US3897425A

US3897425A - 3-Chloro-tetrahydro-1,3-oxazines or oxazolidines

Info

Publication number: US3897425A
Application number: US456744A
Authority: US
Inventors: Nicolae S Bodor; James J Kaminski
Original assignee: Interx Research Corp
Current assignee: Interx Research Corp
Priority date: 1974-04-01
Filing date: 1974-04-01
Publication date: 1975-07-29
Anticipated expiration: 1992-07-29
Also published as: FR2274617B1; FR2274617A1; GB1488073A; JPS50142562A; AU7970975A

Abstract

There is provided, novel 3-chlorotetrahydro-1,3-oxazine or oxazolidine compounds, exhibiting antibacterial activity and being of low chlorine potential of the formula:

WHEREIN EACH OF R1 and R2, which may be the same or different, represent an alkyl group of from 1 to 20 carbon atoms (C1-C5 being preferred); wherein each of R5 and R6, which may be the same or different, represent a hydrogen atom or an alkyl group of from 1 to 20 carbon atoms (C1-C5 being preferred); wherein l represents an integer of 1 or 2 and wherein each of R3 and R4, which may be the same or different, represent an alkyl group of from 1 to 20 carbon atoms (C1-C5 being preferred), a -(CH2)nX group, wherein n represents an integer of from 1 to 20 and wherein X represents a dimethylamino group, a diethylamino group, a trimethylammonium group, a triethylammonium group, a dimethylammonium group, a diethylammonium group, a -COOR7 group, a -OOCR8 group, and a -OR9 group, wherein each of R7 through R9, respectively, represent an alkyl group of from 1 to 5 carbon atoms or a benzyl group. In addition, R3 and R4 can also represent a

group, wherein Y represents a -(CH2)n-W-(CH2)m- group or a >CH-Z group, wherein W represents a -O- atom, a -CH2- group, a >NCH3group, a >NHCH3 group, a >NC2H5 group, a >NHC2H5 group, a >N(CH3)2 group, or a >N(C2H5)2 group, wherein n is the same or different from m and wherein each of n and m represent an integer of from 0 to 2; and wherein Z is defined in accordance with X above.

Description

United States Patent 1 Bodor et al.

[ 3-CHLORO-TETRAHYDRO-1,3-OXAZINES 0R OXAZOLIDINES [75] Inventors: Nicolae S. Bodor; James J.

Kaminski, both of Lawrence, Kans.

[73] Assignee: lnterx Research Corporation,

Lawrence, Kans.

[22] Filed: Apr. 1, 1974 [21] Appl. No; 456,744

[52] U.S. CL. 260/244 R; 260/307 FA; 260/293.66; 424/248; 424/267; 424/272 [51] Int. Cl. C07D 265/06 Primary ExaminerSherman D. Winters Attorney, Agent, or Firm Charles N. Blitzer [57] ABSTRACT There is provided, novel 3-chlorotetrahydro-1,3- oxazine or oxazolidine compounds, exhibiting antibacterial activity and being of low chlorine potential of the formula:

(C R Rgl R x- 3 R N R [451 July 29,1975

wherein each of R, and R which may be the same or different, represent an alkyl group of from 1 to 20 carbon atoms (C -C being preferred); wherein each of R and R which may be the same or different, represent a hydrogen atom or an alkyl group of from 1 to 20 carbon atoms (C -C being preferred); wherein 1 represents an integer of 1 or 2 and wherein each of R and R which may be the same or different, represent an alkyl group of from '1 to 20 carbon atoms (C -C being preferred), a (CH ),,X group, wherein n represents an integer of from 1 to 20 and wherein X represents a dimethylamino group, a diethylarnino group, a trimethylammonium group, a triethylammonium group, a dimethylammonium group, a diethylammonium group, a COOR group, a OOCR group, and a OR group, wherein each of R through R respectively, represent an alkyl group of from 1 to 5 carbon atoms or a benzyl group. in addition, R and R, can also represent a group, wherein Y represents a (Cl-l ),,-W--(CH group or a Cl-l-Z group, wherein W repre- 11 Claims, No Drawings BACKGROUND OF THE INVENTION wherein each of R and R which may be the same or different, represent an alkyl group of from 1 to 20 carbon atoms (C -C being preferred); wherein each of R and R which may be the same or different, represent a hydrogen atom or an alkyl group of from 1 to 20 car:

1. Field of the Invention 5 y H The present invention is directed to novel antibacteatoms 1- 5 being P wherein f rial low chlorine potential compounds and more specif- SefltS an integer 0f 1 9 2 and wherein each f 3 n ically, the present invention is directed to a totally new 4 which y be the same of diffel'fim, p s t n class of such compounds, termed 3-chloro-tetrahydr0- y group of from 1 to 20 Carbon atoms is g, 1,3-oxazines or oxazolidines as described hereinafter. 10 Preferred), a 2)n group, wherein represents 2 Description f the P i Art an integer of from 1 to 20 and wherein .X represents a it is known in the art that certain N-chloro-2- dimethylamiho groupf a diethylamiho group, a tl'hhfith- I oxazolidinones possess antibacterial activity. However, ylammohium group, a hieihylammohium g p a review of the literature concerning such compounds dimethylammchium p a diethylammohium p, will readily reveal that these compounds are higher a 1g P a O s group, 9 gr up, chlorine potential compounds and as aresult thereof, Whefeifl each of 1 h g 9 respectively, p e t while such compounds can exhibit a sufficient antibacan alkyl group of from 1 to 5 carbon atoms or a benzylterial activity, their higher chlorine potential imparts to group. In addition, R and R, can also represent a these compounds, a bleach capability. That is, due to their high chlorine potential, the- N-chloro-2- v oxazolidinones, while capable of controlling bacterial growth, will also tend to be more corrosive. Conse- 2 y quently, for the most part, these compounds have been 2 employed as bleaching agents. See, US. Pat. No. 3,59l ,bOl

SUMMARY OF THE INVENTION group, wherein Y represents a -(CH ),,W(CH 1 group or a CH-.-Z group, wherein W representsv 7 In view of the foregoing, it IS readily apparent that an atom a group, there is a great need to develop suitable antibacterial a NHCH3+ group, a NC2H5 group agents of low chlorine potential, which exhibit suffigroup a N(CH3)2+ group or a N(2H5)2+ group: cient antibacterial activity and yet, are less corrosive. wherein n is the Same or dierent from m wherein Therefore, h is one Object of the l invention to each ofn and m represent an integer of from O to 2; and develop antibacterial agents of low chlorine potential, wherein Z is defined in accordance with X above which exhibit sufficient antibacterial activity In the Case where R5 and R6 may represent an alkyl it IS a second ob ect of the present inyention todegroup of from 1 to 20 Carbon atoms or a hydrogen velop antibacterial agents which in addition to exhlbltatom, the hydrogen atom form is preferred. This is true ing sufficient antibacterial activity and of being of low even when R5 and R6 represent a carbon atom range of chlorine potential, also fail to be relatively corrosive. from 1 to 5.

Finally, it is a third object of the present invention to Where feasible applicants prefer to use the p develop antibacterial agents which meet the above cri- 40 salt (HX Salt) wherein X represents a pharmaceutia are P a F That i cOmPOundS Cally acceptable anion derived from a pharmaceutically I Wl'llCi'l, in aqueous media, exhibit sufficient antibacteacceptable acid addition Salt of the Compound though rial activity over a short time span. afterwhich, decomuse of the free base is quite acceptable. protofi Posmon i [he cqmpound i 5 salts can easily be prepared by simply reacting the free Accmdmgly with the foregoing m the present base compound with a pharmaceuticall acce table invention is directed to a novel class of low chlorine poacid such as hydrochloric acid hydrogmi'nicpacid tential compounds, which exhibit antibacterial activity meflmnesulfonic acid and the and are demed nonlpersistam which Compounds have At this point, it shciuld be emphasized that the term the following formula anti-bacterial as employed in this application also includes anti-fungal activity as well. R1 h'fig R3 The compounds of the present invention are readily j prepared by the synthesis procedure outlined below, R2 i wherein 1 2, 3, 4, R R and l are defined as C] above.

Step l )1 R R I 3 4 +1 0 X H2 (CR R OH R2 4 Step (2):

Y XX

The above reaction scheme is carried out under standard temperature and pressure. With respect to step (1), the solvent employed is one which is capable of removing water from the first reaction step as it is formed. Without limitation, illustrative solvents capable of achieving this function are benzene, toluene, or xylene. As an alternative embodiment, a desiccant, such as magnesium sulfate or a molecular sieve can be employed to remove water formed during the reaction.

As for step (2), any conventional chlorinating agent N, 11.00. can be employed and illustrative of such agents, suit- Next, the final compound (3-chloro-2,2,4,4- able for applicants purpose is NaOCL, Ca(OCl) ttetramethyl-l,3-oxazolidine) was prepared from the BuOCl, N-chlorosuccinimide and chlorine. Naturally, precursor material. To 175 ml of 0.65 M sodium hypothe aforementioned chlorinating agents are only illuschlorite (0.11 mole) at 0C, there was added dropwise trative of the wide variety of conventional chlorinating with stirring, the precursor compound obtained earlier, agents suitable for applicants purpose and it is believed while the reaction mixture was maintained between a that this is understood by the skilled artisan concerned pH of from 4 to 6 through the use of 1M HCl. with the subject matter of this invention. After 30 minutes at 0C, the reaction mixture was ex- A better understanding of the present invention will tracted with dichloromethane and the extracts were be gained from a review of the following examples, combined and dried over anhydrous sodium sulfate. which are simply illustrative and non-limitative thereof. Following filtration, the dichloromethane was removed under reduced pressure and the 3-chloro-2,2, 4,4-

EXAMPLE 1 tetramethyl-l ,3-oxazolidine was isolated as a pale yel- (Preparation of low liquid, bp 65-67C (12 mm), 10.1 g (0.062 mole), 3-chloro-2,2,4,4-tetramethy1-1,3-oxazo1idine) a 56% yield.

Firstly, the precursor compound (2,2,4,4-tetrameth- Analysis Calculated for: 1 14 C, 5137; 1 yl-l,3-oxazolidine was prepared. To 237 g. (3.0 mole) 8-62; and Found: C, 51-36311, 8-77; of 2-amino-2-methyl-1-propanol, there was added apand proximately 750 ml of dry benzene containing 174 g Once the final compound was prepared, it was sub- (3.0 mole) of acetone. 4 jected to antibacterial and stability studies as described A few crystals of para-toluenesulfonic acid were in Tables 1 and 2, set forth on the following pages.

TABLE 1 CONCENTRATION DATA Conditions Positive Germicidal Activity Time (min) Compound 1-1 Diluent Compound c1 12228 10536 10031 9027 6538 4617 0.1MNaOAc 1-1,o 8.26 10-M 289 m 0.5 0.5 0.5 0.5 0.5 0.5 CHQ O CHE pH 4.6 1355 ppm c1 1 N CH, 0.1M NaOAc Serum 8.26 X 10-"M 289 ppm 10 3 10 4 10 6 1 pH 4.6 1355 ppm O.1MNaH.PO, 11.0 8.92 10-M 312 m 1 0.5 0.5 1 3 1 c11, o Z1-1 pH 7.00 z 1463 ppm pp C11 N 11;. 0.1M Natl- P0, Serum 8.92 10-='M 312 ppm 0 3 5 7 10 10 a pH 7.00 1463 ppm 0.1M M12840, 11,0 8.13 IO-M 285 ppm 5 2 4 2 5 3 CH O CH pH 8.8 1333 ppm CH3 N CH;I 0.1M N212B,O7 Serum 8.13 X 10"M 285 ppm 10 4 9 4 10 8 1 pH 8.8 1333 m c1 TABLE 2 STABlLlTY ANALYSIS OF 3-CHLORO-2,2,4,4-TETRAMETHYL-l,3-OXAZOLlDlNE EXAMPLE 11 (Preparation of 3-chloro-2,2-[spiro-l '-methyl-4 '-piperidinyl ]-4,4- dimethyl-1,3-oxazolidine and its HX salts) Firstly, the precursor compound, 2,2-[spirol -methyl-4'-piperidinyl]-4,4-dimethyll ,3-oxazolidine was prepared. To 44.5 g (0.5 mole) of 2-amino-2-methyl-lpropanol, there was added approximately 400 ml of dry benzene containing 56.5 g (0.5 mole) of 1-methyl-4 piperidone. The solution was stirred under and Dean- Stark water separator at reflux temperature.

When the theoretical amount of water was collected, the benzene was removed under reduced pressure to yield a brown oil. The precursor compound was collected as a clear, colorless distillate, bp 6365C (1.2 mm), 58.9 g (0.32 mole), 64% yield.

Next, the final compound 3-chloro-2,2-[spiro-l methyl-4'-piperidinyl]-4,4-dimethyl-1,3-oxazolidine was prepared from the precursor material in the manner described. To 50 ml of 0.65 M sodium hypochlorite (0.03 mole) at 0C, there was added with stirring 5.52 g (0.03 mole) of the precursor compound obtained earlier.

After 30 minutes at 0C, the pale yellow solid was isolated by filtration, washed thoroughly with cold water and then dried in vacuo over calcium sulfate to give 3- chloro-2,2-[spiro-l '-methyl-4-piperidinyl]- 4,4-dimethyl-l,3-oxazolidine, mp 4648C, sublimation at 35C (0.5 mm); UV (H 0) )1 max 265 nm, e=270 M' cm.

Analysis Calculated for: C H ClN Oz C, 54.91; H, 8.76; N, 12.81; and CI, 16.2. Found: C, 54.77; H, 8.90; N, 12.85; and Cl, 15.].

The methanesulfonate salt of the above-isolated 7 compound was prepared by simply reacting the free base with an ethereal solution of methanesulfonic acid, mp l24-125C (dec).

Analysis Calculated for: C H ClN O S: C, 41.96; H, 7.36; N, 8.90; and Cl, 11.3. Found: C, 41.27; H, 7.41; N, 8.49; and Cl, 10.6.

In similar fashion, the hydrochloride salt of the aboveisolated compound was prepared as follows. To an ethereal solution containing 1.1 g (0.005 mole), at 0C, there was added dropwise with stirring, 2 ml of 2.26 M HCl/Et 0, diluted to approximately 25 ml using.

anhydrous ether, (0.0045 mole). The suspension was maintained at 0C for 30 minutes and the white solid which formed was isolated by filtration and thoroughly washed with anhydrous ether under an atmosphere of nitrogen. The solid isolated was dried in vacuo over calcium sulfate to give the corresponding hydrochloride salt, mp l20l2lC (dec.), 1.18 g (0.0046 mole), 93% yield.

Analysis Calculated for: C H CI N O: C, 47.06; H, 7.90; N, 10.98; and CI, 13.9. Found: C, 44.39; H, 7.56; N, 9.91; and Cl, 13.1.

TABLE 3 Conditions Concentration Data Antibacterial Activity. Time (min.)

Buffer/ Positive Compound pH Diluent Compound C] 12228 10536 10031 9025 6538 4617 6501 0.1 M NaOAc H O 6.52 X l0 M 231 ppm 1 0.5 0.5 0.5 5 0.5 N H 4.6 1428 CH w ,.c1-1 p ppm CH3 0.1 MNaOAc Serum 5.69 X 10"M 202 ppm 10 2 7 10 10 3 pH 4.6 1246 ppm 0.5 M NaOAc H O 21.00 X 745 ppm 0.5 0.5 0.5 0.5 0.5 0.5 0.5 q IO M N pH 4.6 4578 m CH N CH 3 3 0.5 M NaOAc Serum 20.50 X 727 ppm 2 0.5 0.5 l 3 l 0.5

o (:11 l0-"M pH 4.6 4469 ppm H I CI 0.5 M NaOAc H O 17.0 X l0" 603 ppm 0.5 0.5 0.5 0.5 l 0.5 0.5 N pH 4.6 5355 ppm N w 0.5 M NaOAc Serum 17.0 x 111- 603 ppm 2 0.5 1 1 6 1 1 o CH pH 4.6 5355 ppm Table 4 ANTIBACTERIAL ACTIVITY OF 3-CHLORO-2,2-ISPIRO-l '-METHYL-4-PIPER1D1NYL]-4.4-DIMETHYL-l.3-OXAZOL1D1NE Conditions Concentration Data Antibacterial Activity. Time (min.) Buffer/ Positive Compound pH Diluent Com- CI 1 228 10536 10031 9027 6538 4617 6501 pound 0.5 M NaI-I POJI O 20.75 x 10*M 736 ppm 1 0.5 1 1 1 0.5 1 N N pH 7.0 4525 ppm 01 ,.c11

O CH 0.5 M NaH PO Serum 19.88 X 10 M 705 ppm 5 7 8 10 10 5 7 3 I pH 7.0 4334ppm H I. Cl N 0.5 M NaI-I PO H O 19.75 10-"M 700 m 4 1 1 1 4 1 1 CH 3 CH3 0.5 M NaH PO 19.13 x IO M 678 ppm 10 4 10 10 10 10 10 0 CH3 @oso c11 TABLE 5 TABLE 6-Continued STABILITY OF 3-CHLORO 2,2-[SPIRO-l '-METHYL-4'- PIPERIDINIUM]4,4-DIMETHYL-l,3-OXAZOLID1NE HYDRO- CHLORIDE IN THE NEAT STATE AT 40C "Weight of sample analyzed. "Volume of lO"N sodium thiosulfate required to titrate the sample at time (T). Percentage of positive chlorine in the sample analyzed.

TABLE 6 STABILITY OF 3-CHLORO-2,2-[SPIRO- l '-METHYL-4'- PIPERIDINIUM]1,3-OXAZOLIDINE METHANESULFONATE IN THE NEAT STATE AT 40C Time (days) Wt. (mg) V (m1)" 7c Cl STABILITY OF 3-CHLORO-2,2-[SPIRO-l'-METHYL-4'- PIPERIDINIUM] 1,3-OXAZOL1DINE METHANESULFONATE IN THE NEAT STATE AT 40C Time (days) Wt. (mg) V-,(ml)" Cl "Weight of sample analyzed. Volume of IO N sodium thiosulfate required to titrate the sample at time (T). Percentage of positive chlorine in the sample analyzed.

ANTIBACTERIAL ACTIVITY STUDIES The procedure employed to determine the antibacterial activity of 3-chloro-2,2,4,4-tetramethy1-1,3- oxazolidine and 3-ch1oro-2,2-[spiro- 1'-methy1-4-piperidinyl]-4,4-dimethy1-l,3-oxazo1idine was based primarily on a modification of the serial dilution method of analysis. However, instead of determining the minimum inhibitory concentration parameters for the compound investigated, applicants alternatively chose to determine the bactericidal endpoint for a given concentration of the compound investigated. Consequently, applicants studies were established to determine the time required for complete sterilization of the micro-organism tested, when exposed to a given concentration of the compound investigated.

The method and reagents employed in applicants antibacterial studies are described below:

Overnight Organism ATCC Code Broth Culture (Organisms/m1) Slap/1. epidermidis 12228 5 X l0 E. ((111 10536 10 X 10 Kleb. pneumoniae 10031 12 X 10- 13 X 10 Pseud. aeruginosa 9027 12 X 10- 13 10 Slap/1. aureus 6538 6 X 10 8 X 10 Bord. bronchiseplica 4617 3 X '10 Nutrient Broth B.B.L. 8 g/lOOO ml distilled water. The broth contains 5 g gelysate peptone and 3 g beef extract. The solution has a pH of 6.9. Nutrient Agar 23 g/lOOO ml. distilled .water. The nutrient contains g gelysate peptone, 3 g beef extract and 15 g agar.

Horse Serum T.C. horseserum solution in distilled water. The serum solution was freshly prepared and adjusted to a pH of 7 using carbon dioxide prior to its use.

METHOD A stock solution of each compound identified above was prepared using an appropriate buffered solution.

For screening in the absence of a denaturing agent (e.g., horse serum) an equal volume of distilled water and the resulting solution was subjected to the screen.

For screening in the presenceof a denaturing agent, a volume of the stock solution was diluted using an equal volume of 10% horse serum. When necessary, the final solution was adjusted to the desired pH using [N HCl and the solution was permitted to stand at room temperature for 30 minutes prior to the screening procedure.

To 5 ml of the stock solution being evaluated, there was added 0.2 ml of an overnight broth culture containing the particular micro-organism being investigated [see above). At time intervals of 0.5, l, 2, 3, 4, 5, minutes. a loop of this suspension was subcultured into 5 ml of a sterile nutrient broth. All the samples were then incubated at 37C for 7 days with daily observation for evidence of bacterial growth. The time interval reported is for that sample in which no bacterial growth was observed after the incubation period.

Aside from the foregoing, several controls were also employed as described below.

CONTROL 1 This control was designed basically to insure viability of the overnight broth culture.

To 5 ml of a sterile 0.9% sodium chloride solution,

there was added 0.2 ml of an overnight broth culturecontaining the particular micro-organism being investigated. A loop of this suspension was subcultured into 5 ml of a sterile nutrient broth and incubated at 37C for 7 days.

CONTROL 2 This control was designed to insure that the dilution factor of the nutrient broth was beyond any bacteriostatic activity of each compound (as identified above) tested.

To 5 ml of a sterile nutrient broth there was added a loop of a solution of each compound as described above and the solution was mixed immediately. To this solution, there was then added a loop of an overnight broth culture which was diluted 25x with a 0.9% sodium chloride solution. Incubation was carried out for 7 days at a temperature of 37C.

CONTROL 3 This control was employed to insure the bacterial growth observed was that due to the organism being tested, rather than contamination from a foreign organism.

At the same time intervals used for subculturing the test solution into nutrient broth during the screening procedure, a loop of the test solution was also subcultured onto sterile nutrient agar plates. This technique was useful for observing the characteristic colonial morphology of each organism.

CONTROL 4 This control wasused 'initially'to insure that the pH of the solution and the concentration of the buffer species did not inhibit the bacterial growth during the time intervals used in the screening procedure.

The entire screening procedure was conducted for each buffered solution using the buffered solution rather thanthe solution of each tested compound in the procedure. 1 Y

By following the reaction scheme as illustrated in Examples I and II, all the compounds of the present invention can be'prepared. 1 I

While all compounds encompassed within applicants generic formula do meet applicants criteria, i.e., exhibit sufficient antibacterial and antifungal activity with low chlorine potential and remain non-persistant, still, certain compounds are preferred. These compounds are:

l 3-chloro-2,2,4,4-tetramethyl-1,3-oxazolidine 2. 3-chloro-2,2,4,4-tetramethyl tetrahydro-l,3-

oxazine,

3. 3-chloro-2-methyl-2-(l-diethylamino-3-propyl)- 4,4-dimethyl-1,3-oxazolidine or its HX salt,

'4. 3-chloro-2-methyl-2-(l-diethylamino-3-propyl)- 4,4-dimethyl tetrahydro-l,3-oxazine or its l-IX salt,

5. 3-chloro-2,2[spirol -methyl-4'-piperidinyl]-4,4-

dimethyl-l,3-oxazolidine or its HX salt,

6. 3-chloro-2-methyl-2-(diethylaminoethyl)-4,4-

dimethyl-l,3-oxazolidine or its l-lX salts,

7. 3-chloro-2-methyl-2-(diethylaminomethyl)-4,4-

dimethyl-l,3-oxazolidine or its HX salts These compounds are conveniently used in aqueous solution. They may be applied by any conventional means, e.g., spray, wipe, etc.

Although the present invention has been adequately described in the foregoing specification and examples included therein, it is obviously apparent that various changes and/or modifications can be made thereto without departing from the spirit and scope thereof.

What we claim is:

1. A 3-Chloro-tetrahydro-l ,3-oxazine or oxazolidine compound of the formula:

(CR R Z j 4 Cl wherein each of R and R which may be the same or different, represents an alkyl group of from I to 20 carbon atoms; wherein each of R and R which may be the same or different, represents a hydrogen atom or an alkyl group of from 1 to 20 carbon atoms; wherein 1 represents an integer of l or 2; and wherein each of R and R.,, which may be the same or different, represents an alkyl group of from 1 to 20 carbon atoms, a -(CH ),,X group, wherein n represents an integer of from 1 to 20 and wherein X represents a member selected from the group consisting of a dimethylamino group, a diethylamino group, a trimethylammonium group, a triethylammonium group, a dimethylam- 1 1 12 monium group, a diethylammonium group, a -COOR 6. The compound of claim 1: group, a -OOCR group, and a OR,, group, wherein 3-chloro-2-methyl-2-(diethylaminoethyl)-4,4- each of R through R respectively, represents a memdimethyl-l,3-oxazolidine or its HX salt, wherein X ber selected from the group consisting of an alkyl group represents a pharmaceutically acceptable anion. of from 1 to carbon atoms or a benzyl group. 5 7. The compound of claim 1:

2. The compound of claim 1: 3-chloro-2-methyl-2-(diethylaminomethyl))-4,4- 3-chloro-2,2,4,4-tetramethyl-l ,3-oxazolidine. dimethyl-l ,3-oxazolidine or its HX salt, wherein X 3. The compound of claim 1: represents a pharmaceutically acceptable anion. 3-chloro-2,2,4,4-tetramethyl-tetrahydro-l ,3-oxazine. 8. The compound of claim 1 wherein R, and R rep- 4. The compound of claim 1: 10 resent an alkyl group of from 1 to 5 carbon atoms. 3-chloro-2-methyl-2( l-diethylamino-3-propyl)-4,4- 9. The compound of claim 1, wherein R and R repdimethyl -1,3-oxazolidine or its HX salt, wherein X resent an alkyl group of from 1 to 5 carbon atoms. represents a pharmaceutically acceptable anion. 10. The compound of claim 1, wherein R and R rep- 5. The compound of claim 1: 3-chloro-2-methyl-2- resent a hydrogen atom. l-diethylamino-3-propyl)-4,4-dimethyl-tetrahydro- 11. The compound of claim 1, wherein R and R repl,3-oxazine or its HX salt, wherein X represents a pharresent an alkyl group of from 1 to 5 carbon atoms.

maceutically acceptable anion.

Claims

1. A 3-CHLORO-TETRAHYDRO-1,3-OAZINE OR OXAZOLIDINE COMPOUNDS OF THE FORMULA:

2. The compound of claim 1: 3-chloro-2,2,4,4-tetramethyl-1,3-oxazolidine.

3. The compound of claim 1: 3-chloro-2,2,4,4-tetramethyl-tetrahydro-1,3-oxazine.

4. The compound of claim 1: 3-chloro-2-methyl-2(1-diethylamino-3-propyl)-4,4-dimethyl -1,3-oxazolidine or its HX salt, wherein X represents a pharmaceutically acceptable anion.

5. The compound of claim 1: 3-chloro-2-methyl-2-(1-diethylamino-3-propyl)-4,4-dimethyl-tetrahydro-1,3 -oxazine or its HX salt, wherein X represents a pharmaceutically acceptable anion.

6. The compound of claim 1: 3-chloro-2-methyl-2-(diethylaminoethyl)-4,4-dimethyl-1,3-oxazolidine or its HX salt, wherein X represents a pharmaceutically acceptable anion.

7. The compound of claim 1: 3-chloro-2-methyl-2-(diethylaminomethyl))-4,4-dimethyl-1,3-oxazolidine or its HX salt, wherein X represents a pharmaceutically acceptable anion.

8. The compound of claim 1 wherein R1 and R2 represent an alkyl group of from 1 to 5 carbon atoms.

9. The compound of claim 1, wherein R5 and R6 represent an alkyl group of from 1 to 5 carbon atoms.

10. The compound of claim 1, wherein R5 and R6 represent a hydrogen atom.

11. The compound of claim 1, wherein R3 and R4 represent an alkyl group of from 1 to 5 carbon atoms.