Suitable bases are alkali metal bases such as K₂CO₃, K―O―C(CH₃)₃, NaH, organolithiums e.g. phenyllithium, n-butyllithium, lithium diisopropyl amide.
R₆ is hydrogen or a C₁―C₁₂ alkyl or C₆―C₁₂ carbocyclic aryl residue of any suitable aldehyde
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,
The 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 130°C. 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 HCI, H_zS0₄, CH₃COOH. 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 recemic 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 R₆ 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, whenever 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 formula V oxazolidine in the above reaction the thiazole product (IA) may be obtained directly as a single enantiomer. 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, or 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 the following equation sequences. Conventional reaction conditions are employed. The symbol L represents the ―CH₂―CHOR―CH₂―NHF₁ group.
The thiazoles having an alkylsulfonyl or alkylsulfonyl substituent are prepared by oxidizing the corresponding C₁―C₆ alkylthio containing compound. Any suitable oxidizing agent, e.g. H₂O₂, may be used. The following equation illustrates the reaction
The 4-OH substituted thiazole intermediates used in the oxazolidine coupling reaction described above are prepared using conventional processes illustrated by the following equations:
The following examples illustrate preparation of representative thiazoles of the present invention. All temperatures are in °C.
Preparation of the tolysate of (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine..
To a stirred solution of (S) 2-phenyl-3-tert.butylamino-5-hydroxymethyloxazolidine (2.5 g., 0.01 m) and dry pyridine (5 ml.) is added portionwise p-toluenesulfonyl 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 K₂CO₃ (1.4 g., 0.01 m) in H₂O (10 mi.) and the solution extracted with CHCl₃ (3 x 25 ml.). The organic layer is dried over Na₂SO₄, filtered and concentrated to dryness below 50°C to yield the tosylate of (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine which is used in the next step without further purification.

Example 1

(S) 5-Carbamoyl-2-phenyl-4-(3-tert:butylamino-2-hydroxypropoxy) thiazole hydrogen maleate salt. A. Into a dry flask under N₂ is added ethyl 4-hydroxy-2-phenylthiazole-5-carboxylate (2.5 g., 0.01 m), DMF (20 mi.) and NaH (50% mineral oil, 0.5 g., 0.01 m). After stirring for 15 minutes, a solution of the tosylate of (S) 2-phenyl-3-tert.-butylamino-5-hydroxymethyloxazolidine (0.01 m) in DMF (15 mi.) 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 H₂0 (100 ml.) and extracted with ether (3 x 100 ml.). The organic layer is extracted with 1 N HCI (2 x 50 mi.) 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 aqueous layer is neutralized with saturated Na₂CO₃ and extracted with CHCl₃ (3 x 100 ml.). The organic layer is dried over Na₂SO₄, filtered and concentrated to dryness. The residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with 25% hexane ―CHCl₃. The crude product is crystallized with maleic acid in CH₃CN―ether to yield 0.7 g. (14%) of (S) ethyl-2-phenyl-4-(3-tertbutylamino-2-hydroxypropoxy)-thiazole-5-carboxylate hydrogen maleate, m.p. 165-7°C.
B. A mixture of (S) ethyl-2-phenyl-4-(3-tert. butylamino-2-hydroxypropoxy)thiazole-5-carboxylate, 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. Merk) and the product eluted with CHCl₃. 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-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate

To triphenylphosphine oxide (2.25 g., 0.008 m) in CH₂Cl₂ (20 ml.) is added dropwise at 0-4°C. a solution of trifluoromethansulfonic anhydride (1.4 g., 0.0089 m) in CH₂Cl₂ (15 ml.). After 15 minutes, (S) 5-carbamoyl-2-phenyl-4-(3-tertbutylamino-2-hydroxypropoxy)thiazole (1.4 g., 0.004 m) is added and the solution allowed to warm to room temperature. After stirring overnight at room temperature, the mixture is poured into saturated Na₂CO₃ (100 ml.) and the solution extracted with CH₂Cl₂ (3 x 400 mi.). The organic layer is dried over Na₂SO₄, filtered and concentrated to dryness. The residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with CHCl₃. 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 maleate salt hemihydrate, m.p. 204-6°C.

Example 3

(S) Ethyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate hydrogen maleate salt

Into a dry flask under N₂ is added ethyl-4-hydroxy-2-methylthiothiazole-5-carboxylate (20 g., 0.091 m), DMF (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-5-hydroxymethyloxazolidine (0.106 m) in DMF (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 H₂0 (1 I.) and extracted with ether (3 x 300 ml.). The organic layer is washed with H₂0 (2 x 150 ml.) and 1N HCI (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 CHCl₃ (3 x 300 ml.). The organic layer is dried over Na₂SO₄, filtered and concentrated to dryness. The residue is chromatographed on alumina (activity grade II, E. Merck) and the product eluted with CHCI₃. The crude product is crystallized with maleic acid in IPA-Et₂O to yield 8.8 g. (21%) of (S) ethyl 2-methylthio-4-(3-tertbutylamino-2-hydroxypxopoxy)thiazole-5-carboxylate hydrogen maleate salt, m.p. 114-116°C.

Example 4

(S) 5-Carbamoyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt

Using the same procedure described in Example 1B (S) ethyl 2-methylthio-4-(3-tertbutylamino-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-carbamoyl-2-methylthio-4-(3-tert.butylamino-2-hydroxy- propoxy)thiazole hydrogen maleate salt, m.p. 180-2°C.

Example 5

5 Carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate

A. Using the procedure of Example 1A, 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-5-hydroxymethyloxazolidine (0.053 m) in DMF (100 ml.) are reacted to yield 4.7 g. (30%) of ethyl 3-methyl-4-(3-tert.butylamino_-2_-hydroxypropoxy)thiazole-5-carboxylate.
B. Using the procedure of Example 1 B, ethyl 2-methyl-4(3-tert.butylamino-2-hydroxypropoxy)thiazole-5-carboxylate (4 g., 0.014 m), MeOH (90 mi.) and liquid NH₃ (33 g.) are heated to yield 1.3 g. (22%) of 5-carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate, m.p. 177-78°C.

Example 6

(S) 5 Carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole hydrogen maleate salt hemihydrate

A. Using the procedure of Example 1A, ethyl 4-hydroxy-2-methylthiazole-5-carboxylate (28 g., 0.15 m), DMF (500 mi.), NaH (50% mineral oil, 7.5 g., 0.16 m) and the tosylate of (S) 2-phenyl-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 1 B, (S) ethyl 2-methyl-4-(3-tert.butylamino-2-hydroxy- propoxy)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 CH₂Cl₂ (20 ml.), and (S) 5-carbamoyl-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole (1.4 g., 0.005 m) are reacted to yield 0.9 g. (47% of (S) 5-cyano-2-methyl-4-(3-tert.butylamino-2-hydroxypropoxy)-thiazole hydrogen maleate salt, m.p. 172-174°C.

Example 8

(S) 5-Methyl-2-(4'-pyridyl)-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole.

Using the procedure in Example 1A, 4-hydroxy-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.butylamino-5-hydroxymethyloxazolidine (0.02 m) in DMF (20 ml.) are reacted to yield 0.6 g. (10%) of (S) 5-methyl-2-(4'-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-5-carboxylate (3.6 g., 0.01 m) in 3N HCI (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 well with CHCl₃. The aqueous layer is extracted with CHCl₃ (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-Et₂O 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 9, (S) 5-carbamoyl-2-methylthio-4-(3-tert.butylamino-2-hydroxypropoxy)thiazole (1.7 g., 0.005 m), 3N HCI (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 CHC1₃ 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., 0.005 m) in CH₂Cl₂ (10 ml.), trifluoromethane sulfonic anhydride (0.78 ml., 0.005 m) in CH₂Cl₂ (10 ml.) and (S) 5-carbamoyl-4-(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

1. Compounds having the formula

and pharmaceutically acceptable salts thereof or

wherein

R is hydrogen, C₂―C₁₂ acyl, or C₇―C₁₂ aroyl,

R₁ is C₁―C₁₂ alkyl,

R₂ is hydrogen, CF₃, C₆―C₁₂ carbocyclic aryl, monosubstituted aryl, 6-membered-N-heteroaryl, C₁―C₆ alkyl, C₁―C₆ alkylthio, C₁―C₆ alkyl-sulfinyl, C₁―C₆ alkylsulfonyl, thienyl or furfuryl,

R₃ is C₁―C₆ alkyl, ―COOC₁―C₆ alkyl, ―COOC₆―C₁₂ aryl, cyano, C₆―C₁₂ carbocyclic aryl, CF₃ or

wherein R₄ and R₅ are independently selected from H and C₁―C₆ alkyl or are joined forming together with the nitrogen atom

provided that when R₂ is phenyl, R₃ is other than C₁―C₆ alkyl or ―COOC₁―C₆ alkyl; and

R₆ in formula VI is hydrogen, C₁―C₁₂ alkyl or C₆―C₁₂ carbocyclic aryl, such that when R₃ is -COOC₂H₅ R₂ must be ―S―C₁―C₆ alkyl.

2. Compounds of Claim 1 wherein R is hydrogen and R₁ is C₃―C₄ branched chain alkyl.

3. Compounds of Claim 2 wherein R₂ is C₁―C₆ alkyl.

4. Compounds of Claim 2 wherein R₂ is C₆―C₁₂ carbocyclic aryl.

5. Compounds of Claim 2 wherein R₂ is C₁―C₆ alkylthio.

6. Compounds of Claim 5 wherein R3 is -COOC₂H₅.

7. Compounds of Claim 2 wherein R₃ is CN,

or C₁―C₆ alkyl.

8. Compounds of Claim 7 wherein R₃ is ―CONH₂.

9. Compounds of Claim 2 wherein R₁ is t-butyl, R₂ is phenyl and R₃ is

10. The compounds of Claim 2 wherein R₁ is t-butyl, R₂ is CH₃―S― and R₃ is ―COOC₂H₅ or

11. The compounds of Claim 2 wherein R₁ is t-butyl, R₂ is -CH₃ and R₃ is

12. The compounds of Claim 2 wherein R₁ is t-butyl, R₂ is H and R₃ is -CN.

13. Compounds of Claim 1 having the S-isomer configuration.

14. A pharmaceutical composition for effecting β-adrenergic blockade containing an effective amount of a compound I or Claim 1.

15. Compounds of Claim 1, formula VI, wherein R₁ is C₃―C₄ branched chain alkyl and R₆ is H or phenyl.

16. A process for preparing compounds of Claim 1, formula I, wherein R is hydrogen which comprises hydrolyzing an oxazolidine of the formula

wherein R₁, R₂ and R₃ are defined as in Claim 1 and R₆ is hydrogen, C₁―C₁₂ alkyl or C₆―C₁₂ carbocyclic aryl.

17. A process for preparing compounds of Claim 1, formula I, wherein R is C₂―C₁₂ acyl which comprises acylating a compound having the formula

wherein R,, R₂ and R₃ are defined as in Claim 1.