AU470692B2 - 5-aryl-2,3-dihydro-2,2(or3,3) dimethyl-5h-imidazo [2,1-a] isoindol-5- and 2 (4,4(5,5), dimethyl-2-imidazolin-2-yl) benzolphenone acid addition salts and processes for their preparation - Google Patents

Description

4,8 0 q 171,

This invention provides new compounds having the following general formula:

0 R4

2 6H--MR Rh R3 OH R Ri (I) wherein R is phenyl, monohalophenyl, dibalophenyl, mono- (low:er)alkyWlheniyl, di (lower)alkylphenyl, trifluoromethyl- phenyl, mono(lower)alkoxypheny, di(lower)alkoxyphenyl, thienyl, pyridyl, fury or 5,6,7,8-tetrahydroo-2-naphthyl; R is hydrogen, halogen, amino, (lower)alkylamino, (lower)- alk-yl or (lower)alkocy; R3 is hydrogen when R2 and R3 are dissimilar and when R and R3are the same they are both selected from hydrogen, halogen, (lower)alkyl and (lower)- alkoxy; and5 are hydrogen or (lower)alkyl, 116 is (lower)- alkylsuiphonyl, phenylsuiphonyl, monohalophenylsuluDhonyl, dihalophenylsuinhonyl, mono(lower)alkylphenylsulphonyl, di(lower)alkylphenylsulphonyl or (lower)alkoxyphenylsulphonyl.

These compounds are useful intermediates for preparing compounds possessing pharmacological activity. In particular compounds of the invention are useful in the preparation of new compounds of the general formulae:

N RtR4 R4b- R2 j Qv? C H Z R5 2 R2i+ R R3 C= 3 OH' and R .I1x R

(II) (III)

2 470.692

24.809 in 1' 2 4 5 wherein R I R2 and R are as defined above; R and R are both (lower)alkyl and are attached to the same carbon atom; and X is the anion portion of a pharmacologically acceptable acid addition salt, which compounds are further described herein. The novel compounds of FORMULAS II and III exhibit antidepressant activity but unlike the compounds of United States Patent Specification No. 3 763 178 they do not possess anorectic activity at therapeutic doses. Incidental to this, the present invention also concerns processes which may be applicable in the production of compounds disclosed in United States Patent Specification No. 3 763 178.

In the above FORMULA I, R4 and R5 both preferably represent methyl in the new compounds possessing utility as intermediates for preparation of new compounds according to FORMULAS II and III. Where the new compounds of the invention possess utility as intermediates for the production of compounds disclosed in United States Patent Specification No. 3 763 178, R and R5 represent hydrogen. Illustrative

examples of R 1 include phenyl; m-chlorophenyl; R-chlorophenyl; p-fluorophenyl; g-iodophenyl; 2-bromophenyl; o-chlorophenyl; 3,4-diodophenyl; 3,4-dichlorophenyl; 2,5-dibromophenyl; m- and p-trifluoromethylphenyl; p-tolyl; 3,4-dimethylphenyl; 2- methoxyphenyl; 3,4-dimethoxyphenyl; 2-thienyl; 2-pyridyl and 2-furyl. R2 and R preferably represent hydrogen. Where R2

is a substituent it preferably represents fluorine, bromine, chlorine, iodine, methoxy, ethoxy,'methyl or ethyl. 6 Illustrative examples of R include p-tolylsulphonyl; ethyl- sulphonyl; n-pentylsulphonyl; phenylsulphonyl, p-fluorophenyl- sulphonyl; p-chlorophenylsulphonyl; p-bromophenylsulphonyl;

-3- 470.692

24,80 9 n1 p-iodophenylsulphonyl; 2,5-dichlorophenylsulphonyl; 3,4- dibromophenylsulphonyl; 3,4-difluorophenylsulphonyl; 4-ethyl-

phenylsulphonyl; 3,4-dimethylphenylsulphonyl; 3,4-diethylphen3 sulphonyl; 2-methoxyphenylsulphonyl and p-ethoxyphenylsulphon.

As employed herein the term "(lower)alkyl" is meant to include straight and branched chain hydrocarbon moieties of

from 1 to 5 carbon atoms such as methyl, ethyl, propyl, 1-prop and butyl. The term"(lower)alkoxy"is used to include saturate hydrocarbonyloxy groups which contain from 1 to 6 carbon atoms

such as methoxy, ethoxy, propoxy, butoxy and hexoxy. The terms "halogen" and "halo" as used herein are meant to include

bromine, fluorine, chlorine and iodine.

Those skilled in the art will appreciate that the compounds of FORMULAS II and III are tautomers. It has been found that the base form (III) exists as the tricyclic

imidazoisoindole form and the acid-addition salt (II) exists as the aromatic ketone form. The nature of the reaction by which the compounds are prepared does not allow the position

of the gem dialkyl groups to be fixed with certainty. When the compound exists as the benzophenone type form, it is impossible to fix the position of the gem dialkyl groups

because of the proton shift due to the -NH-C=N- group. Hence, the 2-(gem dialkyl-2-imidazolin-2-yl)benzophenone acid-

addition salts are named as 4,4(5,5)dialkyl substituted

compounds. This is in conformity with the nomenclature for imidazole type compounds set forth in Heterocyclic. Compounds,

R. C. Elderfield, Editor, Vol. 5, pp 198, 199 and 238, John

Wiley and Sons, Inc., New York, 1957. When the imidazoiso-

indol-ol form of benzophenone tautomer is formed, the tauto-

-4- 470.692

24,.809 n

merism of the HN-C=N- moiety does not permit any absolute

prediction as to positioning of the gem dialkyl group in the

imidazoisoindol-ol form. When the steric influence of the

gem dialkyl-group is considered, the probability is great

.that the product obtained is a 2,2-dialkyl compound. Gas

chromatographic studies indicate a single compound is isolated

and not a mixture of the 2,2-dialkyl and 3,3-dialkyl isomers.

As the available evidence does not conclusively eliminate the the possibility of the formation of the 3,3-dialkyl compound, employed herein, although it is alternative nomenclature is

believed that fhe structure is in actuality a 2,2-dialkyl-5H-

imidazo[2,1-a]iboindol-5-ol.

The compounds of FORMULAS II and III may be prepared

by contacting the appropriate phthalimidine with a strong acid such as sulfuric acid and subsequently treating the product with base: 0 R R4

H2S04 H 2120 3 R1 5 3 R1

(IV) base (v)

N R4

R9 OH R1

(VI)

R4 and R are the same as herein above 5 wherein R 1 R2 R3

470.692

24 8 0 9 ni-

defined for FOPJLAS II and IIIand R6 is the same as defined above for FORMULA I. In addition, this method is operable fox the production of compounds wherein R 4 and R 5 are hydrogen.

Thus the present invention particularly provides a process

of preparation of a compound of the general formula:

N RK~ R NI R3 OH o o R3

R1R (VII) (VIII)

where desired in the form of an acid addition salt, wherein a compound of F6RMULA I where R4 and R5 are both hydrogen is treated with a strong acid, and, if desired an acid addition salt form of the product is converted into the free base form or a free base form into an acid addition salt form.

Concentrated sulfuric acid of 75-100% strength Is preferably employed as the strong acid in converting compound IV to compound V. Generally, no criticality attaches to the use of a particular basic compound when the sulfate salt is treated to prepare the imidazoisoindol-ol base form. For example, sodium carbonate, sodium hydroxide, potassium hydroxide or sodium bicarbonate may be used. When the tautomeric acid-addition salt is prepared, the preferred method is to saturate a lower alkanolic solution of the base form of the compound with hydrogen chloride gas. Suitable lower alkanols include methanol, ethanol and propanol.

6 470,692

24.809 m. The intermediate sulfonated phthalimidines may

be prepared as follows:

0 R

R RXOH

Rewhn RgR R 6

S2 6

Ri

wherein R 1 RE, R R R5 and R6 are the same as hereinabove defined and X is a halogen atom. In addition, R4 and R 5 may be hydrogen when intermediates are being prepared for making

compounds wherein the imidazo moiety is unsubstituted. The sulfonation is usually conducted in pyridine although other suitable organic or aqueous solvents with a base such as

sodium carbonate or triethylamine may be employed. The reactants are refluxed for about 12 to 24 hours, then the solvent is evaporated and the residue is partitioned between

water and an immiscible organic solvent such as ethyl acetate,

ether, chloroform or benzene. The organic portion is separated and then the solvent is evaporated. The residue is recrystallized from a lower alkanol such as methanol, ethanol or propanol to yield the sulfonated product.

The phthalimidines may be obtained by the hydrolysis of an imidazoisoindolone or by reaction of the -acid chloride of an o-aroyl benzoic acid with the appropriate 1,1-dialkylethylenediamine:

47 0.692

24,809 ,;1 0 IR4 R hydrolysis R1

R4 1 i'4 R I1 T-CH 2 2 -C-NH 2

3ri~" I~t

wherein R 1 R2 R.3 RV R5 and R6 are the same as hereinabove defined.

The imidazoisoindolone compounds may be prepared by condensing a 1,1-dialkylethylenediamile with the appropria; o-(substituted carbonyl)benzoic acid:

COOH R4

2 C =O

H2 N-CH 2 -C-NH 2

reflux

wherein R1 R2 R R4 and R5 are the same as hereinabove defined.

470,692

24,809/7m. The imidazoisoindolones may be prepared by solvent refluxing thq reactants in a water immiscible organic

such as toluene, benzene, xylene, ckloroform, carbontetra-

chloride, pyridine. The flask should be equipped with a 12-24 hours. water separator and the usual period of reflux is

The solution is then extracted with water and the organic

evaporated in vacuo to a solid-residue. On re- layer is

crystallization from ethanol, ethyl acetate, hexane-acetone, good yield. chloroform, the imidazoisoindolone is obtained in

The final products made from the new intermediates acceptable of the invenlion contain salts with pharmaceutically

acids and the invention also provides such salts. Suitable hydro- acids for the formation of acid addition salts include chloric, hydrobromic, sulphuric, nitric, phosphoric, acetic, lactic, citric, tartaric, maleic, gluconic, benzenesulphonic, and toluenesulphonic, methanesulphonic and similar inorganic organic acids.

The invention further provides a pharmaceutical active compound composition which comprises a pharmaceutically compounds of of FORMULA VII or VIII, derived from the new 5 active compound FORMULA I where R and R are hydrogen, which 4

may for example, ba micronised, and a pharmaceutically acceptable carrier.

Any suitable carrier known in the art can be used

In such a .to prepare the pharmaceutical compositions. or mixture composition, the carrier may be a solid, liquid

of a solid and a liquid. Solid form compositions include

powders, tablets and capsules. A solid carrier can be one or agents, more substances which may also act as flavouring

-9- 470.692

24,8 0 9/71.

lubricants, solubilisers, suspending agents, binders, or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in adlmixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99%, preferably 10-80%, by weight of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly cachets are included.

Sterile liquid compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharma- ceutically acceptable sterile liquid carrier, such as sterile water, a sterile organic solvent or a mixture of both. Preferably a liquid carrier Is one suitable for parenteral. injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it Is too insoluble for this it can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is

10 -470,692

24,809

generally suitable. In other instances compositions can be

made by -dispersing the finely-divided active ingredient in

aqueous starch or sodium carboxymethyl cellulose solution,

or in a suitable oil, for instance arachis oil. Liquid

pharmaceutical compositions which are sterile solutions or

suspensions can be utilised by intramuscular, intraperitoneal

or subcutaneous injection. In many instances a compound is liquid orally active and can be administered orally either in

or solid composition form.

Preferably the pharmaceutical composition is in

In such form, the composition is sub-divided unit dosage f9rm. the active in unit doses containing appropriate quantities of

ingredient; the unit dosage form can be a packaged composition,

the package containing specific quantities of compositions, The unit for example packeted powders or vials or ampoules. or it- dosage form can be a capsule, cachet or tablet itself, form. can be the appropriate number of any of these in packaged composition The quantity of active ingredient in a unit dose of ag. or more, may be varied or adjusted from I mg. or less to 500 of the active according to the particular need and the activity

ingredient. The invention also includes the unit dosage form compounds of of compounds of FORULPAS VII and VIII, made from

FORMULA I, in the absence of a carrier.

to illustrate The following examples have been added examples I to IX but not to limit the scope of the invention, materials beinG concerned with the preparation of starting invention. leading to the preparation of compounds of the

11 470,692

2 4, 8 0*9 Example I

A solution of 50 of o-(p-chlorobenzoyl')benzoic acid, 100 ml. of toluene and 40O mi. of l,2-diamino-2-methyl- propane is refluxed in a flask equipped with a water separator. After refluxing for seventeen hours, the solution is extracted with water and the organic portion evaporated in vacuo to a solid residue. On recrystallization from ethanol, there is obtained 9b- (p-chlorophenyl)--l,2,3,9b-tetrahydro-2,2-dimethyl -5H-imidazo[2,l- a~isoindol-5-one, m.p. 132-4 0 C.

Anal. Calc'd for C.1 8 H1 1 7 C1N 2 0: C, 69.34; H, 5.17; 8.99;

Found: C, 69.gl; H, 5.40; N, 8.65; Cl, 11.36.

In a similar manner, reacting appropriate 1,1- dialkylethylene diamine with o-ben zoylbenzoic acids, there is obtained:

1,2,3, 9b-tetrahydro-2, 2-diethyl-9gb-phenyl-5H- iLmidazo[2, 1-a

2,2-diethyl-9b- (3,4-diiodophenyl)-1,2,3,9b-

9b-(3,L!-diethoxyphenyl )-l,2,3,9b-tetrahydro-2,2- dimethyl-5H-imidazo[2, 1-a lisoind 01-5-one;

2-ethyl-9b- (4-hexylphenyl)-l,2,3,9b-tetrahydro-2- methyl-5H-imidazo[2,l-a

-12-j 470.692

2,2-dipropyl-A4kiidaz0 l-a]isoindol-5-one; and

2 7-chloro-9 b-(4ethylphefyl),2,3,btetrahydro- 2 methyl-2..propyl-511-imidazo( 1-a

Exampole 11

A solution of' 50 g. of' o-(R-.fluorobenzoyl)beflzoic acid, 150 ml. of toluene and 75 ml. of l,2-diamiflo-2-methyl- propane is refluxed in a flask equipped with a water separator. After refluxing for nineteen hours the solution is extracted and with water.' Thd toluene layer is evaporated to dryness thp residue is recrystallized from aqueous alcohol to obtain

imidazo(2,1-a]isoindol-5-ofle, m.p. 108-110 C.

Anal. Calc'd for C18 H1 7 N2F'0 C, 72.95; k, 5.78;' N, 9.415. Found: C,.72.83; H, 5.86; N, 9.145.

Similarly, gb(-rm--oy)123g-erayr -22dmty-Hiiao[,-~sidl5oe 1,2,3,91b-

terhdo227tiehyl9-hnl5Hiiao21-a lisoindol and 1,2,3,9b-tetrahydro-2, 2-dimethyl-9b-phefyl-9 propyl-5H-imidaz~o[2,la]ioindol5one are prepared.

13- 4 70,6 92

24,8 09 l: Example TI1

A solution of 40 g. of 0-benzoylbenzoic acid, 60 mi. of l,2-diarino-2-methylprcpane, and'150 ml. of toluene is refluxed in a flask equipped with a water separator. After refluxing eight hours the solution is extracted with water and the toluene portion is evaporated to dryness. The residue is recrystallized from ethanol to obtain l,2,3,9b-tetrahydro -9b-phenyl-2,2-dimethyl-511-imidazo[2,1-a r.p. 146-90 C.

Anal. Calc'd for C18 H18 N 20: C, 77.67; H, 6.52; N, 10.07. Found: C, 77.35; H, 6.88; N, 10.15.

Repeating the above procedure, the following compounds are prepared:

9b-(3,4-dichlorophenyl)-l,2,3,9b-tetrahydro-2,2- dimethyl-5H-imidazo[2,1-a

2,2-diethyl-9b-(D-fluorophenyl)-1,2,3,,b-tetrahydro-

5H-imidazo[2,1-a]isondol-5-one; and

1,2,3,gb-tetrahydro-2, 2-dimethyl-9b- imidazo[2,1-a

.14- 470.692

24.809 O'- Example IV

A solution of 35 g. of o-(p-bromobenzoyl)benzoic of l,2-diamino-2-methyl- acid, 125 ml. of toluene, and 50 ml. with a water separator. propane is refluxed in a flask equipped is extracted with After refluxing six hours, the solution to dryness in vacuo. water. The toluene-layer is evaporated there is obtained On recrystallization from dilute alcohol 9b- (p-bromophenyl)-l2,3,9b-tetrahydro-2,2-dimethyl-5 m.p. 133-5 C.

C, 60.51; H, 4.80; N, 7.84. Anal. Calc'd for C181H7 N2 BrO Found: C, 60.80; H, 4.91; N, 7.91.

Example V

repeated When the procedure of Examples r-IV is diamine with to condense an appropriate 1,1-dialkylethylene 2 3 9 b_ a o-ketoacid, the following 2,2-dialkyl-9b-ary1-l, !Pimidazo [2,1-a]isoindol-5-ones are produced:

0-

R2 N R4 N R3 NN.

wherein R1 R2 R, R4 and are as follows:

47 O 92

24,6 09ral H- -H H H HH 4 H HA H- H -4

S C 4 4 4' +3 -P 4> 140 4-L 4 0I 0) -j 0) :3 0 4-1 0) a) a) a) a) (D f- Ei 505 0, El0 M E r;

HA H H- H- Hq H H H H H H- H- r- H- 14

04.35 0 5' 05 0) 4) 0 0 0 0 0 0 0)

W W 0 W~ c0 wJ X w 0 bww bD 5,tO bbD tO b9g ta m~ 0 0 H- 0 -P 0 4'0 0 0 0 0 l? 0 0 0 0 0 k k C $4 C) $4 $k H &454 4' k5k54k4Si5k. MI Vo VV .0 go a a a 5'>1

0

0 H 4 H;q x 0 O0 >~X0 54 .0 0 0 0 Lb H w 0 .0 c 4' 10 00 54 4 -1 4- 0) 41 0) 0 H1 0 0. 0 0 0.0 k4 54 k 4 E a) r: ai 4 a a4 V0 'o V0 I I a)0 P4 tGo 0;a A

H H 5', HH 0 .0 H 04 .0 H H 04 5', a, .0 0, 0 a, 0 0 4' .0 a 0 .0 0 Fi C 0X 04C'i 045 H a 00 0 0 4-1 H H 0 0 04 .vi X 54 .054 0 0 0 5< o, 5 4'.V .0 ~S 0~ 4' H .0 H TI H 0 0 4-4 V a, S 43 P4 in5' a 54 a 54 4' Vi 014' C\u c p C CU rr~ 0 4'

36 4 7 0.6 9 2

S248 09. Example VI

A mixture of 30 g. of 9b-(v-chlorophenyl)-l,2,3,9b- .tetrahydro-2,2-dimethyl-5H-imidazo(2,1-lisoidol-5-one, as prepared in Example I, and 100 ml. of 50% hydrochloric acid is heated in a steam bath. Solution occurs on heating for

ten minutes; then 'solid begins to precipitate immediately. The mixture- is cooled, filtered and washed with acetone to

obtain 2-(2-amino-2-methylpropyl)-3-(-chlorophenyl)-3 0 hydroxyphthalimidine hydrochloride, m.p. 230-2 C.

This hydrochloride salt is neutralized with sodium carbonate solution to obtain the corresponding phthalimidine base, m.p. 208-10 0 (recrystallized from ethanol).

Anal. Calc'd for C18 Hl9 N2 C10 2 C, 65.35; H, 5.79; N, 8.47;

Cl, 10.72. Found: C, 65.48; H, 5.75; N,.8.43; cl, 10:88.

Similarly, the following compounds are prepared from the other 2,2-dialkyl-gb-aryl-1,2,9b-tetra o d

of Example I:

2-(2-amino-2-ethylbutyl)-3-hydroxy-3-(3, phenyl)phthalimidine;

2-(2-amino-2-nethylpropyl )-3-(3,14diethoxyphenyl)

-3-hydroxyphthalimidine;

.17...470.692

24, 89 '?1 2 (2-amino-2-reth ylbutyl)-3-(4-hexylphenyl)-3- hydroxyphthalimjdine;

6 -amino-2-(2-arn1iio-2-propylpentyl)-3-(p-fluorophenyl)

-3-hydroxyphthalinidine; and

2- (2-amino-2-ethylpentyl)-6-chloro-3- (-ethylphenyl) -3-hydroxyphthalimidine.

Example VII

A mixture of 45 g. of 9b-(p-fluorophenyl)l,23,b- tetrahydro-2,2 diethyl>5H.-imidazo[2, l..isoindol-5-one, as prepared in Example II, and 150 ml. of 50% hydrochloric acid is heated in a steam bath. After ten minutes a clear solution forms; then solid begins to precipitate. The mixture is heated for an additia-aiten minutes, then cooled, filtered and washed with acetone. 'The solid obtained is 2 -(2-amino-2- methylpropyl)-3-(p-fluorophenyl)-3-hydroxyphthalimidine hydrochloride, hydrate m.p. 177-1800C. dec.

The hydrochloride salt is neutralized with sodium carbonate solution to obtain the phthalimidine base, m.p. 0 196-9 C.

nal.Calc1d for C N2 O2 C, 68.78; H, 6.09; N, 8.91. Found: C, 68.83; H, 6.18; N, 8.99.

.18 47.692

24,809 11 Similarly, 2-(2-amino-2-methylpropyl)-3-(3-bromo-p-

tolyl)-3-hydroxyphthalimidine; 2-(2-amino-2-methylpropyl)-3-

hydroxy-6-methyl-3-phenylphthalmidie; and 2-(2-amino-2-

methylpropyl)-3-hydroxy-3-phenyl-4 l h mi

Example VIII

A mixture of 47 g. of l,2,3,9b-tetrahydro-9b- phenyl-2,2-dimethyl-11-imidazo2,1-a~is as

prepared in Example III, and 150 ml. of 50% hydrochloric

acid is heated on a steam bath. Clear solution forms within

fifteen minutes then reprecipitation occurs. After heating an additional five minutes, the mixture is cooled and filtered to obtain 2-(2-amino-2-methylpropyl)-3-hydroxy-3- phanylphthalimFidine hydrochloride, m.p. 252-5 C. (dec.).

The above-prepared hydrochloride salt is neutralized

with sodium carbonate solution to obtain the phthalimidine *0 base, m.p. 172-3 C.

Anal. Calc'd-for C18H 20 N2 02 C, 72.94; H, 6.80; N, 9.45.

Found: C, 72.80; H, 6.93; N, 9.32.

Repeating.the above procedure, the following compounds are prepared:

2- (2mino-2-methylpropil) (3,I-dichloroPhenyl)

-3-hydroxyphthalimidine;

19; 47.6 92

24,8 09 n1i 2-(2-amino-2-ethylutyl)-3-(p-fluorophcnyl)-3- hyd roxyphtha lirni dine; and

2-(2-amino-2-methylpropyl)-3-hydroxy-3-(P-tolYl) phthalimidine.

Example DC

A mixture of 33 g. of 9b-(p-bromophenyl)-l,2-,3,9b- tetrahydro-2,2-di:ethyl-511-imidiazo(2,1-a]isoindol-5-one and 120 ml. of 50% hydrochloric acid is heated in a steam bath. Clear solution forms within ten minutes, then reprecipitation occurs. After heating an additional ten minutes, the-mixture is cooled and filtered to obtain 2-(2-amino-2-methylpropyl)

-3-(p-bromophenyl)-3-hydroxyphthalimidine hydrochloride, 0 n.p. 227-230 C. (dec.).

The above-prepared hydrochloride, salt is neutralized with sodium carbonate solution to obtain the phthalimidine base, m.p. 194-60C.

Anal. Calc'd for C18 I11 N 2Br2 0 C, 57.61; H, 5.10; N, 7.46. Fotnd: C, 57-37; H, 5.19; N, 7.29.

4 7 0.6 9

24,8 09m Example X

Whep the procedure of Examples VI-IX is repeated

to hydrolize an appropriate 2,2-dialkyl-9b-aryl-l,2,3,9b- Himidao[2,1-]isoindol-5-one, as described in

Example V, the corresponding 2-(2-mino-2,2-dia1ylethyl-3- aryl-3-hydroxyphthalimidine hydrohalide is afforded which is the then neutralized to produce the bases thereof having formula:

"3

follows: wherein Rl, R2 R3 P R4 and R5 are as

21 47Q69&

24, 6 09:

C: 4) 3 4) 43 3 4 4

2 0) Q 0) 12 E A) .0 j Q 2 0 E2 2 i 2i E

H H

4 .2 P' 4) 4+ P 4 4a) v+ 0) W) 0) a- 4) :3 0) d) 0) C 1 W) 0 Q) IVo r3 2.0 22 A22 Q2 P R 0 i

2 2 0 a (D 0) 0 0) b90) t) 0- C) .2 bD W 0 ttD bft~tO bOb bO W to -P 0 0 :5 '2 H2 0 0 0 0.2 0 0 0 0 14 0 I Ei I v- JL t q k k 00 .2 co A2 CI

0 0 0 OHi 14 H >1 X 0 0 k- 2. 4) H C: H HD 2 C)b (I 0 4-2 -1 4JI0 0 b P 0 f 0 4 4' 0 0-0. 0 .2 0 0 .2 I t, tL 0; t- t- l t- I- O C- t. .2 CO .2 .2 4

H 2 H 2 H H> C) 0> 0 k2 H 2 02 H H 0 0 0 2 SA .2 ILI 0) 4-' 0. 0 4>, 0 H 0 0 .2 0) A 0> 2 (D >.P n~ 0 4 2. o 0 0 ~0 '2 O 0l H3 44 H E -d 4 I

22 2 OL6 -47 92

2 4.8 0 9 ni. Example XI

o-(p- The acid chlorideprepared from 26 g. of in 40 ml. of acetone chlorobenzoyl)benzoic acid is dissolved ml. of 1,2-diamio and is added dropwise with stirring to 35 The mixture is -2-methylpropafe and 150 ml. of pyridine. to dryness stirred and refluxed for one hour then evaporated and separated in vacuo. The residue is slurried with water is by filtration. On recrystallization from ethanol there

obtained 2-(2-amino-2-methylropyl)-3- (o-chlorophenyl)-3- 0 hydroxyphthalimidie, m.p. 208-210 C.

appropriate In a similar manner, the acid halide of the following o-benzoylbenzoic acids are acylated to afford compounds:

2-(2-amino-2methylpropyl)-3- (nfluorophenyl)-3- 0 hyroxyphthalimidie, m.p. 177-180 C.; ~7 2- (2-amino-2-methylpropyl)'3-hiydroxy-3-ph1-

phthalimidine, m.p. 172-30C.; and

-3- 2- (2-amino-2-methylpropyl )-3-(p-bromophenyl) hydroxyphthalimidine, m.p. 194-60C.

-23- 470692

S 2 80 9 Exampl e XIII

A mixture of 35 g. of 2- (2..amino-2-methylpropyl)

(p2-chlorophenyl )-3-hydro'xyphthalimidine hydrochloride, as prepared in Exanple VI, 25 9. of p-toluenesulfonyl chloride and 125 mnl. of. anhydrous. pyridine is. refluxed for

three hours. The solution -is evaporated to dryness and the

residue partitioned between ethyliacetatead water.. The On ethyl acetate portion is. evaporated to a solid residue. recrystallization from ethanol there is obtained

(pR-chlorophenyl -3hydroxy-2-phthalimidinyl]-l,1-dimethylethyl -27toluelesulfoflSalide, 225-7

61.91; H, 5.20; N, 5.78; Anal.' 2 5 C1N 2 0 4 S: Caled for C2 5 H1 C,

C1, 7.31; s,6.1 Found: C, 61.83;4 H, 5.00; N,5.3

Cl, 7.143P ,68.

A solution of.15 9. of the above-prepared N-(2-

-3hydroxy-2-phthalimfldWIn I-dimethyi-', (R-chlorophenyl ethyl)-p.~toluenesulfonamide and itO ml. of 90% sulfuric ac id

isallowed to stand at room temperature for forty-five m~ijes. The reaction mixture. which contains the sulfate 2 salt of 41 -cWhoro- (4,14(5,-dimethyl-2-imidazolin-2-yl)belzo- phenone is quenched with several volumes of ice water and

neutralized with concentrated sodium hydroxide solution. On recrystal- The solid is separated and washed with water. .Ydro liazation there is obtained 5-(R-chlorophenyl-2,3-dih

202 00.

24 470.692

*A suspension of 1.5 9. of the above-prepared

(p-chlorophenyl)2,3-dihydro-2,2(or3,)dmty:-Hiiaz in 25 ml. of absolute ethanol is saturated

with hydrogen chloride. The solution is evaporated to dryness

in vacuo. The residue is. triturated with ethyl acetate and

separated by filtration. On recrystillizatiol from ethanol-

*ethyl acetate mixture, there is obtained 1'-chloro-2-(4,4(5,5)- m.p. dimethyl-2-imidazolin2-y)benzophenone hydrochloride, 235-8 C. dec.

Anal;. Calc'd for Cj8 H17 Nj0Cl1{Cl: c, 61.90; 5.19;

N8.20 Cl, 20.30. .4

pound: C, 6.59; H .9

A, 8.20;' Cl,

iR (KBr) 167o cm-1, 2558-2941 cm3.

(Isopropanol) max. 263 mtL =l2,1460)

-Example X31

2 A mixture of 32 g. of t-(2-anino- -methylpropyl) 22 g. of R-toluefle- (R-f luorophernyl) -3-hydroxyphthalimfidifle, luxed for sulfonyl chloride and 200 ml. of pyridine is ref -in vacuo efght hours. The sblution is evaporated to dryness and water. and the residue is partitioned. between ethyl acetate The The ethyl acetate portion is evaporated to dryness. residue is recrystallized from ethanol to obtain (7fluoropehyl)-3ydroxy-2phthalimidinyl ]-1,1dimethylethyl).

I t 06692 '25

24,8 09 /l p-toluene sulfonamide, m.p. 206-9 0 c.

Anal. Calc'd for C25 B 25 112FS04 C, 64.09; Hi,5.37; 1j, 6.30. Found: C, 64.25; H, 5.39; N, 6.30.

A-solution of 22 U. of N-(2-t34-(p-fluorophenyl)-3- hydroxy-2-phthalimid inyl]-l,l-dimethyl ethyl)-R-toluenesulfon- amide, and 50 mi. of 90;, sulfuric acid is allowed to stand at room temperature for forty-five minutes. The mixture which conta the sulfate salt of O-i-rluoro-2-(4,4(5,5)-dimethYl-2-imidazolin -2-yl)benzohenone is quenched with several volumes of ice water and neutralized with concentrated sodium hydroxide solution. The solid is separated and washed with water. On recrystalliza- tion from ethylacetate there is obtained 2,3-dihydro-2,2(or 3,3)-dinethyl-5H-imid'azo [2,1-a 0 ol, m. 194-6 C.

Anal. Calc'd for C18H1 7 N2 F0: C, 72.96; H, 5.78; N, 9.45. Found: C, 72.88; H, 5.91; N, 9.45.

IR (KBr) 1658 2273-2278 cm-1 U.V. (95% EtOH) max 260 rit 5,760) max 272 n' 5,000 (pill) max 252 Mu i(c=13,000

On treating 5-(p-fluorophenyl)-2,3-dihydro-2,2-dimethy -5Hi-iinidazo[2,1-ajisoindol-5-ol with hydrogen chloride, there is obtained 4'-fluor-o-2-(4,4(5,5)-dicthyl-2-imidazolin-2-yl)benzo- phenone hydrochloride. m.P. 203-50 C. Anal. Calc'd for C18 H117N 2!0'HCl: C, 64.96; H, 5.45; N, 8.42. Found: C, 64.79; H, 5.47; N, 8.39. 1 1 IR (KBr) 1658 cm- 2600-2941 cm' U.V. (isopropanol) max 250 nll (6=12,100)

4 7 0.6 92

24,8 09m' XIv Example th1-

A mtixture of 27.5 g. of 2-(2-amino-2-methylpropyl) -3-hydroxy-3-phenyl phthalimidine, 20 g. of p-toluenesulfonyl chloride and 200 ml. of pyridine is refluxed for eight hours. The solution is evaporated to dryness. The residue is triturated with water and separated by filtration. On recry- stallization from 95% ethanol there is obtained N-(2-[3-phenyl-

3-hydroxy-2-phthalimidinyl]-l,l-dimethylethyl)-p-toluene- 0 sulfonamide, m.p. 197-200 C.;

Anal. Calc'd for C2 5 H2 6NS04: 2 C, 66.64; H, 5.81; N, 6.22. Found: C 66.30; H, 5.70; N, 6.13.

A solution of 17 g. of N-(2-[3-phenyl-3-hydroxy-2- phthalimidinyl]-1,1-dimethylethyl)-p-toluenesulfonamide and

ml. of 90% sulfuric acid is allowed to stand at room temperature for forty-five minutes. The solution which con- tains the sulfate salt of 2(4,4(5,5)-dimethyl-2-imidazolin-2-

yl)benzophenone is quenched with several volumes.of ice water and neutralized with concentrated sodium hydroxide solution. The solid is separated and washed with water. On recrystal- lization from ethanol there is obtained 5-phenyl-2,3-dihydro -2,2-dihydro-2,2(or 3,3)-dimethyl-5H-imidazo[2,1-a]isoindol-5- ol, m.p. 211-2120 C. Anal. Calc'd for C 18 H 18 N 20: C, 77.67; H, 6.52; N, 10.07. Found: C, 77.44; H, 6.64; N, 9.87.

IR (KBr) 1645 cm-1 2273-2790 cm-1 U.V. (95% EtOH) max 260 m E= 4,900 max 272 ml E= 4,440 (pH1) max 250 mu E= 13,480

470.692

24,8 09 ni On treating 5-phenyl-2,3-dihydro-2,2(or 3,3)-dimethyl -5H-imidatzo(2,l-n.iiflndol-5-ol with hydrogen chloride, there is obtained 2-(4,li5,5)-d imethyl-2-imidazoli-2-yl)benzophclnone, 0 hydrocnIoride, m.p. 174-6 C.

Anal. Calc'd for C18H 1 0I2 0HC1: C, 68.68; H, 6.08; N, 8.90.

Found: c, 68.86;' H, 6.07; N, 8.87. 1 IR (KBr) 1645 cm-1 2564-3077 cm-

U.V. (isopronanol) max. 249 m (c=12,940)

Exam XV

A mixture of 16.8 g. of 2-(2-amino-2-methylpropyl)

(Rbromophenyl)-3-hydroxyphthalimidihe, 10 g. of k-toluene- sulfonyl chloride and 100 ml. of pyridine is refluxed for eight hours. The solution is evaporated to dryness and the residue is partitioned between ethyl acetate and water. The

ethyl acetate portion is evaporated to a solid residue. On

recrystallization from ethanol there is obtained (p-bromophenyl) -3-hydroxy-2-phthalimidinyl] 111 dmetyleh l -p-toluenesulfonamide, m.p. 234-7 0 C.

Anal. Calc'd for C25 H 25N 2BrSO 4 C, 56.71; H, 4.76; N, 5.30.

Found: C, 56.91; H, 4.65; N, 5.45.

A solution of 11 e. of N-(2-[3-(p-bromophenyl)-3- hydroxy-2-phthalimidinyl]-1,1-dimethylethyl)-p-toluenesulfon- amide and 50 ml. of 90% sulfuric acid is allowed to stand at

470.692

24,809n,1 The solution which room temperature for forty-five minutes. 2 contains the sulfate salt of 4'1bromo-(4,4(5,5)-dimethyl- with several volumes imidazolin-2-yl)benzohenone is quenched sodium hydroxide of ice water and neutralized with concentrated with water. On solution. The solid is separated and washed from ethyl acetate, there is obtained 5-(2- recrystalliatiof

bromophenyl)2,3-aihydro-2,2(or 3,3)-dimethyl-5H-imidazo[2,1-a] 0 m.p. 192-4 C.

H, 4.79; N, 7.85. Anal. Calc'd for C1 8 H17 N 2BrO: C, 60.51; Found:. C, 60.51; H, 4.82; N, 7.82. 1 1 IR (KBr) 1639 cm-r 2273-2778 cm- 4 U.V. (95% EtOH) max. 224 B41 dU 0 max. 263 C= 6,780 max. 275 m.L 6,400 (pHi) max. 267 m. (E=l3,64O) 2 On treating 5 -(p-broophenyl)-2,3-dihydro-

idazo j2,1-aisoifdol-5-0 with hydrogen chloride

there is obtained 41-bromo-2-(4,4(5,5)-dimethyl-2-midazolin

yl)benzophenone, hydrochloride. m.p. 222-5 0

C, 54.91; H, 4.61; N, 7.12i Anal. Calc'd for C18 H17 BrN2 0-HCl. Found: C, 55.09; H, 4.67; N, 6.75. 1 1 IR (Kr)1661.cm- 2500-2941 cm-

U.V. (Isopropanol) max. 267mlJ (e=14,500)

Example XVI

is repeated When the procedure of Examples XIII-XV

to react appropriate 2-(2-amino--2-alkylakyl-3-aryl-3-hydroxy alkyl sulfonyl halides, phthalimidine hydrohalide with aryl or 2 there is afforded the following H4([3aryl-3-hydroxy- which are phthalimidinyl]-l,l1dialkylaikyl)sulfonmiden appropriate sulfate then contacted with sulfuric acid to afford heny aroyl compouini salts of II 5 ,5)-dilkyl-2-imidzolin-2-yl-p (TI) iiic.h ar' ntralxizfd to fofrd appropriate 2,2(or 3,3)-din 4 1 0.692

2413 09 /71 -5-aryl-2, 3-dihydro-5H-imidazo [2,1-a Jisoindol-5-ols (III) wl-Ach may be acidified e.g. hydrochloric acid, to afford the corresponding 11,4(5.5)-diaky1-2-1-midazolin-2-y phenyl aroy' compound acid-addition salts (TV) e.g. hydrochloride, which compounds (III) and (IV) are depicted by the following formulae:

N r R4

R2 -1 A H H .1/2 J2 S

(II)

R2 H R3 4R C=OCN

R I1Cl

(IV) (III)

wherein R, R2 R R4 Ra and Rj are defined below:

J,7 0.6 92

24,8 09 ni H r- H 0. 0 04 H- U' 0 r- 0 H 04 a) 0. .0 0 .0H .0 Ha 0 H4 0- x w 0 0 0 ou 0 .0 4 V) 0) H 4 U 0 0. 0 0. 4-l I H Lr~- I H>) 0 I a' a' M) 0.I 1 0 In 4 a) 4) .0 0. Cuj 4J 43 S.)H 0 )4 0>)

~;LAj~~ H

4) 4-) 4 4 +J 0 4 4d 0) 0 0 4-3 4 0H 40 0 0 43 4) a) 0) N) 0L 4) I- A rz U 9i r 04 .r .2 El 4

4-a)

H H H H U U

0 000 HO 0 '0 000 000 I) $4 &1 0 4) 0 43 $4 a) a) 43 H C 4 1bD W 0 W~ C0 tO bO 0 bD tO tO) bD W td) bo

P4 0 0 O .0 .3 .0 4J .0 :F .0 .0 .0 O 0 .0 .0 0 14 IL 14

.0 00 C~~~jbf 0 0 0.0 .0 4)3 w 0 4)H- 0.0 0 0q 0 0 0 .0 0

t-C 0c t t t- 'I'D tL- t- tLC 0 .0 CO

$4 r44) 0) I H H .0 E H r 10 0 .0 o 0. Cal H H H 0.0P 0. k) ;4 a) 0. 0 0.0 00I .41 4) 01 0 0 X0 04 0 ED Ho I a 0 0 0. 0 0 m P. *-4i 4 ITi0 'ci I $4 $4 0 $4 c 41 Ce) .0 $4h 4 I CO. 4- 01 I

4 70, 6-2 xvri

A solution of 21.5 G. of 2- (2-arninoethyl) -3 (p- oh orohoyl)-3hy. roypthaiiidie,13.3 g. of p-tol'aene- sulronyl chloride and -150 ml. of pyridine is allowed to st;and at roomn tormperatiure for eighteen hourls. The mixture is qlerched with va and extr-'cted with ethyl acetate. The u-thyl ace:tate portion lis uvaporated to dryness and the residue crystall,,.es on standintg. for three days. On recrystallization 1 'un a'w'~s e 1t -,ire obtained N-(2-[3-(p-chlorophenyl) Li -L1]ehy)-_-toluenesulfoamide, 33-150C. Anal. Calctd for C2 3 Hp2!N,04SCl: C, 60.32; 4.84; N, 6.12; Cl, 7.74. Found: C 60.54; H, 4.50; N, 6.08; C1 7.56.-

A s~ji1of 18 g. of N-(2-f3-(p-chlorophenyl)-3- hydrxy--phh~A midnylethyl)-R-toluenesulfonamide and 50 ml.

ni O% .z,;Ifuric acid is allowed to stand at room temperature ior forty-five mninutes. The solution~ containing-the sulfate salt of )l'-chloro-2-(2-imnid!zolin-2-y)benzophenone is quenched with several vol,.acms of e water and neutralized with concentra sodiu m hydroxide s~n.The !solid is separated and %w.ashed with water. On i-ecrystalli-zation from dimethylacetamide there is obtained 5-(p-chloro:phenyl)-2,3-dihyro-5H-;midazo

[f..l--a]iso.J~dol-5-o1, w.p. ""-,3-2100 C.

.m~.Calc'd for C 1 6 H 1 2 c, 67.49; H, 4.60; N, 9.84;' 1P.

Found: C, 67.18; H, 4.32; N, 9.68; f!1, 12-70.

92 47-0,692

24,809 mi 1 IR (KBr) 1645 cm- 2380-3000 cm 1 1 U.V. (95% EtOH) max. 223 C=1 ,000 1 inll. 242.5 Pn E= 9,300 max. 268.5 fl e= 4,400 max. 272 mg e= 4,400 (pHi) max. 251 mP *E=11,000 max. 264 iL l=0o,800

On treating 5-(p-chlorophenyl)-2,3-dihydro-5H- with hydrogen chloride, there is

obtained 4 Schloro-2Z(2-imidaolin-2-yl)benzophenofe hydro- chloride, m.p. 170-20 C.

Anal. Calc'd for C 16 H1 3 N 2C10'HC1: C, 59.80; H, 4.40;

N, 8.72; Cl, 22.08. Found: C, 59.63; H, 4.50;

N, 8.72; Cl, 21.79. 1 IR (KBr) 1647 cm- 2300-3200 cm-1 U.V. EtOH) max. 252 in (e=12,100 max. 265 mn1 e=12,300) 6 (Isopropanol) max. 2 4mt1 e=l1,000) XVII Example kXxX

When the procedure of Example XVII is repeated to react 2-(2-aminoethyl) -3-aryl-3-hydroxyphthalimidine br hydro- halides with appropriate aryl or alkyl sulfonyl halides, there is afforded aryl-3-hydroxy-2-phthalimidinyl] sulfonamides which'are contacted with sulfuric acid to afford sulfate salts of 2-imidazolin-2-yl-phenyl aroyl compounds which are neutralized to yield the following 5-aryl-2,3- dihydro-511-imidazo[?,l-a]isoindol-5-ols which are acidified

e.g. hydrochloric acid to produce their corresponding herein- after listed 2-imidazolin-2-yl phenyl aroyl compound acid- addition salts hydrochlorides.

470.692

24,809/71 5-ARYL-2, 3-DIIIYDRO-5- 2- IM.MDAZOIN-2-YL DMIDAZO C2, I -aISOINDOL PW"NYI A1ROYT COMPOUND 1__iYD.ROCILORIDFS

2,3-dihydro-5-(3' ,1- 2- (2-imidazolin-2-yl diiodophenyl )-fH1-imidazo- 3',414-diiodobenzophenole

[2,1-a Jisoindol-5-01 hydrochloride 5..(3t,14 '-diethoxyphenyl)- 3' ,4'diethoxy-2-(2- 2,3-dihydro-5!H-imidazo- inidazolin-2-yl )benzophenonc

[2,1-a ]isoindo1-5-ol hydrochloride

2,3-dihydro-5-(4 '-tolyl) 2-(2-imidazolin-2-yl)-4

[2,1-a Jisoindol niethylbenzophenone hydro- -5-o1 chloride

-hexylphenyl)-2,3- 1-hexyl-2- (2-imnidazolin- d ihydro-5.i-i!.:dazo 2-yl )benzophenone hydro- isoindol-3-ol chloride

2,3-dihydro-5- (2-thienyl)- 2-(2-imidazolin-2-yl)phenyl (2,1-a lisoindol-. -2-thienyl ketone hydro- 57-0 chloride

2, 3-dihydro-8-rnethyl-5-pheflyl 2- (2-imidazolin-2-y)- 4- -5H-imidazo[2, 1-a Jisoindol-. methylbenzophelofe hydro- -01 chloride 6 2- (2-imidazolifl-2-yl 2, 3-dihyvdro-5-phenyl- -propyl 1-a ]isoindol propylbenzophelofe hydro- -5-o1 chloride

5-(41'-broxophenyl.)-2,3- 4' -broino-2- (2-imidazolin dihydro- 51-imidazo -2-yl )benzophenone hydro- i soindol-D-ol chloride

,4 -dichloronhelyl) 3' ,4 '-dichloro-2- (2- 3-dihydro- 5i-irnidaZO- imjdazolin-2-yl )benzophenoni 1-a ]isoindo_- 5-ol hydrochloride

(I4-fluorophenyl 3- 4'-fluoro-2-(2-imidazolil

[2,1-a] -2-yl)benzopheloe hydro- chloride

5-(31-bromo-& '-methylphenyl) 3' -bromo-2- 1 (2-imidazolin-2- 3-dihydro-5{-irnida zo[2,l-a]- yl)- -methylbenzopheloe is oindol- 5- ol hydrochloride

7-brorno-2, 3-dihydro-5- (4-tolyl) 5-bromo-2- (2-imidazolin-

[2,1-a ]isoindol-5- 2-yl 4 '-zethylbenzophelofe ol7 hydrochloride

470.692

24.8 0-9Tm 5-ARYL-2, 3-DIHYDRO-5- 2- IMIDAZOLIN-2-YL IMIDAZO 1-a IISOInDOL PHENYL AROYL COMPOUND _-5-OLS H{YDROCHLORIDES

7,8-dibronio-5- (4-bronophenyl) 1,4' ,5-tribroino-2-(2- -2,3-dihydro-5H-imidazo *imidazolin-2-yl )benzophenone isoindol-5-01 hydrochloride

2,3-dihYdroz5- (2,4-dimethoxy- 2- (2-ixidazolin-2-yl ,1- phenyl )-5H-imidazoj2, 1-a]- dimethoxyben zophenone hydrochloride

(2,4-dibromophenyl..2,3- ,4'-dibronio-2- (2-imidazo-, lin-2-yl )benzophenone hydrochloride

2,3-dihydro-5- (5,6,7,8-tetra-- 2- imidazolin-2-yl )phenyl hydro-2-naphthyl -H-imidazo- (5,6,7,8-tetrahydro-2- 1-a JisoiLndol-5-0l naphthyl)ketone hydrochiorid

(4-trifluoromethylphenyl)- 4 '-trifluorornethyi-2- (2- 2,3-dihydro-5H-imidazo imidazolin-2-yl )benzophenone hydrochloride

(2-trifluoromethylphenyl)- 2'-trifluoromethyl-2- (2- 2,3-dihyclro-5H-imidazo imidazolin-2-yl )benzophenon isoindol-5-ol7 hydroch loride I 5-furyl-2, 3-dihydro-5H--imidazo- furyl-2- (2-iiidazolin*-2-yl)

[2,1-a ]isoindol-5-0l phenyl ketone hydrochloride

5-(3-amino-AI-chlorophenyl)-2,3- 3 '-amino-4 '-chloro-2-.

[2,1-a ]iso- *imidazolin-2-yl)benzophelofl dihydrochioride

7-chloro-2, 3-dihydro- 5-phenyl- 5-chloro-2-< 2-imidazolin- H-imidazo [2,1-a Jisoindol-5-o1 2-yl )benzophenone hydro- chloride 4 2,3-dihydro-8-methyl -5-phelyl- 2- (2-imidazolin-2-yl)-

[2,1-a]isoindol-5-ol methylbenzopheloe hydro- *chloride

7-ethylamiflo-2, 3-dihydro-5- 5-ethylamino-2- (2-imidazolii (2,s1-a Jiso- 2-yl )benzophenone dihydro- chloride

7 ,8-dichloro-2,3-dihydro-5- 4 ,5-dichloro-2-(2-imidazolii pheny1-5H-imidazo(2,1-a liso- -2-yl )benzophenone hydro- indol-5-01 chloride

2,3-dihydro-7,8'-dimethoxy- -2.-(2.-imidazolin-2-yl

5-phenyl-51-ifidazo dimethoxyben zoohenone hydrochloride

470.692

24,8097M 2,.3-DIHYfDRO-5- 2- IMIDAZOLIN- 2-YL IMI DAZO 1 -a IISO INDOLt PILE14YL AROYL COMPOUND __HYDROCHLOR IDES

2,3-d ihydro 5- iodophconyl) (2-iridazolin-2-yl)-3 511I-imida o 2, Iisoi "do 1--5- iodobenzophenone hydro- 01 8 -anYl-2,3-d ihydro-5-phcnyl- 4-amyl-2- (2-iniidazolin-2- yl)benzophenone hydro- ol, chloride 2, 3-dihydro- 5-plienyl-7-propyl 2-(2-imidazolin-2-yl 5H-imidazo[2,1-alisoindol-5- propylbenzophenone hydro- o17 chloride 8-butoxy-2, 3-dihydro-5-phenyl 4 -butoxy-2- (2-imidazolin- 2-yl )benzophenone hydro- chloride 2,3-dihydro-5-0(,L&-.dimethyl- 2-(2-imidazolin-2-yl)-3' ,4' phenyl -5H--imidazo 1-a]I dimethylbenzophenone hydro- chloride 2,3-dihydro-5- (4-propoy 2-(2-imidazolin-2-yl phenyl -5 -imidazo propoxybenzophenone hydro- chloride

.36 .86470.692

24,8 09n XIX Example/ X

A solution of 10 g. of 2-(2-aminoethyl)-3-hydroxy

-3-phenyl phthalimidine, 8 g. of p-toluenesulfonyl chloride and 50 ml. of pyridine is allowed to stand at room temperature for six hours. The mixture is quenched with water. The

aqueous portion is separated and the oily residue is dissolved in ethyl acetate. The solution is extracted with water then evaporated to dryness in vacuo. The residue solidifies on standing. On recrystallization from ethanol there is obtained N-(2-[3-phenyl-3-hydroxy-2-phthalimidinyl]ethyl)-p-toluene- sulfonamide, m.p. 160-20 C.

Anal. Calc'd for C2 3 H22 N 2 04 S: C, 65.38; H, 5.24; N, 6.63;

S, 7.59. Found: C, 65.22; H, 4.98; N, 6.52;

Ss 7.48.

Example XX

A solution of 7 g. of N-(2-[3-phenyl-3-hydroxy-2-

phthalimidinyl]ethyl)--toluenesulfonamide and 20 ml. of sulfuric acid is allowed to stand at room temperature for minutes. The solutibn is quenched with ice water and extracted with ethyl acetate. The aqueous portion is neutralized with concentrated sodium hydroxide solution. The solid is separated

and washed with water. On recrystallization from dimethyl

470.692

24,8 09 n acetamide there is obtained r-5-pheny1.-2,3-dibydril-0J1: -iida.;o

[2.1-a]isoindol-5-01, 207-210(C. (dec.).

Anal. Calc'd for C 16H 14 N 2 0: C, 76.7r; H, 5.63; N, 11.20.

Found: C, 76.63; 5. 66; N. 11.00.

IR (KBr) 1645 cm-, 2300-3000 cm-l U.V. (95% EtOH) inf. 225 m c=14,900) 1 max. 268 rt 4200 (pIll) max. 268 jfl E=13,500

On treating 5-phenyl-2,3-dihydro-5H-imidazo[2,1-a]-

isoindol-5-o1 with hydrogen chloride, Lhere is obtained 2-(2- 0 imidazolin-2-yl)benzophenone hydrochloride, m.p. 195-7 C. (dec.)

Anal. Calc'd for C 16 Hl1iN2 0'HC1: C, 67.03; 5.27; N, 9.77; Cl, 12.36. Found: C, 66.88; 5.33; N, 9.83; C, 12.50. 1 IR (KBr) 1650 cm-1 2400-3200 cm 1 8 U.V. (95% EtOH) max. 250 mg (E=12, 00).

470,692

Claims (1)

1. 24,8 09 M The claims defining the invention are as follows:

   1. A compound having the general formula:

   0 R N -C 2 -C-NlM

   RI

   wherein R is phenyl, monohalophenyl, dibalophenyl, mono- (lower)alkylphenyl, di (lower)alkylphenyl, trifluoromethyl- phenyl, mono(lower)alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl or 5,6,7,8-tetrahydro-2-naphthyl; 2 is hydrogen, halogen, amino, lower alkylamino, lover alkyl 3 or lower alkoxy; R is hydrogen when R and R3 are dissimilar from and when R2 and R are the same they are both selected 3

   hydrogen, halogen, (lower)alkyl and (lower)alkoxy; R and R 6 are hydrogen or (lower)alkyl and R is (lower)alcylsulphonyl, phenylsulphonyl, monohalophenylsulphonyl, dihalophenylsulphonyl, mono(lower)alkylphenylsulphonyl, di(lower)alkylphonylollphonyl or (lower)alkdxyphenylsulphofyl, the terms "(lower)alkyl", "(lower)alkoxy", "halogen" and "halo" being as hereinbefore defined.

   2. A compound according to Claim 1, wherein R4 and R are methyl groups.

   4 3. A compound according to Claim 1, wherein R and R are both hydrogen.

   4. A compound according to any one of Claims 1 to 3, wherein R 1is s.elected from phenyl, m-chlorophenyl, p-chloro- phenyl and p-fluorophenyl.

   470.692

   24,8 09/'71 A compound according to any one of Claims 1 to 3, wherein R1is selected from jR-iodophenyl; p-bromophenyl; a2- chiorophenyl; 3,4-diiorophenyl; 3,4-dichiorophenyl; dibromophenyl and mn- and p-trifluoromethylphenyl.

   6. A compound according to any one of Claims 1 to 3, wherein R Iis selected from.2-tolyl; 3,4-dimethyiphenyl; 2- methoxyphenyl; 3,4-dimethoxyphenyl; 2-thienyl; 2-pyridyl and 2-furyl.

   7. A compound according to any one of Claims 1 to 6, wherein R2anid R3both represent hydrogen.

   8. A compound'according to any one of Claims-I to 6, wherein R2is selected from fluorine, bromine, chlorine, iodir. inethoxy, ethoxy, methyl and ethyl.

   9. A compound according to any one of Claims 1 to 8, wherein R6 is p-tolylsulphonyl.

   A compound according to any one of Claims 1 to 8, wherein R6is selected from ethylsuiphonyl; M-pentylsulphonyl; phenylsulphonyl; p-fluorophenylsulphonyl; D-chiorophenyl- 'sulphonyl; p-brom-ophenylsulphonyl; p-iodophenyloulphonyl; dichloLrplenylsiilphonyl; 3 ,4-dibromophenylsulphonyl and 3,4- di flurophenylsulphonyl.

   11. A compound according to any one of Claims I to 8, wherein R6 is selected from 4-ethylphenylsulphonyl; 3,4- dime thyluhenylsulohonvi; 3,4-diethyiphenylsuiphonyl R-methoxy- phenylsulphonyl; and j2-ethoxyphenylsulphonyl.

   470.692

   24,809/nL 12, N-(2-[3-(P--Ch:Loropherzyl)-3-hydroxy-2-phthaimidiny... 1,1-dimethylethyl)-2-toluenesulphonamide.

   13 2- (2R-luorophenyl -3-hydroxy-2-phthalimidinyl] 1, 1-dimethylethyl)--toueneau3.phonamide.

   14. N- (3-Hydroxr-3-phenyJ.-2-phtbalimidiny1J 1- diinethyletbvl )-E-toluenesulphonamide.

   2- [3 (-Bromophenyl )-3-hydroxy-2-phtbalimidinyl]- 1 ,1I-dimethylethyl )-2-toluenesulphonamide.

   160 N- 3-(?.-Chlorophenyl )-3-hydroxy-2-phthalimidinyl]J- ethyl )-2-toluenesulphonamide.

   17. H- 3-Hydroxy-3-phenyl-2-phthalI -1dinytl] ethyl toluenesulphona~rnide.

   18. A compound according to Claim substantial-ly -as described herein with reference to the relevant Examples.

   19. A process for the preparation of a compound as claimed'in Claim 1, which comprises reacting'a compound having the general formula:

   R 3 OH

   wherein R1 R2 RR 4 and R5 are as defined in Claim 1, with 'a sulphonyl halide of the formula:

   R 6X

   wherein R 6 is as defined in Claim 1 and X is halogen.

   4 70,6 92

   248 09 71 A process according to claim 19, which comprises, contacting a compound of the general formula:

   0 R2 0

   R 1 wherein R R and R 3 are as defined in claim 1, with a compound of the general formula: 4 R

   H2 N-CH2 C-NH2

   wherein R 4 and R 5 are lower alkyl as defined in claim 1, in a solvent and refluxing the reaction mixture until the reaction is complete, for the preparation of a compound havinl the general formula:

   0 II R4 R2 N-CH 2 -C-NH2

   1 S R 1

   wherein R 1 R2 R3 R and R 5 are as defined above, then reacting the resultant compound with a sulphonyl halide of the formula:

   R6 X wherein RO is as defined in claim 1 and X is halogen.

   21. A process according to Claim 19 or 20 wherein X is chlorine.

   22. A process according to Claim 19, or 20 substan- tiall as described herein with reference to the relevant Exa-mles.

   12 470.692

   24,809/71 23. A compound prepared by a process according to any

   one of Claims 19 to 22.

   24. A process for the preparation of a compound of the

   general formula:

   R

   2 N2 5 4

   where desired in the form of an acid addition salt, wherein 2 acompound according to Claim 1 and wherein R, R R, R

   and R 5 are as defined in Claim 1 is treated with 75-100S

   strength sulfuric acid, and, if desired, an acid addition base form salt form of the product is converted into the free or a free base form into an acid addition salt form.

   A process according to Claim 24, substantially

   Examples. .as described herein with reference to the relevant

   26. A compound prepared by a process according to 24

   or

   27. A pharmaceutical composition comprising a compound

   according to Claim 26 in association with a pharmaceutically

   acceptable carrier.

   24th day of February, A.D. 1976 DATED this

   AIRICAN HOIlE PRODUCTS CORPORATION, By its Patent Attorney,

   EDWIN F.JTe GTON Fellow of the Institute of Patent Attorneys of Australia, (Inc.)

   -43- 4i 0.6 92