IL36948A - 7-phenylpyrimido-(1,2-a)(1,4)-benzo-diazepin-1(5h)-ones - Google Patents

Description

36 ^8/2 ^PHENYLPYRIMIPO- (l .2-a (ΐΛ)-BBNSODIAZBPIN- 1 ( 5H)-0NBS «-(5H)1 -a .T*»-m» ΑΤ7 A-2.7"»P» VB^*»-7 r ABSTRACT OF THE DISCLOSURE 7-Phenylpyrimido Tbenzodiaze in-l (5κ)-οηβ of the formula wherein R is selected from the group consisting of hydrogen, hydroxy and acetoxy; ie hydrogen or chlorine, R_ ie chlorine in 2 J . or nitro and here/x ie oxygen, sulfur or =NH, are synthesized by condensing a 2-amino-5-phenyl-3H-l, ^-benzodiazepine of the formula I wherein R , R and R are de ined as above with a diketene of 1 2 3 the formula wherein Re — rs d e Γ ί ι led db dbuvo-, and heating the thus produced N-acetoacety 1 derivative to obtain the compounds of formula !X, in which i is hydrogen Θ-Ρ — lower o 1 ky K, and X is oxygen. These compounds, as well as the products in which X is sulfur and = ΝΗ and Ri is also hydroxy and acetoxy, and their pharmaceutical ly acceptable acid addition salts are useful tranqui l izer for mammals. 369 8/2, This invention is directed to new organic compounds and is particularly concerned with novel 9-phenylpyrimido (5H)-one (ix) and the process and intermediates therefor* The invention furthermore includes the pharmaceutically acceptable acid addition salts* In South African Patent Application No. 6,706,256 there are described certain compounds which are similar to thoseof the present Invention. The compounds according to the South African Patent Application differ from those of the present invention in that thoy have only one double bond, they are unsubetltuted in the 1-position and the other eubstltuente differ* Compounds according to the present invention have a pronounced sedative-tranquillzing effect.

The novel compounds IX, intermediates, and the process of production thereof can be Illustratively represented as followst 369^8/2 Scheme A 36 ^8 /2 wherein R1^ i a hydrogen, Rg ie hydrogen or chlorine, R^ is chlorine or nitro ' 6 '..'"■ ' ·:" ..." ' -· ■■ '· ' The products of formula IX wherein B is hydroxy and acetoxy can be made from these products III in which R'^ is hydrogen by the following Scheme Bi . , . · .' Scheme B and wherein are defined as above.

The compounds of formula VII and VIII can be converted to their corresponding thiones and imines as shown for compound III.

The process of scheme A comprises: treating a 2-amino- 5-phenyl-3H- 1 , 4-benzodiazepine (I) with diketene or alkyl substituted diketene to obtain the corresponding N - a c e t o a c e t y l i n t e r m e d i a t e ( I I ) , heating II to convert it to the corresponding 7-phenylpyrimido [1 , 2-a] [ 1 , 4] benzodiazepin-1 (5H) -one (III). If a thione (IV) is wanted compound III is reacted with phosphorus pentasulfide to give the corresponding 7-phenylpyrimido [1 , 2-a] [ 1 , 4] benzodiazepine- 1 (5H) -thione (IV) which by treatment with a ammoniacal lower alkanpl gives the corresponding 7 -phenylpyrimido [ 1 , 2 -a] [1 , 4] benzodiazepin-1 (5H) - imine (V).

The compounds of formula IX in which is acetoxy or hydroxy (scheme B) are produced by treating a compound of formula III wherein R^ is hydrogen with an organic peracid to obtain the N-oxide (VI) which is treated with acetic anhydride to give the 5-acetoxy- 7-phenylpyrimido-[1, 2-a] [1, 4] -benzodiazepin-l(5H) -one (VII). By hydrolysis the corresponding 5-hydroxy analog (VIII) is obtained.

In the same manner as shown with compound III, the 1-thione and 1-imine derivatives can be obtained from compounds VII and VIII.

DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alky(L groups of 1 to 3 carbon atoms, inclusive, exemplified liy methyl, ethyl, propyl and isopropyl. 369¾8 2 Compounds III, Ilia, IV, V , VII and VIII are sub-classes of the compound of the generic formula IXt wherein R^ ie hydrogen, hy roxy or acetoxy; w erein R ie hydrogen, or chlorine, ^ is chlorine or nitro and wherein X is oxygen, sulfur or oNH.

The pharmacological acceptable acid. addition. salts of compound IX are also part of this invention.

The novel compounds of the formula IX including acid addition salts thereof have sedative, tranquilizing and muscle relaxant effects in mammals and birds.

The acid addition salts of compounds of formula IX contemplated in this invention, are the hydrochlorides, hydrobromides , hydriodide, sulfates, phosphates, cyclo-hexanesulfamates , methanesulfonates , ethanesulfonates , benzenesulfonates , toluenesulfonates and the like, prepared by reacting a compound of formula IX with the stoichiomet-rically calculated amount of the selected pharmacologically acceptable acid.

The sedative tranquilizing effects of 9-chloro-5-methyl - -phenylpyrimido [ 1 , 2 -a] [ 1 , 4] benzodiazepin-1 (5H)-one are shown by the following tests in mice: Chimney test: [Med. Exp. 4, 11 (1961)]: The effective intraperitoneal dosage for 50% of mice (ED-.Q) is 0.32 mg./kg. The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, 501 of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, high, partially embedded in wood shavings), climb out in a very short time, when not treated.

Mice remaining in the dish for more than 3 minutes indicates tranquilization. ED 50 equals the dose of test compound at which 50% of the mice remain in the dish. The ED 50 (intraperitoneal administra- tion) in this test was 0.14 mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more, than 1 minute. The (intraperitoneal, administration) is 0.32 mg ./kg .

Nicotine Antagonism test: Mice in a group of 6 are injected with the test compound,. 9-chl.oro-3-methyl-7 -phenylpyrimido [1 , 2 -a] [ 1 , 4] benzodiazepin-1-(5H)-one. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show overstimulation, i. e., (1) running convulsions followed by (2) tonic extensor fits: followed by (3) death. An intraperitoneal dosage of 0.14. mg./kg. of the test compound protected 50 of the mice against (2) and (3) .

Antagonism to strychnine (as sulfate):. The effective dosage of 9-chloro-3-methyl -7-phenylpyrimido [1, 2-a] [ 1 , 4 ] benzodiazepin-1 (5H) -one is 1.8 mg./kg. orally in mice. The test consists in orally, administrating into groups of 6 mice the test compound, 9-chloro-3 -methyl -7-phenylpyrimido [1,2-a] [l,4]ben-zodiazepin-1 (5H) -one , and 30 minutes later 3 mg./kg. strychnine sulfate intraper itoneally . The survivors after 4 hours reflect the activity of the compound as a muscle relaxant and antispasmodic. A dosage of 3 mg./kg. of strychnine sulfate is routinely fatal to all the control mice.

For 9-chl.oro- 3-methyl-7- (o-chlorophenyl)pyrimido -[1,2-a] [1,4] -benzodiazepin-l [5H] -one the following ED., values were found: TESTS Chimney Dish Pedestal ED50 (mg ./kg.) .23 .23 .20 TESTS Nicotine (2) Nicotine (3) Strychnine ED50 (mg ./kg .) .018 .023 .78 Nicotine (2) = Antagonism to nicotine tonic extensor fits Nicotine (3) = Death protection from nicotine The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions , suspensions , sterile injectable forms, suppositories, bougies, and the like.

Suitable diluents or carriers such as carbohydrates (lactose) , proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Oil, e.g., coconut oil, .sesame oil, saf-flower oil, cottonseed oil, peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added.

For mammals and birds food premixes, with starch, oatmeal, dried fishmeat, fishmeal, flour and the like can be prepared. 2740A 369^8/2 As tranquilizer the compounds of formula IX can be used in dosages of 0.01 mg.-2.0 mg./kg. in oral or injr~table preparations as described above, to alleviate tension and anxiety in mammals,, or birdSj such as e.g., occurs when animals are in travel. _ .

Other acid addition salts of the compounds of formula IX can be made such as the fluosilicic acid addition salts which are useful mothproofing compounds or the t r i ch loroacetates useful as herbicides against Johnson grass, Bermuda grass 0 yellow foxtail and green foxtail, and quack grass.

The starting compound used in this invention is 2-amino-5-phenyl-3H-l ,4-benzodiazepines (I) . These amines I are prepared from the well-known 1 , 3-dihydro- 5-phenyl -2H[1 ,4] -benzodiazepine-2-thiones [Archer et al. , J. Org. Chem. 29,.231 (1964) and U. S. Patent 3,422,091] by treatment with ammonia in methanol. Details of this reaction are shown in Preparation 1 and in Example 3.

Representative 2 -amino compounds of formula (I) thus produced include: \ 2 -amino-5 -phenyl -3H-1 , 4-benzodiazepine ; 36 8/2 In carrying out the proceae of the invention! a selected 2-amlno-5-phenyl*3H-l,4-benzodiazepine (l) ie reacted in an acetone, diethylether, dlpropylother, dibutylether, cyclo- hexano* pentane, hexane, heptane, mixtures thereof and the like* The (diketones) useful in The reaction can be carried out between 0° and 30°, preferably at between 10° and 30°C. in tetrahydrofuran. The reagenta, benzodiazepinea and diketene8 are ueed in about equimolar quantities to about 200% stoichiometr ically calculated excess of diketene. The reaction time at room temperature is between 4 hours and 72 hours. After the reaction is terminated which can be determined by thin layer chromatography (e.g. with silica gel -methanol : toluene 1:9), the product,, a N-aceto-a c e t yj i nt e r m e'd i a t e (II) is recovered by conventional means, such as concentrating the solution. The solids are then purified by standard procedures e .g . crystallization, chromatography, extraction or the like. methyl Compound II is. converted to compound III, a 3 - a,] kyJ--7-phenylpyr imido [ 1 , 2 -a] [1 , 4] benzodiazepin-ϊ (5H) -one by heat.

It can be heated up to the melting point to give III. Preferably, however, compound II in a high boiling hydrocarbon solvent is heated to reflux for 1 to 24 hours. Such hydro-carbon solvents are selected from the group consisting of toluene, xylenes and ethylbenzene , or the like. Compounds of formula III are recovered by conventional means, such as concentrating the solution, chromatograph (etc.). Recrys-tallization from solvents e.g. Skellysolve B hexanes, heptane, cyclohexane, ethyl acetate mixtures thereof and the like give pure material III.

The compounds of formula III can be converted to the methyl corresponding J-eri-kyl -7-phenylpyrimido[l,2-a] [1 ,4]benzodiazepine-l(5H)-thione (IV) by the method of G. A. Archer et. al . [U. S. Patent 3,422,091] i.e. by heating the ketone in pyridine with phosphorous pentasulfide for about 1 to 24 hours. methyl The thiones IV are converted to the corresponding 3-¾Hcyi— 7 -phenylpyr imido [ 1 , 2 -a] [ 1 , 4] benzodiazepin-1 ( 5H) - imine (V) by stirring for 1 to 6 hours the thiones of formula IV in an ammoniacal alkanol solution, usually methanol or ethanol acetoxy Compound of formula IX with a 5 -hydroxy or ^ irxy sub-stituent are produced from compounds of formula Ilia (R =H) .

A selected compound of formula Ilia is treated in the cold, -20° to +20° C, with an organic peracid. In the preferred embodiment of this invention the peracid is used in a solvent such as methanol, ethanol, ether, tetrahydrofuran and the like.

As peracids, peracetic, performic, perpropionic, perbenzoic m-chloroperbenzoic , pertoluic acid or the like can be used in equimolar to 3-4 equimolar quantity. The reaction. period is from 2-24 hours in an icebath followed by 2-24 hours at methyl room temperature. The thus obtained J -aikyJ-r 7 -phenylpyr imido -[1,2-a] [1, 4]benzodiazepin-l [5H] -one 6-oxide VI is recovered from the mixture by conventional procedures, e.g. concentration of the mixture, extraction and evaporation of the extracts.

The thus -obtained N-oxide (VI) is treated with acetic anhydride, usually in a solvent such as acetic acid. The reaction is performed at elevated temperature 60-120° C, pre- methy 1 ferably on a steam bath. The product, a 5 -hydroxy -3 -al kyl- 7-phenylpyr imido [ 1 , 2 -a] [ 1 ,4]benzodiazepin-l [ 5H] -one acetate (VII), is recovered by standard methods such as concentration, extraction, chromatography and combinations thereof. meth l The free hydroxy compound, 5 -hydroxy -3 -aJ-k-yJ-- 7 -phenyl -. pyr imido [ 1 , 2-a] [ 1 , 4] benzodiazepin- i[ 5H] -one (VIII) is produced by a conventional base hydrolysis e.g. methanol, ethanol or the like in the presence of a base e.g. sodium or potassium hydroxide or carbonate. Compound VIII is obtained from the methods, such as concentration, extraction or the like.

Both compounds VII and VIII can be converted from their 3-ketone forms to the thiones and imines as discussed 2740A The following preparations and examples are illustrative of the processes and products of the present invention, but are not to be construed as limiting.

Preparation 1 2 -Amino- 7-chloro-5-phenyl -3H-1 , 4 -benzodiazepine A solution of 2.87 g. (10 millimoles) of 7-chloro:l,,3-dihydro- 5-phenyl - 2H-1 , 4-benzodiazepine- 2-thione in 50 ml. of methanol saturated with ammonia gas was stirred at 24-26° C (room temperature) for 2 1/2 hours. Crystallization occurred during stirring. The crystals of 2 -amino- 7 -chloro- 5-phenyl -3H-1 , 4-benzodiazepine were recovered by filtration and dried,, yield 1.55 g. (57.5%) of melting point 236-237°C.

Anal . Calcd. for C15H12C1N3: C, 66.79; H, 4.49; CI, 13.15; N, 15.57.

Found: C, 66.97; H, 4.53; CI, 13.15; N, 15.49.

In the manner given above (Preparation 1) other 2-thiones are treated with ammoniacal methanol to give the corresponding 2 -amino- 5 -phenyl -3H- 1 , 4 -benzodiazepines . o Anal. Calcd. for 46; F, 17.79; 01 73; F, 17.83; 26.

Example 1 9-Chloro-3 -methyl -7 -phenylpyr imido [ 1 , 2 -a] [l,4]benzo-diazepin-1 (5H) -one A. N-Acetoacety 1 intermediate | | (of example l ). acety 1 meda i te A solution of 1.35 g. (5.0 millimoles) of 2 -amino-7 -chloro-S-phenyl -3H- [ 1 , 4] benzodiazepine and 0.50 g. (6.0 millimoles) of distilled diketene in 25 ml. of tetrahydrofuran was stirred at room temperature (23-25° C.) for four hours. An additional 300 mg. of diketene was added and the mixture refrigerated for two days at 9-10° C. The solution was concentrated to dryness and crystallized from ethyl acetate to yield 1.15 g. (65%) of N-acetoacety 1 intermediate I I (of example | ) of melting point 150° C. dec.

Anal. Calcd. for C19H16C1N302 : C, 64.50; H, 4.56; CI, 10.02; N, 11.88.

Found: C, 64.23; H, 4.47; CI, 10.48; N, 12.21.

B . 9 -Chior 0-3 -methyl - 7 -phenylpyr imido [ 1 , 2 -a] benzodiazepin-1 (5H)-one A solution of 1.5 g. of N-acetoacety 1 intermediate I I (of example l) in 75 ml. of toluene was refluxed for 2 1/2 hours and then stirred at room temperature (22-25° C.) overnight. The solid which crystallized out was filtered off; yield 600 mg. of 2 -amino-7 -chloro -5-phenyl -3H [ 1 , 4] benzodiazepine, formed by hydrolysis or pyrolysis .of starting material .

From the mother liquors of the reaction mixture was isolated by crystallization from ethyl acetate 310 mg. of 9-chloro- > -methyl -7 -phenylpyr imido [ 1 , 2 -a] [1 , 4] benzodiazepin-1 (5H) -one. Recrystallization. from ethyl acetate-Skellysolve B hexanes gave 175 mg. of analytically pure material with a melting point of .193-194° C.

Anal. Calcd. for C19H14C1N..0 : C, 67.96; H, .4.20; .CI, 10.56; N, 12.51.

Found: C, 67.21 ; H, 4.64 ; CI, 10.20; N, 9.82.

Ultraviolet: λ max> 27, e 41,800; λ max _ 253 (sh) , ε 12,300; maXf 293 (si. sh), ε 10,000.

Example 2 9-Chloro-3 -methyl - 7 -phenylpyrimido [ 1 , 2 -a] [ 1 , 4] benzodiazepine-! (5H)-thione A stirred mixture of 800 mg . of 9 -chloro-J -methyl -7 -phenyl -pyr imido [ 1 , 2 -a] [1 , 4] benzodiazepine -1 (5H) -one in 40 ml. of dry pyridine and 690 mg. of phosphorus pentasulfide was refluxed 2740A^ 36948/2 A suspension of the residue in ice water was extracted wit methylene chloride and washed with water. The extract was drie over anhydrous sodium sulfate and concentrated. The residue wa crystallized from ethyl acetate to give 290 mg . of 9-chloro-3-methyl-7 -phenylpyrimido[ 1, 2-a] [ 1 , 4] benzodiazepine - 1 CSf-i) - thione . m. p. 207° C. (d) .

Example 3 9-Chloro-3-methyl-7-phenylpyrimido[l, 2-a] [l,4]benzo-diazepin-1 (5H) - imine .

A solution of 1.0 g. of 9-chloro-3-niethyl-7-phenylpyrimido [1, 2-a] [l,4]benzodiazepine-l- (5H) -thione in 20 ml. of methanol saturated with ammonia gas was stirred at about 24° C. for 3 hours. The reaction mixture was evaporated in vacuo (10 mm. Hg) and the product recrystallized from methanol to give 9-chloro- -methyl-7-phenylpyrimido[l,2-ra] [l,4]benzodiazpin- (5H) - imine .

«IS,¾-lEif .Ί. 9" h lcro-5-hydroxy-3-methy 1 -7 -phenyl pyr 5ml do- [1,2-a] [l, 3ben£ diazepin-l(5H)-one acetate A stirred mixture of 9-ch 1 oro-3-meth 1 -7-phen lpyr imido [1,2-a] [l,4]benzodiazepin-l(5H)-one-6-oxide (704 mg.; 2.0 mmoles acetic anhydride (4.0 ml.) and acetic acid (2„5 ml .) was warmed on the steam bath, under nitrogen, for 30 minutes and concentrated in vacuo. The residue was suspended in water, neutralized with sodium carbonate and extracted with methylene chloride. The extract was dried, concentrated and ch romatographed on si lica gel eluting with ethyl acetate to yield 9-ch 1 oro-5 -hydroxy -3 -me th y 1 -7-pheny lpyr imido[l,2-a] [1,4] -benzodiazepin-l(5H)-one acetate.

Example 5 9-Ch lor 0-5 -hydroxy -3 -me thy l-7^pheny1pyrimido-[1,2 -a] [l,4]benzodiazepin-l(5H)-one A stirred suspension of 9~ch loro-5-hydroxy-3-methy 1 -7β-pheny ? pyr imido[ 1 ,2-a ] [ 1 , ]benzod iazep i n- 1 (5H)-one acetate (394 mg. ; 1 mi l l? mo He) in absolute ethanol (2 > ml.), under nitrogen, was stirred for 3 hours at room temperature (23° C.) with 2.2 ml. of 0.5 N aqueous sodium hydroxide, poured into water and extracted with methylene chloride. The extract was dried and concentrated and the residue ch romatographed on silica gel, eluting with ethyl acetate to yield 200 mg. 9-chloro-5" hydroxy-3-methy 1 -7-pheny 1 py r imidof 1 ,2-a] [ 1, ]benzodi azepi n-3(5H)-one. o Example ^ 69" 1 oro-5-methy 1 -7- (ο- ch 1 oropheny 1 )pyr imido[l,2-a] -[l,4]benzod i azep i n- 1 (5H )- one .

A . 2-Ami no-7-ch 1 oro-5" (o-ch 1 oropheny 1 ) -3H-1, 4-benzod i azepi ne A solution of 5.0 g. of 7-ch 1 oro-l,3_d i hyd ro-5" (o-ch 1 oro phenyl ) -2H- 1 , 4- enzod i azep i ne-2 - th i one in 60 ml. of methanol saturated with ammonia was sti rred at room temperature for 4 hours. The solution became clear and crystall ization occurred after 1-1 l/2 hours. The mixture was fi ltered, washed with methanol and dried, yielding J.14 g. of 2-ami no-7-ch loro-5" (o-ch loropheny 1 -3H- 1 , -benzod i azep i ne of melting point 221-230° C. A second crop (670 mg . ) was obtained from the mother l iquors. ecrys ta 11 i zat i on of the main crop from 95$ ethanol gave an analytical sample of melting point 226-230° C.

Ana 1. calcd. for C15HiiCl2N3: C, 59-23; H, 3-65; C 1 J 23.31; N , I3.8I.

Found: c, 58.72; H, 3.83; Cl, 22.98; N, 13.1 .

B. N-Acetoacety 1 intermediate I I (of example 7) A slurry of βθδ mg . (2 mi l limoles) of 2-ami no-7-ch loro-5- (o-ch 1 oropheny 1 -3H - 1 , 4-benzod i azep i ne in 20 ml . of tet rahydrofu ran was treated'with 840 mg . (10 mi l limoles) of diketene. The solid dissolved after approximately 0 minutes. The reaction was al lowed to proceed for 90 minutes and set in the refrigerator overnight. The solution was then concentrated to dryness, taken up in ethyl acetate, clarified and concentrated to a syrup which was used in the next step.

C. 9" Ch loro-3-methy 1 -7- (o-ch 1 oropheny 1 )py r im i do[ 1 ,2-a ] [1,4]-benzodiazepin-l(5H)-one A solution of 420 mg . of N-acetoacety 1 intermediate I I (of V example 7) was ref luxed in 20 ml . of dry toluene for 2 hours and 40 minutes and then held at room temperature (22-24° C. ) overnight. The solution was then refluxed for an addi tiona l three and one-hal f hours . The mixture was concentrated to dryness and a sma l l amount of 2 -am i no-7- ch 1 oro-5 - (o-ch 1 oropheny 1)~3H - [ 1 , 4] benzod i azep i ne was removed by cyrsta 11 izat ion from toluene .

The fi ltrate was concentrated to give 5 0 mg. of a brown syrup, which was ch romatog raphed on 50 g. of s i l i ca gel , taking 10 ml . fractions of 1 :1 ethyl aceta te- S ke 11 ys o 1 ve B hexanes . Fract ions 48-55 were combined and crystal l izat ion from ethyl acetate gave 85 mg . of ana lyt ical ly pure product melting at 198-200° C.

Anal . Calcd . for C19Hi3Cl2N30: C, 6l.62 ; H, -5^; C 1 , 19-15; N, 11.55.

• Found : C, 61.57; H, 5-72 ; C l , 18.92 ; N, I.O.90. 9-Nitro-5-methyl -7-phenylpyrimido[l,2-a] [lJ4jbenzo-d i azep i n- 1 (5H ) -one A . N- Acetoacety 1 intermed iate I I (of example 8) I n the manner given in Example 1A, 2 -am i no-7- n i t ro~5 -pheny 1 ~5H -1 , 4-benzod i azep i ne and di ketene i n tet rahyd rofu ran was reacted at room temperature to give N-acetoacety 1 intermediate I I (of example 8) .

B. 9_Nitro-5-methyl -7-phenylpyrimido[lJ2-a] [l,4]benzodiazepi n-l (5H)-one I n the manner given i n Example IB, N-acetoacety 1 i ntermed iate (of example 8) was condensed by ref luxing i n toluene to g i ve 9- n i t ro- 5 -me thy l -7-phenylpyrimido-['lJ2-a] [l,4]benzodiazepin -l(5H)-one of melting poi nt 252.5-25 ° C.

Claims (1)

1. WHAT IS CLAIMED A formula wherein is hydroxy or aoetoxyi ie hydro en o R is chlorine or is sulfur 3 or iand their pharmaceutically acid addition The product of claim 1 wherein is hydroxy or wherein R and are as defined in claim and wherein X The compound of claim 2 wherein and Rg are hydrogen and is and the compound is therefore The compounds of claim 2 wherein ie is and the compound is therefore The compound of claim wherein and R are hydrogen the and is is therefore The roduct of claim 1 wh i A compound according to claim 6 wherein R and R are is and sulfur and the compound is therefore The product of claim 1 wherein is or and R and R are as defined in claim and wherein 2 X is A process production of a of the formula ch t and R as defined a 2 tho insufficientOCRQuality