BACKGROUND OF THE INVENTION R . e-lated Ao-D-lications

This application is a continuation-in-part of application Serial No. 839,941, filed March 17, 1986. Field of the Invention

The present invention relates to certain novel anticholinergic and mydriatic compounds as well as pharmaceutical compositions containing the novel compounds and methods of treatment of animals and humans in need thereof. Prior Art

Commercially available anticholinergic drugs such as atropine and scooolamine and their synthetic analogs all share a variety of undesirable side effects. In the elderly, excitement, agitation and drowsiness are frequently observed even in small doses. Dangerous central nervous system mediated psychotic reactions and behavioral disturbances have occurred in children after topical ocular administration. Ophthalmic use may also induce local side effects such as transient stinging, allergic lid reactions, follicular conjunctivitis, edema and photophobia. See Toxicology of Com er'.ial Products, R.E. Gosselin et al, Eds. (Williams & Wilkins, Bait., 4th Ed., 1976) Sec. Ill, pp. 43-46. Mydriatic agents are an important class of compounds that are used to dilate the pupil. Mydriasis is required during ophthalmic examinations, in order to provide for a more complete examination of the fundus, the vitreous and the periphery of the lens, and in various surgical procedures such as those reported by Freeman et al, American Intra-Ocular Society Journal 7:172-173 (1981) (e.g., vitrecto y, lens extraction, and intraocular lens implantation) . Commercially available mydriatic drugs

such as atropine, scopolamine, homatropine and their synthetic analogs all suffer from several disadvantages. Because the mydriasis induced by these agents causes blurred vision and is of a relatively long duration, i.e., several hours, it is necessary to virtually immobilize the patient after the ophthalmic examination until the mydriasis subsides and the patient can resume normal activities. Ophthalmic use of these agents may also induce local side effects such as transient stinging, allergic lid reactions, follicular conjunctivitis, edema and photophobia. See R.E. Gosselin et al supra.

It is an object of the present invention to provide novel anticholinergic compounds which exhibit anticholinergic properties and which induce mydriasis as well as pharmaceutical compositions and methods of treatment embodying those compounds which are more effective and less toxic than those presently available.

SUMMARY OF THE INVENTION

The foregoing and other objects are realized by the present invention which provides certain novel compounds having the formula:

R3

(I)

⁽ CH ₂ ⁾ _n

C IOOR ¹

Wherein: R ^*1 is the esterification residue of a pharmaceutically acceptable non-toxic substituted or unsubstituted straight, cyclic or branched chain alcohol (Rl-OH) having from 1 to 8 carbon atoms such that the ester group, COOR ^* ', is metabolically hydrolyzable to the free alcohol ( R -OH) and a non-toxic metabolite of the compound following administration thereof to a human or non-human animal, R ¹ preferably being a substituted or unsubstituted alkyl or cycloalkyl group having from 1 to 8 carbon atoms;

R ² is a substituted or unsubstituted aryl, cycloalkyl or alkyl group having from 1 to 8 carbon atoms;

R ³ is H or R ² ; n is an integer from 0 to 4;

0 0

11 II

X is —f O - C- ; -f-N - C-hr

R8 wherein ^ is H or straight or branched chain alkyl 0 R9

I' > having from 1 to 5 carbon atoms; —(-C-)-; - -C -K wherein

RIO

R9 and R ¹ - may be the same or different and may be H or lower alkyl having from 1 to 5 carbon atoms; -f- S -}-; -f-0 -}- or — {- NH -}- m is an integer from 0 to 4;

R ⁴ is

wherein ^ and R^ may be the same or different and are alkyls having from 1 to 5 carbon atoms; ^' — or

^R 6^

stituted alkyl

Z is an integer from 0 to

and may be the same or different and are alkyl, cycloalkyl, aryl, or aralkyl having from 1 to 10 carbon atoms whereby to produce a non-toxic quaternary nitrogen salt and X~ is a pharmaceutically acceptable anion, preferably halide, sulfate, aklylsulfate or alkylsulfonate wherein the substituents render the compound non-toxic, and wherein the compound exhibits anticholinergic and/or mydriatic properties.

The invention further provides pharmaceutical compositions in unit dosage form comprising an anticholinergic or mydriasis inducing effective amount of a compound of the above formula and a pharmaceutically acceptable carrier therefor.

Finally, the invention also provides a method of treatment comprising administering to an animal or human in need thereof an anticholinergic or mydriasis inducing effective amount of a compound of the above formula.

DETAILED DESCRIPTION OF THE INVENTION

The invention is predicated on the discovery that certain esters of inactive polar acidic metabolites of atropine, scopolamine and other compounds, as well as synthetic analogs thereof, are active anticholinergic compounds which are significantly less toxic than their parent free alcohols. Several have also been found to be active mydriatic agents which induce a much shorter duration of mydriasis than the parent free alcohols.

For example, the free acids having the structural formula:

are anticholinergically inactive metabolites of atropine and scopolamine, respectively. Certain esters of these ^• acids possess anticholinergic and mydriatic properties equivalent to atropine and scopolamine but are far less -toxic. The esters are metabolically hydrolyzed to the above inactive acidic metabolites (II) and (III) and non-toxic alcohols when administered to animals or humans.

R ¹ in the above formula (I) is the esterification residue of a pharmaceutically acceptable non-toxic alcohol R ¹ 0H such that the ester group therein, -COOR ¹ is metabolically hydrolyzable to the free alcohol and the inactive acidic metabolite -COOH. R^ is preferably a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted cycloalkyl group having 1 to 8 carbon atoms. R ¹ is most preferably lower alkyl, e.g., methyl, ethyl, propyl, etc.

R ² may be a substituted or unsubstituted aryl, aralkyl, cycloalkyl or alkyl group having from 1 to 8 carbon atoms. The terms "aryl" and "aralkyl" are intended to include hydrocarbyl groups, i.e., those composed of carbon and hydrogen atoms.

The substituents on the various groups defined above may be any which render the compound non-toxic and which do not affect the anticholinergic or mydriatic properties thereof.

The quaternary ammonium derivatives are the preferred anticholinergic and mydriatic compounds in that they possess higher anticholinergic activities than the non-derivatized compounds. The quaternary substituents may be any non-toxic group and are preferably any lower alkyl group, most preferably methyl, and X may be any pharmaceutically acceptable anion, preferably halogen, sulfate, alkylsulfate or alkylsulfonate.

For purposes of illustration, the compounds of the present invention are referred to as "soft drug" analogs or derivatives of the corresponding active alcohols.

Soft drug mydriatic agents according to the present invention are illustrated in the following Table A which exemplifies several drugs based upon the above structural formula I.

The esters are prepared in two steps to the tertiary compounds and in three steps to the quaternary compounds from the phenylmalonic acid. The following reaction scheme is illustrative of the method:

TABLE A

1. Tropicaπide Soft Drug atoms)

loakyl

Isopropamide Soft Drug

R slower alkyl (1 to 8 carbon atoms)

CH + R ² ,R ³ =Phenyl or other aryl or cycloakyl

³ ^ 3 COflH _j

Isopropamide Iodide n=0 to 4

alkyl Soft Drug sulfate, sulfate or alkylsulfonate 3. Ipratropium Soft Drug (1 to 8 carbon atoms)

Ipratropium Bromide m=0

TABLE A (cont.)

preferably halogen, Soft Drug alkylsulfate, sulfate, alkylsulfonate

l (1 to 8 carbon atoms) other aryl or

Cyclopentolate Hydroch oride cyc oa y

4 -(ester)

Soft Drug or R-?n R ^δ

R ⁵ .R ⁶ =-CH _{3 n} 5 _B δ _n 7 . where R , R , R ■ 1ower alkyl

(ito 5 carbon atoms), preferably methyl and X ^* " anion, preferably halogen, alkysui ate, sulfate, alkylsulfonate.

Soft drug anticholinergic agents according to the present invention are illustrated in the following Table B which exemplifies several drugs based upon above structural formula I.

TΆBLE B

Following the general procedure end substituting the appropriate reactants affords the following novel soft anticholinergic compounds:

B ¹ __ __ R* (0 to t\ ) (0 to ») x ^Λ

Lower alkyl.cyclic, Any pharmaceut ⁱ cally straight or ft acceptable anion, branc _h ed chain _f~ — N— — halogen, sulfate, alcohols (1 to -\__) H N^O)-Hj- _{0 0} | akylsulfate or alkyl-

8 carbon atoms) CjH- sulfonate

CH CH CH _∑ - ^" {a) CHj-N- -O-i.-

™3

;

CH ₃ (CH i. f O Q,_ 1 4 -0 -

CH

SC

TABLE B ( cont. )

R ^z t (0 to 4) (0 to 4) Any pnar-.aceut. dl./

Tower alkyl.cyclic, acceptable anion, straight or halogen, sulfate, branched chain alkylsulfate or alky, alcohols (1 to sulfonate 8 carbon atoms)

The rates of metabolic hydrolysis of the active esters may be controlled by selection of the esterifying alcohol.

The invention is illustrated by the following non-limiting examples.

EXAMPLE 1

Methyl hydrogen phenyl alonate

A mixture of phenyl alonic acid (3.6 g, 0.02 mol) boron trifluoride etherate (2.4 ml, 0.02 mol) and 0.8 ml of anhydrous methanol (0.02 mol) was refluxed and stirred for 24 hours. After cooling to room temperature, the reaction mixture was filtered and 20 ml of water was added.

The precipitated oil waε extracted with CHCI3 (30x3). The combined extracts were washed with water and dried over anhydrous MgSC.4 and evaporated under reduced pressure. The obtained oily liquid showed nmr spectra is consistent with its structure.

Rf of the acid = 0.52 yield = 57% R _f of the ester = 0.72.

Preparation of methyl phenyl alonyl chloride

To the obtained oily liquid above was added 5 ml of thionyl chloride. The reaction mixture _, was heated on an oil bath for one hour under anhydrous condition. The excess thionyl chloride were removed by the addition and the in vacuo distillation of 10 ml of anhydrous benzene.

The product was oily and was reacted immediately with tropine base.

Esterification of methyl phenylmalonyl chloride and Thoroughly dried tropine (1.4 g, 0.01 mol) was added to the freshly prepared methyl hydrogen phenylmalonyl chloride. The mixture was heated for 5 hrs at 100', while stirring, under anhydrous condition. The

mixture turned to brown and gas evolved. After cooling to room temperature and filtration the mixture was treated with 10 ml of water. The clear solution was adjusted to pH 9 with saturated Na2C(_>3 solution, extracted with ethyl ether and dried over anhydrous M S04. The ethereal solution was filtered and distilled under reduced pressure to produce an oily product.

EXAMPLE 2

Preparation of Ethyl (±)-c.-(carboxy)-8-methyl-8- azabicyclo[3 - 2 - 1]oct-3-yl-benzeneacetate a) Preparation of ethyl hydrogen phenylmalonate (1 ) : Phenylmalonic acid (13.5 σ, 0.07 mol) in dry ether- (40 ml) was treated with thionyl chloride (8.92 g, 5.4 ml, 0.07 mol) and one drop of N,N-dimethyl for amide. The mixture was heated at 40-50°C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue redissolved in dry ether (40 ml), the solution was treated with ethyl alcohol (0.075 mol, 4.1 cc) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N HCl to pH1. The precipitated oil was extracted with CH2CI2 (3x50). The combined extracts were washed with water (4x50) and dried over anhydrous MgSC^. The oil product crystallized on standing.

Yield: - 7.2 g (49.4%) M.p.: 78-9°C (as reported).

b) Preparation of ethyl phenylmalonyl chloride

Ethyl hydrogen phenylmalonate (2.08 g, 0.01 mol) mixed with thionyl chloride (5 ml) and heated at 70°C for one hour under anhydrous condition. The obtained liquid was evaporated under reduced pressure. Anhydrous benzene (10 ml) was added to the residue and redistilled again to remove any residual thionyl chloride. c) Esterification of ethyl phenylmalonyl chloride and tropine The previously obtained acid chloride (0.01 mol) dissolved in 10 ml of dry benzene was added dropwise with stirring for half an hour to a solution of dry tropine (2.8g, 0.02 mol) in dry benzene. The mixture was stirred at room temperature for 24 hours and filtered. The filtrate was washed with water until neutral. The organic layer was dried over anhydrous MgSC>4 and the solvent evaporated. The obtained oily base was converted into oxalate salt by adding an ether solution of oxalic acid to a solution of the base in ether. By scratching the mixture a white solid product was obtained. When cooled in a deep freezer, then washed with cold ether and dried for 24 hours in a desiccaor over CaCl2, the crystalline product represented 78% conversion to oxalate.

Recrystallization was carried out from ethanol-ether mixture.

Rf of the free base = 0.4 Yield of the free base = 75% Yield of the oxalate = 78% M.p. 135-7°C. Anal for C-\9H25O4N. (COOH) ₂

C% H% N%

Theoretical 59.85 6.45 3.32

Found 59.88 ' 6.52 3.30

^" ΗNMR (CDCI3) =57.31 (s, 5H, C ₆ H ₆ ) 5.13-4.88 (S,

1H, C3 tropine) 4.53 (s, 1H, CH" ^C 6 ^H 5). 4.19 (q, 2H, J =

" ^" ^ ^• COOR 7Hz, -COOCH. ₂ CH ₃ ) 3.29-2.9 (br.s, IK, C-] + C ₅ of tropine), 2.83-1.6[m, 11H, N-CH3 (s, 2.25)+, bicyclic envelop of tropine.

According to the microanalytical data and NMR spectra, the obtained compound has the following structure:

EXAMPLE 3

Synthesis of Methyl ( ±)-c_-(carboxy)-8-azabicyclo- [3 _* 2»1]oct-3-yl-benzeneacetate a) Synthesis of methyl hydrogen phenylmalonate (new method)

Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 ml) was treated with thionyl chloride (8.92 g, 5.4 ml, 0.071 mol) and one drop of N,N-dimethyl formamide. The mixture was heated at 40-50 C for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 ml) and the solution was

treated with methyl alcohol (0.075 mol, 3 ml) and refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed with water. The organic layer was extracted with saturated solution of sodium bicarbonate until alkaline. The combined extracts were washed with ether and the aqueous layer acidified with 5N HC1 to pH1. The precipitated oil was extracted with CH2CI2 (3x50). The combined extracts were washed with water (4x50) and dried over anhydrous MgSf_>4. The oil product crystallized on standing.

Yield - 6 g (41.2%) M.p. - 86-88 ^β C as reported, b) Synthesis of methyl phenylmalonyl chloride

The previously prepared ester (2.94 g, 0.01 mol) was mixed with thionyl chloride (5 ml) and heated at 70 ^β C for one hour under anhydrous condition. The obtained liquid was evaporated under reduced pressure. Anhydrous benzene (10 ml) was added to the residue and redistilled again to remove any residual thionyl chloride. c) Esterification of methyl phenylmalonyl chloride and tropine

The previously prepared acid chloride was dissolved in 10 ml of dry benzene and was added dropwise with stirring for half an hour to a solution of dry tropine (2.8 g, 0.02 mol) in dry benzene. The mixture was stirred at room temperature for 24 hours and filtered. The filtrate was washed with water until neutral. The organic layer was dried over anhydrous MgS(_>4 and the solvent evaporated. The obtained oily base was purified by conversion into oxalate salt by adding an ether solution of oxalic acid to a solution of the base in ether. By scratching the mixture and keeping in a refrigerator overnight, a white solid product was separated. Rapid filtration and drying in a vacuum desiccator over anhydrous CaCl2 was carried out.

Recrystallization from methanol-ether mixture gave white crystalline product. f of the free base = 0.41 Yield of the free base = 1 g (64.5%) Yield of the oxalate = 1.5 g (35.7%)

M.p. - 89.91'C. Anal, for C18H23O4N.(COOH)2.H 0:

£_ Hi __,

Theoretical 56.47 6.39 3.29

Found 56.48 6.2 2.94

_3H

2.23-1.4 t(m, 11H, bicyclic envelop + NCH3 (s, 223)].

According to the microanalytical data and NMR spectra, the compound has the following structure:

(C00H) ₂

EXAMPLE 4

Synthesis of isopropyl (±)- -(carboxy)-8- azabicyclo[3«2« 11oct-3-yl-benzeneacetate a) Synthesis of isopropyl hydrogen phenyl alonate

Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 ml) was treated with thionyl chloride (8.92 g, 5.4 ml, 0.07 mol) and one drop of N,N-dimethyl formamide. The mixture was heated at 40-50 ^* C for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual of thionyl chloride. The oily residue was redissolved in dry ether (40 ml), and the solution treated with isopropyl alcohol (0.075 mol, 5.76 ml), refluxed for 2 hours and worked up as before to give the titled compounds.

Yield = 60% (as reported) M.p. - 64-66 ^β C (as reported). b) Synthesis of isopropyl phenylmalonyl chloride

The previously prepared monoester (2.22 g, 0.01 mol) was mixed with thionyl chloride (5 ml) and heated at 70 ^β C for one hour under anhydrous condition. The obtained liquid was evaporated under reduced pressure. Anhydrous benzene (10 ml) was added and the mixture redistilled again. c) Esterification of isopropyl phenylmalonyl chloride and tropine The previously prepared acid chloride was dissolved in 10 ml of dry benzene and added dropwiεe with stirring for half an hour to a solution of dry tropine (2.8 g, 0.02 mol) in dry benzene. The mixture was stirred at room temperature for 24 hours and filtered. The filtrate was washed with water until neutral. The organic layer was dried over anhydrous MqSC.4 and the solvent evaporated. The obtained oily base was purified by formation of oxalate salt. An ether solution of oxalic

acid was added to an ether solution of the base. By scratching the mixture and keeping in a deep freezer for 24 hours, a white solid product was obtained. Filtration followed by drying in a vacuum desiccator over CaCl2 was carried out.

Recrystallization from methanol-ether mixture gave a white crystalline product.

Rf of the base - 0.3 Yield of the base - 2.5 g (72.4%) Yield of the oxalate - 3 g (68.9%)

M.p. - 78-80 ^β C. Anal ^, for C20 ^H 27°4 ^N « (C00H)2- ! _____. J__i

Theoretical 60.68 6.71 3.21

Found 60.41 6.77 3.13

¹ HNMR (CDCl ₃ ): δ 7.23 (s, 5H, .8 (br. s, 1H, C ₃ tropine), 4.46 (s, 3.1-2.91 (br. s, 2H, C- _] + C5 of tropine), 2.3-1.44 [(m, 11H, bicyclic envelope), + 2.2 (s, 3H, -N-C ₃ ), 1.23 (d, 6H, -CH' ^C ^3).

According to both microanalytical data and NMR spectra, the obtained compound has the following structure:

(C00H) ₂

EXAMPLE 5

Synthesis of cyclohexyl (±)-g-(carboxy)-8-methyl- 8-azabicyclo-[3.2.1]oct-3-yl-benzeneacetate a) Preparation of cyclohexyl hydrogen phenylmalonate Phenylmalonic acid (13.5 g., 0.07 mol) in dry ether (40 ml) was treated with thionyl chloride (8.92 g, 5.4 ml, 0.07 mol) and one drop of N,N-dimethyl formamide. The mixture was heated at 40-50 ^β C for 3 hours. The clear solution was distilled under vacuum. The oil residue redissolved in dry ether (40 ml), the solution was treated with cyclohexyl alcohol (0.075 mol, 7.9 cc) and refluxed for 2 hours. The mixture was worked up as before to give an oily product which crystallized on standing. Recrystallization was carried out from benzene-petroleum ether (40-60 ^β C) mixture to give a white crystalline product.

R _f - 0.76 M.p. - 80-2 ^β C Yield - 12.5 g (64.14%). Anal, for C-\ - -\ ~0^ C% H_%_

Theoretical 68.69 6.9

Found 68.79 6.92

¹ HNMR (CDCI3): 6 8.96 (s, 1H, -COOH) , 7.3 (s, 5H, C ₆ H ₅ ), 4.6 (s, 1H, CH' ^C 6 ^H 5 ) , 1.96-1.10 (br. s, 11H,

~^C00R C ₆ H11 ⁾ .

According to the previous data, the synthesized compound has the following structure:

b) Synthesis of cyclohexyl phenylmalonyl chloride The cyclohexyl ester prepared above (2.6 g, 0.01 mol) was mixed with thionyl chloride (5 ml) and heated at 70 ^* C for one hour under anhydrous condition. The obtained liquid was evaporated under reduced pressure. Anhydrous benzene (10 ml) was added to the residue and redistilled again to remove any residual thionyl chloride. The oily product was solidified on standing and was used for the next step without further purification. c) Esterification of cyclohexyl phenylmalonyl chloride and tropine

The acid chloride was dissolved in 10 ml of dry benzene and added dropwiεe with stirring for half an hour to a solution of dry tropine (2.8 g, 0.02 mol) in dry benzene. The mixture was stirred at room temperature for 24 hours and filtered. The filtrate was washed with water until neutral. The organic layer was dried over anhydrous MgS04 and the solvent evaporated. The obtained oily base was converted into oxalate salt by adding an ether solution of oxalic acid to a solution of the base in ether. By scratching the mixture and cooling in a refrigerator, a white solid product was separated. Filtration and drying over CaCl2 in a vacuum desiccator was carried out. On recrystallization from methanol-ether mixture, a white crystalline product was obtained.

R _f - 0.22

Yield of the base - 3 g 77% Yield of the oxalate - 3. 1 g 63% M .p - 160 ^β -2'C . Anal , for C23H31 O4. ( C00H ) 2

___l .il ___i

Theoretical 63.15 6.99 2.94

Found 63.05 7.26 2.78

1__NMR (CDC1 ₃ ): δ 7.33 (s, 5H, CgHs) , 4.61 (s, 1H,

CH ^C 6 ^H 5) _f 3.2-2.9 (br s, 2H, Ci + C ₅ of tropine); -^COOR 2.23-1.06[m, 21H, bicyclic envelop + N-CH3 (s, 2.23) +

CgHn (br s, 1.66-1.06)] .

According to the microanalytical data and NMR spectra the obtained compound has the following structure:

EXAMPLE 6

Preparation of: Tropanyl hydrogen phenylmalonate (±)- - (carboxy)-8-methyl-S-azabicyclo-[3 - 2 - ] ]oct-3-yl benzeneacetic acid

Phenylmalonic acid (2.5 g, 0.014 mol) in dry ether (10 ml) was treated with thionyl chloride (1.78 g, 1.09 ml, 0.01 mol), and N,N-dirnethyl formamide (two drops). The mixture was. heated at 50 ^β -60 ^* C for 2 hr. Ether and excess thionyl chloride were removed and three separate portions of dry benzene were added and removed the same way. The residue (1.9 gm, 0.01 mol) was dissolved in 20 ml dry benzene and added dropwise over a period of 0.5 hr to a stirred solution of dry tropine (2.82 g, 0.02 mol) in 10 ml dry benzene. The mixture was stirred at ambient

temperature for 24 hr and filtered. The filtrate was washed with water until neutral and the organic layer was dried over anhydrous gSU and evaporated. The oily product was transformed to the corresponding oxalate by addition of an ethereal solution of oxalic acid to the solution of the compound in ether. A white solid product was obtained by scratching the ethereal solution and keeping in a refrigerator overnight.

The white solid was isolated by filtration and thoroughly washed with ether and dried to give 0.7 gm (23%). R _f (CHC1 ₃ : MeOH 3:1)=0.23, .p. 112-115 ^β C.

Anal, for C ₁₇ H ₂ ιθ4 (COOH) 0.5H ₂ O

£ϊ. ϋ HI

Theoretical 56.71 6.01 3.48

Found 56.94 6.26 3.32

¹ HNMR (CDCI3) δ 7.16 (s, 5H, Cgj^) 4.88 (s, 1H, CH^ ^C 6 ^H 5); 3.13-2.86 (br ε, 2H, Ci+Cc of tropine); ^N C00R 2.23-1.7 [m, 11H, bicyclic envelope of tropine + N-CH3

(s, 2.23)] .

According to the above data, the obtained compound has the following εtructure:

(COOH) ₂

EXAMPLE 7

Preparation of: Cyclohexyl (± )-cr(carboxy)-8-methyl- 8-azabicyclo-[3 - 2 -1]oct-3-yl benzeneacetate methiodide

A solution of cyclohexyl (±)-α-carboxymethyl- 5 8-methyl-8-azabicyclo (3'2*1 )oct-3-yl benzeneacetate

(3.85 g, 0.01 mol) and 10 ml of methyl iodide in 30 ml of dry benzene was stirred at room temperature for 6 hr. The mixture was filtered and the solid was dried and recrystallized from methanol-ether mixture to give a 0 yellowiεh-white solid product.

R _f - 0.35 Yield - (55.9%) M.p. - 228-230 ^β C. Anal for C24H34INO4.O.25 H ₂ 0 5 C% H% N%

Theoretical 54.19 6.53 2.63

Found 54.00 6.48 2.50

^" •HN P (DMSO-d ₆ ) δ 7.33 (s, 5H, C ₆ H ₅ ) ; 4.99 (ε, 1H,

-?0 CH" ^C 6 ^H 5 + C3 of tropine); 3.1-1.4 [m, 24H, M+CF3 (ε, - I00R __ ~ ~

3.1) + N ⁺ CH3 (s, 3) + bicyclic envelop + CgH-n

(br s, 1.7-1.4)] .

Accordinq to the previouε data, the obtained compound haε the following εtructure:

COOC Λi

EXAMPLE 8

Preparation of: Ethyl (±)-α-(carboxy)-8-methyl-8- azabicyclo[3'2»1]oct-3-yl benzeneacetate methiodide

A solution of ethyl (±)-α-(carboxy)-8-methyl-8- azabicyclo [3 ^« 2 ^« 1]oct-3-yl benzeneacetate (3.31 σ, 0.01 mol) and 10 ml of methyl iodide in 25 ml of dry benzene was stirred at room temperature for 6 hr. The mixture waε filtered and the solid was dried and recrystallized from alcohol-ether mixture.

R _f - 0.41

M.p. - 232-234 (dec) Anal ^, for C ₂ oH28l ^N0 4

C% H% N%

Theoretical 50.75 5.92 2.96 Found 50.55 5.97 2.97

¹ HNMR (DMSO-dg) δ 7.28 (s, 5H, Cg_H ₅ ; 4.96 (ε, ^" 1H, ^CH rnn? ' ' ^{13 (q} ' ^2H ' ^{J = 7HZf} ~ ^oc l2C ^H 3 ^)' 3.23-1.9 [ , 14H, bicyclic envelop + N ⁺ CK ₃ (s, 3.23) + 1.6 (t, 3H,

J = 7Hz, -OCH2CH3) .

According to the previous data the compound has the following structure:

EXAMPLE 9

Preparation of: Methyl ( ±)-c.-(carboxy)-8-methyl-8-aza- bicyclo[3« 2*1]oct-3-yl-benzeneacetate dimethylsulfate

A solution of methyl (±)-α-(carboxy)-8-methyl- 8-azabicyclo[3«2*1 ]oct-3-yl-benzeneacetate in dry ethyl ether and dimethylsulfate (2 x moles of the ester), was stirred at room temperature overnight. The white solid was filtered, dried, and recrystallized from methanol-ether. M.p. - 138-140 ^* C Anal, for C ₂ oH29N0 ₈ S-1/2 H ₂ 0

C% H% N% S%

Theoretical 53.08 6.68 3.09 7.08

Found 53.06 6.65 3.01 7.14

^■ E NMR (DMSO-dg) δ 7.4 (s, C H ₅ ); 5.1 (ε, Cl ; 3.8 (s, -OCH ₃ ); 3.4 (s, CH3SO4); 3.1 and 3 (s, ^ ^CH 3) 2.7-1.6 (m, bicyclic ring).

\ CH ₅ According to the previouε data the compound has the following structure:

COOCH0,

EXAMPLE 1 0

Preparation of: Ethyl (± )- -(carboxy)-8-methyl-8- azabicyclo[3• 2 - 1]oct-3-yl-benezeneacetate dimethylsulfate A solution of ethyl (±)- -(carboxy)-8-methyl- 5 8-azabicyclo[3*2*1]oct-3-yl-benzeneacetate in dry ethyl ether and dimethylsulfate (2x moles of the ester) was stirred at room temperature overnight. The white solid was filtered, dried and recrystallized from methanol-ether. M.p. - 165-167 ^* 0 Anal, for C ₂ ιH ₃₁ N0 ₈ S

C% H% N% S%

Theoretical 55.13 6.83 3.06 7.01

Found 55.10 6.87 2.96 7.02 =5 ^' 7.4 (s, CgHs); 5.1 (s, -CH CH ₃ ) ; 3.4 (s, CH ₃ SO4); 3.1 2.8-1.7 (m, bicyclic ring); 1.2 (t, 0 According to the previous data the compound has the following structure:

COOC7H 5

EXAMPLE 1 1

Preparation of: Isopropyl ( ±)-α-(carboxy)-8-methyl-8- azabicyclo[3«2« 1]oct-3-yl-benzeneacetate dimethylεulfate A solution of isopropyl (±)-α-(carboxy)-8- methyl-δ-azabicycloU^'1]oct-3-yl-benzeneacetate in dry ethyl ether and dimethylsulfate (2x moles of the ester) was stirred at room temperature overnight. The white solid was filtered, dried, and recrystallized from methanol-ether. M.p. - 128-130 ^* Anal, for C22H-33NO8S

C% H% N% S%

Theoretical 56.03 7.05 2.97 6.80 Found 55.91 7.08 2.96 6.78

Accord ng to t e prev ous ata, the compoun has the following structure:

C0CCH-CH- I ^J CH-

EXAMPLF 1 2

Preparation of: Cyclohexyl ( ±)- -(carboxy)-8-methyl-8- azabicyclo[3«2*1]oct-3-yl-benzeneacetate dimethylsulfate A solution of cyclohexyl (±)-α-(carboxy)-8- methyl-δ-azabicyclo _. S'Σ'^oct-S-yl-benzeneacetate in dry ethyl ether and dimethylsulfate (2x moles of the ester) was stirred at room temperature overnight. The white solid was filtered, dried, and recrystallized from methanol-ether. M.p. - 196-198 ^* Anal, for C25H37NO8S. 1/2 H2O

C% H% N% S%

Theoretical 57.67 7.36 2.69 6.16

Found 57.91 7.15 2.68 6.17

¹ H NMR (DMSO-dg) δ 7.4 (s, C H ₅ (s, 3.8 (s, CH3 SO4); 3.1 and 3 (s, ); 2 bicyclic ring, CgH-ji).

According to the previous data the compound haε the following εtructure:

C00C ₆ H _1:L

EXAMPLE 1 3

Kinetic Studies of the New Tropanyl Esters

A high pressure liquid chromatography (HPLC) method was used for the determination of rate of hydrolysis of the newly prepared tropanyl esters in aqueous buffered solution at pH 12.0 and in human plasma.

The chromatographic analysis was performed in a system consisting of LCD/Milton Roy Consta Metric III metering pump and LCD UV III Monitor Detector operated at 254 nm. A 30 cm x 3.9 mm (internal diameter) reverse phase ASI/U Bondpak C18 column operated at ambient temperature was used for the analysis. The mobile phase consisted of 32% acetonitrile in 0.01 M potassiur. dihydrogen phosphate, 0.004 M 1-octaneεulfonic acid, εodium in 0.1% acetic acid at a flow rate of 2.3 ml/min.

Determination of the hydrolytic rate constants in aσueouε buffered solution at pH 12 at 37 ^* C

Sodium hydroxide and sodium dibasic phosphate were used to prepare the buffer at pH 12. The ionic strength was maintained at 0.1 M with sodium chloride.

One hundred icroliterε of a freεhly prepared solution of the compound in methanol waε added to 10 ml buffered εolution, previously equilibrated to 37"C in a water bath and mixed thoroughly to make an initial concentration of 6 x 10~ ³ mol. liter ^"1 . Saπpleε of 100 μl were injected into the column at various time intervalε. The rate conεtantε, half-lives, and standard errors were calculated and the reεults are listed in Table 1. The following retention times at a flow rate of 2.3 ml/min using 32% acetonitrile are:

N.B. Compound (1) had a retention time of 3.0 minutes.

Compound (2) had a retention time of 7.3 minutes.

Compound (3) had a retention time of 9.3 minutes.

Compound (5) had a retention time of 4.7 minutes. Compound (7) had a retention time of 3.5 minutes.

At a flow rate of 2.0 ml/min, compound 7 had a retention time of 4.0 in. A mobile phase of 40% acetonitrile was used to separate compounds 4 and 6 at a flow rate of 2.0 ml/min.

Compound (4) had a retention time of 8.0 minutes.

Compound (6) had a retention time of 6.6 minutes.

TABLE 1

The observed First Order Hydrolytic Rate Conεtantε (k), the standard error (S.E.) and half-life (t 1/2) in 0.01 N sodium hydroxide at pH 12.0, at 37°C

Compound No. K ^a ± S.E (min ^"1 ) t 1/2 (min)

-CH ₃ 1.43 ± 0.12 x 10 ^"1 4.80

-CH ₂ -CH ₃ 16.9 ± 0.15 x 10 -2 4.08

CH3

/

^■ CH 30 ± 0.77 x 10" ³ 22.81

CH-

a) Average of three runs ± S.E.M.

Compound ( 5 )

COOCH ₂ CH ₃

. K ± S.E. (min-1) = 80.8 ± 0.75 x 10~2 t 1/2 (min) = 0.85.

The kinetic studies for the hydrolyεiε of the new tropineε in aqueouε buffer solution at pH 12.0 and in human plasma was carried out using HPLC method.

EXAMPLE 14

Determination of the hydrolytic rate constants in aqueous buffer at pH 12.0

The previous method adapted for the hydrolysis of compounds 1, 2, 3 and 5 was used for the determination of rate of hydrolysis of compounds 4, 6 and 7. In case of compounds 4 and 6, the mobile phase is 40% acetonitrile, 0.01 M KH2PO4, 0.Q4M 1-octanesulfonic acid sodium salt and 0.1% HAC, at a flow rate 2 ml/min. Compounds 4 and 6 had retention times of 8.0 and 6.6 min, respectively, as shown in Table 2. Compound 7 had a retention time of 3.1 min at a flow rate of 2.3 ml/min and 3.5 min at 2.0 ml/min.

TABLE 2

The observed pεeudo firεt order hydrolytic rate conεtants (K) were half lives (t 1/2) in 0.01 M sodium hydroxide at pH 12 and 37 ^* C

Compound No. K (min- --l ¹ )a S.E.M. t 1/2 (min)

H 19.8 ± 0.3 x 10~ ⁴ 350

a) Average of three runs- b) The quaternary iodide salt of the ester 4.

EXAMPLE 1 5

Determination of the enzymatic hydrolytic cleavage rates in human plasma at 37 ^* C

Freshly collected plasma was used which contained about 80% plasma diluted with anticoagulant citrate phosphate dextrose solution, U.S.P.

A 100 μl volume of a freshly prepared solution of the compound in methanol was added to 10 ml plasma, previously equilibrated a 37 ^* C in a water bath, and mixed thoroughly to result in an initial concentration of 6 x 10 ^-3 mol. liter ^-1 . One ml samples of plasma were withdrawn from the test medium, mixed immediately with 3 ml ice cold acetonitrile, centrifuged and the supernatant analyzed by HPLC. The first order hydrolytic rate constant was determined by following the disappearance of the compound aε function of time. The reεultε are given in Table 3.

TABLE 3

The observed first order hydrolytic rate constants (K) and half lives (t 1/2) in human plasma at 37 ^* C

Compound R K (min" ¹ ) ± S.E.M. t 1/2 (hr)

No.

2 -CH ₂ CH ₃ ^a 15.0 ± 0.3 x 10-5 77.4

3 -C 6.27 ± 0.3 x 10 ^-5 185.5

^CH ₃

4 -f S 4.44 ± 0.4 x 10- 269.8

5 -CH ₂ CH ₃ b 14.1 ± 0.6 x 10" ⁵ 82.2

6 - S 6.31 ± 0.8 x 10-5 183.2

a) Average of 4 runs, the rest of data are average of 3 runs. b) The quaternary iodide salt of the eεter 2. c) The quaternary iodide salt of the ester 4.

EXAMPLE 1 6

Determination of the rate of hydrolysis of tertiary ethvl ester (2) and rate of formation of itε deqradation product (7) in 0.01 M NaOH at pH 12 and 37 ^* C The mobile phase used for the separation of compound (2) and its degradation product, the half ester (7) consisted of 32% MeCN, 0.01M KH ₂ P0 ₄ , 0.004M 1-octanesulfonic acid sodium salt and 0.1% acetic acid. At flow rate of 1.5 ml/min (2) and (7) have retention times of 9 min and 4.6 min, respectively. Procedure

100 icroliters of a freshly prepared solution of compound (2) in methanol was added to 10 ml buffered solution (pH 12), previously equilibrated to 37 ^* C in a water bath to result in an initial concentration of 6 x 10"3 mol liter" ¹ . Samples of 1 ml were taken at time intervals and mixed with 3 ml of acetonitrile. 100 microliters of the collected samples were injected and disappearance of (2) and formation of (7) was followed by HPLC.

The resultε are given in Table 4.

TABLE 4

Rate of hydrolysis of tertiary ethyl eεter (2) to the half eεter (7) in 0.01 N NaOH pH at 37 ^* C

Compound No. K ₀ b _s d( i ⁿ ~ ¹ ) ^± S.E.M. t 1/2 (min)

16.5 ± 0.58 x TO" ² 4.19 0.14

1.68 ± 0.34 x 10~ ¹ 3.79 ± 0.66

EXAMPLE 17

Rate of hydrolysis of tropanyl hydrogen phenyl malonate (7) to the dibasic acid (phenyl alonic acid) in 0.01 N sodium hydroxide, pH 12 at 37"C The previously described method for the determination of rate of hydrolyεis of compound (2) waε followed for the determination of hydrolysis of compound (7).

The disappearance of compound (7) was followed by HPLC.

The concentration of the formed dibasic acid was determined by HPLC. 15% acetonitrile, 0.01M KH ₂ PO4 and 0.1% acetic acid was used as a mobile phase. At a flow rate of 2 ml/min, the product haε a retention time of 4 min.

The collected samples after determination of rate of disappearance of compound (7) were used for the determination of rate of formation of the hydrolysis product (8). 100 microliters of the sample was injected and the formation of the product was followed by HPLC.

The results are given in Table 5.

TABLE 5

Compound No. K ^ ^min ^-"1 ■ ^{± S} * ^E « ^M « - ^{1 2} (min)

7 20.9 ± 0.27 x 10-4 331.25 ± 4.31

8 21.7 ± 0.95 x TO" ⁴ 316.01 ± 33.5

EXAMPLE 1 8

Determination of the Enzymatic Hydrolysis of the New Esters in Rat Liver Homogenate at 37 ^* C

The liver homogenate was prepared by the following method. Two Sprague-Dawley rats were killed by decapitation, and the livers were removed, weighed and homogenized in a tissue homogenizer in 0.11 M aqueous phosphate buffer, pH 7.4, to make 20% liver homogenate. The homogenate was centrifuged and the supernatant was used for the test. 100 1 of 0.6 M solution of the ester in methanol was mixed with 10 ml of the homogenate, previously equilibrated to 37 ^β C in a water bath, to result in an initial concentration of 6 x 10" ³ mol/liter" ¹ . Samples of 1.0 ml were withdrawn at time intervals from the medium, added immediately to 3 ml ice-cold acetonitrile, shaken vigorously, and placed in a freezer. When all samples had been collected, they were centrifuged, and each supernantant was analyzed by HPLC. The results are shown in Table 6.

TABLE 6

Rates of hydrolyεiε in liver homogenate of selected tropanyl esters

Compound

No. R K (min ^-1 ) ± S.E. t 1/2 (min)

-CH ₂ CH ₃ ^a 1.99 ± 0.996 x 10" ¹ 3.48

_/ CH ₃ -CH 97.2 ± 0.76 x 10~3 7.12 CH ₃

5 -CH ₂ CH ₃ ^b 10.5 ± 0.28 x 10~ ² g.6

6 10.4 ± 0.23 x 10" ³ 66.8

a) Mobile phase used for Compound 2, 3, and 5 was 32% acetonitrile, 0.01M KH ₂ P0 , 0.004M 1-octane εulfonic acid sodium salt and 0.1% HAC. Mobile phase used for compound 4 and 6 was 40% acetonitrile, 0.01M KH2PO4, 0.004M 1-octane-sulfonic acid sodium salt and 0.1% HAC. b) It is 2 - methiodide. c) It is 4 - methiodide.

EXAMPLE 1 9

Pharmaceutical Study of the New Tropanyl Esters

The anticholinergic activity of all the new compounds was investigated _in_ vitro by studying the inhibitory action of the drugs on carbachol-induced spasms of strips of ileum from freshly killed guinea pigs. The terminal ileum from guinea pig (200-500 g) was cut into 2-3 cm strips and suspended in freshly prepared Tyrode's solution in 40 ml organ bath. The solution was aerated with 95% oxygen and 5% carbon dioxide at 37°C. A tension of 1 g was applied to the tissue, and cumulative-response curves recorded with carbachol until constant responseε were obtained. A concentration of the antagoniεt waε then added to the bath and after 10 εeconds, further concentration response curves to carbachol were established. This procedure was then repeated using increasing concentrations of the antagonist. EC50 was calculated for carbachol alone and for carbachol in the presence of the various antagonist concentrations. P 2 value for each tested compound is listed in Table 7. Atropine was used as standard for comparison. The P 2 waε calculated aε followε:

PA2 = log (-^--1) —log [antagoniεt]

A = EC50 or carbachol in preεence of the antagoniεt a = EC50 for carbachol alone before adding antagonist

TABLE 7

Compound No. ^a PA ₂

Atropine 8.29

-CH ₃ 6.55°

-CH ₂ CH ₃ 6.72

< 6.59°

-CH ₂ CH ₃ 7.86

H 6.20

a) These results were average of two experiments. b) Average of three experiments. c) Quaternary iodide salt of tertiary ethyl ester, d) Quaternary iodide salt of cyclohexyl ester.

EXAMPLE 20

Synthesis of isopropyl ( t )-g-(carboxy)-8-methyl-8- azabicvclo[3«2« 1 ] oct-3-vl-benzeneaceta e methiodide

To a solution of 2.07 g (0.006 mol) of isopropyl (±)-cι-(carboxy)-8-methyl-8-azabicyclo-[3 -2 *1]oct- 3-1-benzeneacetate in 20 ml of dry benzene was added 6 ml methyl iodide and the mixture was stirred at room temperature for 6 hr. The yellowish white solid product was filtered, dried and crystallized from ethanol-ether mixture to yield 1.8 g (61.56%) of the title compound m.p. 251-254°C.

¹ H NMR (DMSO-dg) ξ 7.3 (s, 96 (s, 3H C ₃ of tropine + -COOCH(CH ₃ ) ; 3.16-1.. [m, 14H, N ⁺ CH ₃ (s, 3.16) + 6) + bicyclic envelop of tropine]; 1.27 (br s, 6H,

Anal, for C21H30INO4.0.5 H ₂ 0

C% H% N%

Theoretical 50.81 6.29 2.82

Found 50.67 6.25 2.95

The pharmacological result: PA ₂ = 7.61.

EXAMPLE 21

The mydriatic activity of the compounds iε illustrated by the following procedure.

The mydriatic activity of the soft ester drugs (Compound 5) was evaluated in 0.9% saline solution at concentrations of 0.05% and 0.1% compared to 0.1% tropica ide (Mydriacyl®). Normal New Zealand albino rabbits of either sex, weighing about 2 kg were employed. The animals were placed in wooden restraining boxes. Standard doses of 50 μl were applied to the rabbits' eyes and pupillary changes were measured in a light and temperature controlled room. The degree of pupil dilation, in millimeters, was measured with a Starrett micrometer held at a constant distance at time intervals of 15, 30, 60 90, 120, 180, 240, 300 and 360 minutes. The differences in the same animals between the pupil diameter of the eye with drug versus the other eye with saline was recorded. Each point on the graph is the average obtained on 3-6 animals. The recovery time is defined as that time required for the pupil diameter to return to 1.0 millimeter in diameter.

The results are set forth in Fig. 1 which depicts mydriasiε as a function of time. Tropicamide iε typical of the shortest acting of the commercially available anticholinergic mydriatic agents. The active agent therein is tropicamide - chemical name =

Benzeneacetamide N-ethyl-α-(hydroxymethyl)-N-(4-pyridinyl- methyl)-. As is apparent from the results depicted in Fig. 1, the "recovery time", i.e., recovery from mydriasiε, iε much shorter with the compoεitions and methods of the invention than with the commercially available products.

Tables 8, 9 and 10 below set forth yield and analysiε data for compounds depicted therein prepared according to the above-deεcribed procedureε:

TABLE 8

OXALATE SALTS OF SOFT ANTICHOLINERGIC AGENTS

Compd m.p, Yield Foπmila Calcul ated Found 4

Or % CX . HX NX CX HX NX

11 H 112-115 23 ^C 17 ^H 21 ^N0 4 ^'C 2 ^H 2°4 56.71 6.01 3.48 56.94 6.26 3.32 0.5H ₂ 0

Va CH ₃ 89-91 64.5 C ₁₈ H ₂₃ N0 ₄ -C ₂ H ₂ 0 ₄ .H ₂ 0 56.47 6.39 3.29 56.48 6.2 2.94

Vb CH ₂ CH ₃ 135-137 75 ^C 19 ^H 25 ^N0 4 ^#C 2 ^H 2°4 59.85 6.45 3.32 59.80 6.52 3.3

Vc CH(CH ₃ ) ₂ 70-80 72.4 C ₂₀ H ₂₇ N0 ₄ .C ₂ H ₂ 0 ₄ 60.68 6.71 3.21 60.41 6.77 3.13

Vd ^C 6 ^H 11 160-162 77.91 C ₂₃ H ₃₁ 0 ₄ -C ₂ H ₂ 0 ₄ 63.15 6.99 2.94 63.05 7.26 2.78

Al l compounds were recrystal l ized from methanol-eth er.

TΛI.I.P. 9 QUATERNARY IODIDES

COOR

σ.

Comp m.p. Cryst. Solvent Yield Formula Calculated Found °C % C H N H

V lb -CII ₂ CH ₃ 232-234 (dec) methanol-ether 50.9 C ₂₀ ll ₂₈ IN0 ₄ 50.75 5.92 2.96 50.55 5.97 2.97

Vic -c.i(ci( ₃ ) ₂ 251-254 othanol-ether 61.56 C ₂₁ H ₃₀ IN0 ₄ 50.81 6.29 2.82 50.67 6.26 2.95 0.5H-.0

Vld

^C 6»ll 228-230 methanol-ether 55.9 C ₂₄ H ₃₄ IN0 ₄ 54.19 6.53 2.63 54.00 6.48 2.50 0.25H ₂ 0

TΛBI.l. 10 qUATERHAIlY DIHETIIYLSULFΛTES

Compd R m.p. Cryst. Solvent Yield Formula Calculated Found o- X

Vila Cll ₃ 138-110 Methanol/Ethor 22 ^c ₂ 0 " ₂ 9 ^M0 o ^s* l ^H 2° ^S3 - ^{00 6} ' ^{60 3,} ° ^{9 7,0} ° ^{53,06 6} ' ^{65 3} - ^{01 7>H}

VI lb C _Z H ₅ 165-167 Methanol /Ether 62 C ₂₁ H _3j N0 ₀ S 55.13 6.83 3.06 7.01 55.10 6.87 2.96 7.02

Vile CM(CII ₃ ) _Z 128-130 Methanol/Ether 40 C _2z H ₃₃ ..0 ₀ S 56.03 7.05 2.97 6.80 55.91 7.08 2.96 6.78

VI Id C ₆ H _π 196-190 Methanol/Ether 36 C^H.-NOgS-.H-O 57.67 7.36 2.69 6.16 57.91 7.15 2.68 6.17

Table 11 sets forth hydrolysis kinetic data in various media for several compounds according to the invention.

TΛI.1.I. 11

HYDROLYSIS KINETICS IN AQUEOUS SOLUTION (pH 12), HUMAN PLASMA (37°C), AND RAT LIVER HOMOGENATE (37°C) t 1/2 (Min) t 1/2 (h) t 1/2 (Min)

JCOUS SOLN, pll 12 ^a , 37°C HUMAN PLASMA, 37°C ^a RAT LIVER HOMOGENATE,

< ^k obsd ^{min"1 )} < ^k obsd ^ra,n"1 ) < ^k obsd ^{min"l )}

I I H 350 . (19.8 + 0.3 x 10 ^"q )

Va Me 4.00 . (1.43 +. 0.12 x 10 ^"1 )

Vb Et 4.08 , 77.4 3.48 (1$.9 + 0.15 X lO ^" ^ (15.0 + 0.3 x 10 ^" (1.99 + 0.996 x 10 .- ^" I'I)

Vc i-Pr 22 8 185.5 7.12 , (30 _+ 0.77 X 10 ^"3 ) (6.27 + 0.3 x 10 - ^J 5)t (97.2 + 0.76 x 10 ^"J )

Vd c-llexyl 102 . 269.8 18.7 , (379 +_ 0.0 x 10 ^'s ) (4.44 ^■ _ 0.4 x 10r,- ^" 5 ³ .) (37.0 _ 0.3 x 10 ^"J )

Vlb Et (N*) ^b 0.05 , 02.2 6.6

(80.8 +.0.75 x 10 ^"Z ) (14.1 iθ!β x 10 ^"5 ) , (10.5 _ 0.20 x 10 ^"2 )

Vld c-llexyl (ll ⁺ ) ^b 1.28 . 103.2 , 66.8

(5.43 +.0.1 x 10 ^" ') (6.31 +. O.β x 10 ^"a ) (10.4 ± 0.23 x 10" ³ . ^a Average of three runs +_ SEM. ^b Tests were performed with the quaternary methiodide salts.

Table 12 sets forth anticholinergic activities for various of the compounds according to the present invention. See Table 11 for the identities of the compounds identified by Roman numerals. The activities were obtained according to the method described in Example 19.

TABLE 12

COOR

ANTICHOLINERGIC ACTIVITY OF SOFT ATROPINE AGENTS

SOFT DRUG I PA ₂ 1 ^

R TERTIARY AMINE QUATERNARY AMINE ³ I

H 6.20 ( I I)

Me 6.55 (Va)

Et 6.72 (Vb) 7.85 (VIb)

1-Pr 7.55 (Vc) 7.61 (VIcJ c-Hexyl 6.59 (Vd) 7.35 (VId)

Atropine 8.29

•'Test s were carried out wi th the qua ternary inethiodide soft esters .