US3472861A

US3472861A - N-substitution products of norscopolamine and quaternary salts thereof

Info

Publication number: US3472861A
Application number: US611262A
Authority: US
Inventors: Karl Zeile; Rolf Banholzer; Gerhard Walther; Werner Schulz; Helmut Wick
Original assignee: CH Boehringer Sohn AG and Co KG
Current assignee: CH Boehringer Sohn AG and Co KG; Boehringer Ingelheim GmbH
Priority date: 1966-01-26
Filing date: 1967-01-24
Publication date: 1969-10-14
Anticipated expiration: 1986-10-14
Also published as: FR6937M; FI48189B; IT1117193B; DE1670048A1; CH481922A; US3557125A; DE1670048B2; IL27311A; YU10467A; DK120756B; FR1558279A; IT7949430A0; GB1178305A; YU32683B; FI48189C; DE1670048C3

Description

United States Patent 4 Int. Cl. C07d 99/04, 43/16; A61k 27/00 US. Cl. 260-292 3 Claims ABSTRACT OF THE DISCLOSURE The compounds are of the class of N-substituted derivatives of norscopolamine and quaternary ammonium salts thereof, useful as central nervous system depressants, anticholinergics and spasmolytics.

This invention relates to novel N-substituted derivatives of norscopolamine and quaternary ammonium salts thereof, as well as to a process of preparing these compounds.

More particularly, the present invention relates to (1) Novel racemic or optically active norscopolamine derivatives of the formula wherein R is straight or branched acyclic hydrocarbyl of 2 to 16 carbon atoms, monocyclic or bicyclic aryl, halo-substituted monocyclic or bicyclic aryl, alkoxy, alkoxycarbonyl, aliphatic or aromatic acyl of 1 to 10 carbon atoms, aliphatic or aromatic acyloxy of 1 to 10 carbon atoms, monoalkylamino of 1 to carbon atoms, dialkylamino of 2 to 20 carbon atoms, aralkylamino, hydroxy-substituted straight or branched alkyl of 1 to 16 carbon atoms, amino-substituted straight or branched alkyl of 1 to 16 carbon atoms, theophyllinyl-substituted straight or branched alkyl of 1 to 16 carbon atoms, cyano-substituted straight or branched alkyl of 1 to 16 carbon atoms, or cycloalkyl, and

R is hydrogen or aliphatic, aromatic or araliphatic acyl of 2 to 16 carbon atoms,

(2) Non-toxic, pharmacologically acceptable acid addition salts thereof, and

(3) Quaternary salts thereof of the formula R and R have the same meanings as in Formula I,

X is the anion of an acid, such as a hydrohalic acid or an aliphatic or aromatic sulfonic acid, and

R is acyclic hydrocarbyl of 1 to 16 carbon atoms.

The norscopolamine derivatives of the Formula I above may be prepared by reacting norscopolamine or an O- acyl derivative thereof, that is, a compound of the formula wherein R has the same meanings as in Formula I, with a molar equivalent of a compound of the formula RX (III) 'ice wherein R has the same meanings as in Formula I, and X has the same meanings as in Formula la.

The reaction between compounds 11 and III is carried out under conditions which are customarily employed for reactions of this kind, that is, in the presence of an inert organic solvent and of an acid-acceptor, and at a temperature between the solidification point and boiling point of the reaction mixture. Examples of suitable inert organic solvents are ether, lower alkanols, benzene, toluene, carbon tetrachloride and preferably acetonitrile. If reactant III is itself a solvent for compound II, then a suflicient stoichiometric excess of compound III may simultaneously serve as the solvent medium for the reaction; in other words, under these conditions the reaction proceeds without the addition of a separate solvent. Examples of suitable acid-acceptors are inorganic bases and tertiary organic bases, such as sodium carbonate and trimethylarnine. However, the use of a separate acid-acceptor is not obligatory; instead, a portion of the norscopolamine base, i.e. compound II, may simultaneously serve as the acid-acceptor. In those instances where the reaction mixture has a relatively high boiling point, i.e., in excess of 160 C., a reaction temperature of 160 C. is advantageously used.

In those instances Where the above reaction yields a compound of the Formula I wherein R is hydrogen, this reaction product may subsequently be transformed into the corresponding compound of the Formula I wherein R is aliphatic, aromatic or araliphatic acyl by reacting said reaction product with a customary acylating agent. This acylation reaction may also be carried out in the presence of an inert organic solvent of the type referred to above. Examples of preferred acylating agents are acid halides and acid anhydrides which, upon hydrolysis, form the carboxylic acid corresponding to the desired meaning of R An optically active compound of the Formula I is generally prepared from the corresponding optically active starting compound of the Formula II; however, it may also be obtained by customary separation of the racemate into its optically active components with the aid of optically active auxiliary acids, such as dibenzoyl- D-tartaric acid or d-3-bromocamphor 8-sulfonic acid. For the preparation of a racemic compound of the Formula I a racemic starting compound of the Formula II is used.

The above described process yields a tertiary norscopolamine derivative of the Formula I, which may, if desired, be transformed pursuant to customary methods into a nontoxic, pharmacologically acceptable acid addition salt thereof; this transformation may, for example, be effected by acidifying a solution of the free tertiary base with the desired acid, or by double decomposition. Examples of acids which will form nontoxic, pharmacologically acceptable acid addition salts with a norscopolamine compound of the Formula I include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, lactic acid, tartaric acid, succinic acid, maleic acid, 8- chlorotheophylline and the like. For the double decomposition method it is advantageous to select as a reaction partner for the norscopolamine derivative addition salt a salt which forms with the anion to be replaced a difficultly soluble and therefore easily separable salt. For instance, if a hydrochloride addition salt is to be transformed into another acid addition salt, it is advantageous to use as a double decomposition reaction partner for the hydrochloride the silver salt of the anion to be introduced.

If desired, a tertiary norscopolamine derivative of the Formula I may be transformed into a corresponding quaternary N-substituted norscopolammonium salt of the Formula Ia above by reacting the tertiary compound with an alkylating agent of the formula R2X V) wherein R and X have the same meanings as in Formula Ia. The quaternization reaction is carried out under the same conditions as the reaction between compounds 11 and III, except that it is advantageous to use room temperature or an only slightly elevated reaction temperature, such as from 30 to 40 C. In order to obtain an optically active quaternary salt of the Formula Ia, the corresponding optically active tertiary compound of the Formula I must be used as the starting material; similarly, a racemic quaternary salt is prepared from the corresponding racemic tertiary compound.

In those instances where the quaternization reaction yields a compound of the Formula Ia wherein R is hydrogen, this hydrogen atom may subsequently be replaced by an aliphatic, aromatic or araliphatic acyl radical of 2 to 16 carbon atoms in the same manner as described above in connection with the subsequent acylation of a tertiary compound of the Formula I wherein R is hydrogen.

The anion X- in a quaternary compound of the Formula Ia obtained by any of the above methods may, if desired, be exchanged for another anion by customary procedures, such as by double decomposition; the double decomposition reaction is carried out in the same manner and under the same conditions as the double decomposition reaction described above in connection with the conversion of an acid addition salt of a teritary compound I into another acid addition salt.

The following examples further illustrate the present invention and will enable others skilled in the art to understand the invention more completely. It should be understood, however, that the invention is not limited to the particular illustrative examples given below:

EXAMPLE 1 Preparation of -N-ethyl-norscopolamine and its hydrochloride 14.5 gm. (0.05 mol) of ()-norscopolamine and 5.4 gm. (0.05 mol) of ethyl bromide were dissolved in 30 cc. of acetonitrile, 5.3 gm. (0.05 mol) of anhydrous sodium carbonate were suspended in the solution, and the suspension was heated at the boiling point for ten hours. After a boiling time of 2.5 and 5 hours, respectively, the supply of ethyl bromide and sodium carbonate in the reaction mixture was replenished by adding each time 5.4 gm. (0.05 mol) of ethyl bromide and 5.3 gm. (0.05 mol) of anhydrous sodium carbonate. At the end of ten hours of boiling, the inorganic sodium salts which had separated out were separated by vacuum filtration, the filter cake was washed with acetonitrile, and the ace tonitrile was distilled out of the filtrate. The distillation residue was dissolved in ether, the solution was extracted with a small amount of water and then dried, and the ether was distilled off, yielding raw ()-N-ethyl-norscopolamine. The calculated amount of hydrogen chlo ride was added to the raw base, whereby the raw hy: drochloride thereof was obtained, which was recrystallized from acetonitrile. 15.1 gm. (85.1% of theory) of white crystalline (--)-N-ethyl-norscopolamine hydrochloride, M.P. 188-190 C., specific rotation CH: (H) (DH-O C-CH-CeHs-HC] CH2 CHzOH were obtained.

4 EXAMPLE 2 Using a procedure analogous to that described in Example 1, N-n-propyl-norscopolamine hydrochloride, white crystals (from acetonitrile), M.P. 177178 C., specific rotation [a] =30 C. (c.=2.0), was prepared from norscopolamine and propyl bromide. The total heating time was 20 hours, and the propyl bromide and sodium carbonate were replenished after five and eight hours of heating. The yield was 15.8 gm. (85.8% of theory).

EXAMPLE 3 Using a procedure analogus to that described in Example 1, ()-N-n-butyl-norscopolamine hydrochloride, white crystals (from acetone), M.P. l46-148 C., specific rotation [a] =28.5 (c.=2.0), was prepared from n-butyl bromide and norscopolamine. The total heating time was 20 hours, and the butyl bromide and sodium carbonate were replenished after five and eight hours of heating. The yield was 57.5% of theory.

EXAMPLE 4 Using a procedure analogous to that described in Example 1, ()-N-n-amyl-norscopolamine hydrochloride, white crystals (from acetonitrile), M.P. 160162 C., specific rotation [a] =29.5 (c.=2.0), was prepared from n-amyl bromide and norscopolamine. The total heating time was 20 hours, and the amyl bromide and sodium carbonate were replenished after five and eight hours of heating. The yield was 16.7 gm. (84.3% of theory).

EXAMPLE 5 Preparation of ()-N-n-hexyl-norscopolamine hydrobromide 14.5 gm. (0.05 mol) of ()-norscopolamine and 8.3 gm. (0.05 mol) of n-hexyl bromide were dissolved in 25 cc. of acetonitrile, and the solution was heated to its boiling point. After about 1.5 hours of boiling a crystalline precipitate of ()-norscopolamine hydrobromide separated out, which went into solution again in the course of 50 hours of boiling. Thereafter, the acetonitrile was distilled oflf, and the residue was dissolved in boiling acetone. Upon cooling the solution, a crystalline precipitate formed which was collected and recrystallized from acetone. 12.0 gm. (52.9% of theory) of white crystalline ()-N-n-hexyl-norscopolamine hydrobromide, M.P. ISO-152 C., specific rotation [a] =25 (c.=2.0), were obtained.

EXAMPLE 6 Preparation of -N-n-heptyl-norscopolamine and its hydrochloride 14.5 gm. (0.05 mol) of ()-norscopolamine were dissolved in 30 gm. of n-heptyl bromide, 26.5 gm. (0.25 mol) of anhydrous sodium carbonate were suspended in the solution, and the suspension was heated for five hours at C. Thereafter, the inorganic sodium salts which had separated out were collected by vacuum filtration, the filter cake was washed, and the excess unreacted n-heptyl bromide was distilled out of the filtrate in vacuo, leaving as a residue raw (-)-N-n-heptyl-norscopolamine. The residue Was admixed with the calculated amount of hydrogen chloride, and the product formed thereby was recrystallized from a mixture of methanol and ether. 12.5 gm. (58.9% of theory) of white crystalline ()-N-nheptyl-norscopolamine hydrochloride, M.P. ISO-157 C., were obtained.

EXAMPLE 7 Using a procedure analogous to that described in Example 6, ()-N-n-octyl-norscopolamine hydrochloride, white crystals (from acetone/ether), M.P. 153154' C., was prepared from ()-norscopolamine and n-octyl bromide. The yield was 15.5 gm. (70.7% of theory).

EXAMPLE 8 Using a procedure analogous to that described in Example 6, ()-N-isonony1-norscopolamine hydrochloride, white crystals (from methanol/ether), M.P. 191194 C. (decomposition), was prepared from (--)-nrscop0lamine and isononyl bromide. The yield was 87.3% of theory.

EXAMPLE 9 Using a procedure analogous to that described in Example 6, (-)-N-n-decyl-norscopolamine hydrochloride, white crystals (from ethyl acetate), M.P. 149-150 C., was prepared from ()-norscopolamine and n-decyl bromide. The yield was 15 gm. (64.3% of theory).

EXAMPLE 10 Using a procedure analogous to that described in Example 6, ()-N-n-undecyl-norscopolamine hydrochloride, white crystals (from acetone/ether), M.P. 128 C., was prepared from (-)-norscopolamine and n-undecyl bromide. The yield was 14 gm. (58.3% of theory).

EXAMPLE 11 Preparation of (-)-N-ethyl-norscopolamine methobromide CH CH CH: O [0 CHa-EH-CaHs 311-0 ]CH-CsH 1 B1" CH CH CH2 GHQ-0H were obtained.

EXAMPLE 12 Using a procedure analogous to that described in Example 11, -)-N-n-butyl-norscopolamine methobromide, M.P. 188-189 C. (decomposition), specific rotation [u] =26.5 (c.=2.0), was prepared from ()-N-nbutyl-norscopolamine and methyl bromide. The yield was 4.5 gm. (95.7% of theory).

EXAMPLE 13 Using a procedure analogous to that described in Example 11, (')-N-n-hexyl-norscopolamine methobromide, white crystals (from methanol/ether), M.P. 169- 170 C. (decomp.), specific rotation [u] =25.7 (c.=1.986), was prepared from (1)-N-n-hexyl-norscopolamine and methyl bromide. The yield was 16.7 gm.

(83.1% of theory).

EXAMPLE 14 Using a procedure analogous to that described in Example 11, )-N-n-heptyl-norscopolamine methobromide, white crystals (from methanol/ether), M.P. 179- 180 C. (decomposition), was prepared from n-heptylnorscopolamine and methyl bromide. The yield was 7.9 gm. (87.7% of theory).

EXAMPLE 15 Using a procedure analogous to that described in Example 11, ()-N-n-octyl-norscopolamine methobromide, white crystals (from methanol/ether), M.P. 179-180 C. (decomposition), specific rotation [a] ='-26.6 (c. =0.977), was prepared from (-)-N-n-octyl-norscopolamine and methyl bromide. The yield was 11.5 gm. (94.9% of theory).

EXAMPLE 16 Using a procedure analogous to that described in Example 11, (-)-N-isononyl-norscopolamine methobromide, white crystals (from methanol/ether), M.P. 193- 194 C. (decomposition), specific rotation C. (c.=1.0), was prepared from ()N-isononyl-norscopolamine and methyl bromide. The yield was 9.0 gm. (81.9% of theory).

EXAMPLE 17 Using a procedure analogous to that described in Example 11, (-)-N-decyl-norscopolamide methobromide, white crystals (from methanol/ ether), M.P. 168- 169 C. (decomposition), was prepared from ()-N- n-decyl-norscopolamine and methyl bromide. The yield was 10.0 gm. (91.7% of theory).

EXAMPLE 18 Using a procedure analogous to that described in Example 11, ()-N-n-undecyl-norscopolamine methobromide, white crystals (from methanol/ether), M.P. 176-177 C. (decomposition), was prepared from N-n-undecyl-norscopolamine and methyl bromide. The yield was 6.8 gm. (93.4% of theory).

EXAMPLE 19 Using a procedure analogous to that described in Example 11, ()-N-n-dodecyl-norscopolamine methobromide, White crystals (from methanol/ether), M.P. l79l80 C. (decomposition), was prepared from -N-n-dodecyl-norscopolamine and methyl bromide. The yield was 6.3 gm. (84.1% of theory).

EXAMPLE 20 Using -a procedure analogous to that described in Example 1, (i)-N-isopropyl-norscopolamine hydrochloride, white crystals (from methanol/ether), M.P. 213- 214 C. (decomp.), specific rotation [@1 :iO (c.=2.0), was prepared from (i)-norscopolamine and isopropyl bromide. The total reaction time was nine days, and the supply of isopropyl bromide and sodium carbonate was replenished once a day for seven days.

EXAMPLE 21 Using a procedure analogous to that described in Example 1, (-)-N-isopropyl-norscopolaime hydrochloride, white crystals (from ethanol), M.P. 214216 C. (decomp.), specific rotation [a] =27.3 (c.=2.0), was prepared from ()-norscopolamine and isopropyl bromide. The total reaction time was 60 hours, and the supply of isopropyl bromide and sodium carbonate was replenished after 5, 8 and 17 hours. The yield was 4.5 gm. (21.1% of theory).

EXAMPLE 22 Using a procedure analogous to that described in Example 6, (i)-N-n-butyl-norscopolamine hydrochloride, white crystals (from acetone), M.P. 133134 C., specific rotation [a] =i'0 (c.=2.0), was prepared from ()-norscoplamine, n-butyl bromide and sodium carbonate. The total reaction time was 24 hours at C.

EXAMPLE 23 Using a procedure analogous to that described in Example 4, ()-N-iso-amyl-norscopolamine hydrochloride, white crystals (from acetonitrile), M.P. 186-l88 C., specific rotation [a] -='-28.0 (c.=2.0), was prepared from ()-norscopolamine and isoamyl bromide. The total reaction time was 22.5 hours. The yield was 17.2 gm. (86.9% of theory).

EXAMPLE 24 Using a procedure analogous to that described in Example 6, (i)-N-n-hexyl-norscopolamine hydrochloride, white crystals (from acetone), M.P. 144-153 C., specific rotation [a] =i0, was prepared from (i)- norscopolamine and n-hexyl bromide. The total reaction time was five hours. The yield was 10% of theory.

EXAMPLE 25 Using a procedure analogous to that described in Example 6, (=)-N-n-hexyl-O-acetyl-norscopolamine hydrochloride, white crystals (from acetone/ether), M.P. 126-127 C., of the formula CH-CH CH2 l H O\ IIF-C HB H--O C-CH-CgH5 CH-CH CH1 OHOCOCH:

was prepared from 25.2 gm. (0.074 mol) of ()-O- acetyl-norscopolamine, 66.0 gm. (0.4 mol) of n-hexyl bromide and 8.8 gm. (0.083 mol) of sodium carbonate. The total reaction time was five hours at 150 C. The yield was 17.1 gm. (51.1% of theory).

EXAMPLE 26 Preparation of -N-n-hexyl-O benzoylnorscopolamine hydrochloride were obtained.

EXAMPLE 27 Using a procedure analogous to that described in Example 26, ()-N-ethyl-O-benzoyl-norscopolamine hydrochloride, white crystals (from acetone/ether), M.P. 190-191 C. (decomp.), specific rotation (c.=2.0), was prepared from 0.025 mol of ()-N-ethylnorscopolamine hydrochloride and 10.0 gm. (0.07 mol) of benzoyl chloride. The total reaction time was 24 hours. The yield was 10.5 gm. (91.7% of theory).

EXAMPLE 28 Using a procedure analogous to that described in Example 1, (-)-N-n-nonyl-norscopolamine hydrochloride, white crystals (from acetone), M.P. 145148 C. (decomp.), specific rotation [a] =24.3 (c.=2.0), was prepared from -(-)-noroscopolamine and n-nonyl bromide. The total reaction time was 18 hours. The yield was 19.6 gm. (86.7% of theory).

EXAMPLE 29 Using a procedure analogous to that described in Example l, (-)-N-n-hexadecyl-norscopolamine hydrochloride, white crystals (from acetonitrile), M.P. 151-152 C. was prepared from ()-norscopolamine and nhexadecyl bromide. The total reaction time was 41 hours, and the supply of hexadecyl bromide and sodium carbonate was replenished after 5, 8 and 31 hours. The yield was 15.7 gm. (57.1% of theory).

EXAMPLE 30 Using a procedure analogous to that described in Example 5, (-)-N-allyl-norscopolamine hydrochloride,

white crystals (from acetonitrile), M.P. -166" C. specific rotation [a] =-27.5 (c.=2.0) of the formula was prepared from 7.0 gm. (0.024 mol) of (-)-norscopolamine and 2.9 gm. (0.024 mol) of allyl bromide. The total reaction time was 24 hours. The yield was 4.3 gm. (48.0% of theory).

EXAMPLE 31 Using a procedure analogous to that described in Example 1, ()-N-benzyl-norscop0lamine( white crystals (from benzene/petroleum ether), M.P. 86 C., was prepared from (-)-norscopolamine and benzyl chloride. The total reaction time was five hours, and the benzyl chloride and sodium carbonate were replenished after three hours. The free base became crystalline after being admixed with a small amount of ether. The yield was 17.9 gm. (94.4% of theory).

EXAMPLE 32 Using a procedure analogous to that described in Example 31, ()-N-p-chlorobenzyl-norscopolamine, white crystals (from cyclohexane), M.P. 75-76 C., was prepared from ()-norsc0polamine and p-chlorobenzyl chloride. The total reaction time was 12 hours, and 0.025 mol of p-chlorobenzyl chloride and 0.025 mol of sodium carbonate were added after 2.5 hours to replenish the supply. The yield was 18.0 gm. (86.9% of theory).

EXAMPLE 33 Using a procedure analogous to that described in Example l, ()-N-4-diphenylmethyl-norscopolamine hydrochloride, white crystals (from acetonitrile/ether), M.P. 215 C. (decomp.), was prepared from 4.68 gm. (0.016 mol) of ()-norscopolamine, 4.0 gm. (0.016 mol) of 4-diphenylmethyl bromide and 1.7 gm. (0.016 mol) of sodium carbonate. The yield was 7.2 gm. (90.7% of theory).

EXAMPLE 34 Using a procedure analogous to that described in Example 1, ()-N-(N',N'-dibenzyl-aminoethyl)-norscopolamine dihydrochloride, white crystals (from ethanol/ ether), M.P. 193-194 C. (decomp.), was prepared from (-)-norscopolamine, N,N-dibenzyl-aminoethyl bromide and sodium carbonate. The total reaction time was four days. The yield was 19.8 gm. (67.6% of theory).

EXAMPLE 35 Using a procedure analogous to that described in Example 1, -N- 7-ethyl-theophyllinyl) -norscopolamine hydrochloride, white crystals (from methanol/ether), M.P. l66-167 C. (decomp.), was prepared from norscopolamine, 7-ethyl-theophylline bromide and sodium carbonate. The total reaction time was seven days. The yield was 15.5 gm. (58.3% of theory).

EXAMPLE 3 6 Using a procedure analogous to that described in Example 1, -N-ethoxycarbonyl-methyl-norscopolamine hydrochloride, white crystals (from ethanol/ether), M.P. 166 C. (decomp.), specific rotation [1x1 =27.5 (c.=2.0), was prepared from (-)-norscopolamine, bromoacetic acid ethyl ester and sodium carbonate. The total reaction time was 7.5 hours, and the supply of re-: actants and sodium carbonate was not replenished. The yield was 14.7 gm. (71.4% of theory).

EXAMPLE 37 Using a procedure analogous to that described in Example 1, ()-N-acetonyl-norscopolamine hydrochloride, white crystals (from ethanol/ether), M.P. 178-180 C. (decomp.), specific rotation [0;] =40.5 (c.=2.0),

ample 1,

was prepared from (-)-norscopolamine, bromoacetone and sodium carbonate. The total reaction time was ten hours, and 0.005 mol of bromoacetone was added after 4.5 hours. The yield was 5.9 gm. (30.9% of theory).

EXAMPLE 3 8 Using a procedure analogous to that described in EX- ample 1, ()N-phenoxyl-norscopolamine hydrochloride, white crystals (from methanol/ether), M.P. 176-179 C. (decomp.), specific rotation [a] =-33.O (c.=2.0), was prepared from 13.9 gm. (0.048 mol) of (-)-norscopolamine, 9.6 gm. (0.048 mol) of bromoacetophenone and 5.1 gm. (0.048 mol) of sodium carbonate. The total reaction time was 2.5 hours, and the supply of reactant and sodium carbonate was not replenished. The yield was 8.4 gm. (39.4% of theory) EXAMPLE 39 Using a procedure analogous to that described in Example l, ()-N-hydroxyethyl-norscopolamine hydrochloride, white crystals (from methanol/ether), M.P. 182-183 C. (decomp.), specific rotation [a] =-21.5 (c.=2.0), was prepared from ()-norscopolamine, bromoethanol and sodium carbonate. The total reaction time was 30 hours, and 0.025 mol of bromoethanol and 0.025 mol of sodium carbonate were added after 5, 16 and 19 hours. The yield was 16.2 gm. (87.6% of theory),

EXAMPLE 40* Using a procedure analogous to that described in EX- -N-[i-cyanoethyl-norscopolamine, white crystals (firom water), M.P. 106 C., was prepared from ()-norscopolamine, B-bromo-propionitrile and sodium carbonate. The total reaction time was 90 hours, and 0.025 mol of fi-bromopropionitrile and 0.025 mol of so dium carbonate were added after 7, 14, 28, 54 and 61 hours. The yield was 10.1 gm. (59.0% of theory).

EXAMPLE 41 2.0), was prepared from N isopropyl-norscpolamine and methyl bromide. The yield was 44.3% of theory.

EXAMPLE 43 Using a procedure analogous to that described in Example 11, (i)-N-nbutyl-norscopolamine methobromide, white crystals (from acetonitrile/ether), M.P. 163-165 C. (decomp.), specific rotation [a] =i (c.=2.0), was prepared from (i)-N-n-butyl-norscopolamine and methyl bromide. The yield was 66.3% of theory.

EXAMPLE 44 Using a procedure analogous to that described in Example 11, (-)-N-allyl-norscopolamine methobromide, white crystals (from acetonitrile), M.P. 157-l58 C. (decomp.), specific rotation [a] ='28.5 (c.=2.0), was prepared from ()-N-n-amyl-norscopolamine and methyl bromide. The yield was 84.3% of theory.

EXAMPLE 45 Using a procedure analogous to that described in Example 11, ()-N-isoamyl-norscopolamine methobromide, white crystals (from acetonitrile), M.P. 178178.5 C. (decomp.), specific rotation [u] ='26.2 (c.= 2.0), Was prepared from (-)-N-isoamyl-norscopolamine and methyl bromide. The yield was 78.9% of theory.

EXAMPLE 46 Using a procedure analogous to that described in Example 11, (-)-N-n-nonyl-norscopolamine methobromide, white crystals (from methanol/ether), M.P. 171 C. (decomp.), was prepared from ()-N-n-nonylnorscopolamine and methyl bromide. The yield was 85.0% of theory.

EXAMPLE 47 Using a procedure analogous to that described in EX- ample 11, ()-N-n-hexadecyl-norscopolamine methobromide, white crystals (from acetone), M.P. 174-175 C. (decomp.), was prepared from ()-N-n-hexadecylnorscopolamine and methyl bromide. The yield was 75.8% of theory.

EXAMPLE 48 Using a procedure analogous to that described in EX- ample 11, ()-N-allyl-norscopolamine methobromide, white crystals (from acetonitrile/ether) M.P. 182.5 183 C. (decomp.), specific rotation [a] ='27.0 (c.=2.0), was prepared from ()-N-allyl-norscopolamine and methyl bromide. The total reaction time was five days. The yield was 77.6% of theory.

EXAMPLE 49 Using a procedure analogous to that described in Example 11, ()-N-benzyl-norscopolamine methobromide,

white crystals (from ethanol/ether), M.P. 180-l8l C.

(decomp.), was prepared from ()-N-benzyl-norscopolamine and methyl bromide. The total reaction time was ten days. The yield was 8.0% of theory.

EXAMPLE 50 Using a procedure analogous to that described in Example 11, (-)-N 4 diphenylmethyl-norscopolamine methabromide, white crystals (from methanol/ether), M.P. 191l92 C. (decomp.), was prepared from N-4-diphenylmethyl-norscopolamine and methylbromide. The total reaction time was one month. The yield was 18.2% of theory.

EXAMPLE 51 Using a procedure analogous to that described in EX- ample 1 1, -N-ethoxycarbonylmethyl-norscopolamine methobromide, white crystals (from ethanol/ether), M.P. 170 C. (decomp.), specific rotation [a] -27.5 (c.=2.0), was prepared from (-)-N-ethoxycarbonylmethyl-norscopolamine and methyl bromide. The total reaction time was ten days. The yield was 53.1% of theory.

EXAMPLE 52 Using a procedure analogous to that described in Example 11, ()-N-fl-hydroxyethyl-norscopolamine metho bromide, white crystals (from ethanol), M.P. 211 C. (decomp.), specific rotation [a] ='20.5 (c.=2.0), was prepared from ()-N-B-hydroXyethyl-norscopolamine and methyl bromide. The total reaction time was five days. The yield was 64.8% of theory.

EXAMPLE 5 3 Using a procedure analogous to that described in EX- ample ll, ()-N-ethyl-norscopolamine bromoallylate, white crystals (from methanol/ether), M.P. -176 C. (decomp.), specific rotation [a] ='20 (c.=2.0) of the formula was prepared from 8.6 gm. (0.027 mol) of ()-N-ethylnorscopolamine and 6.6 gm. (0.054 mol) of allyl bromide in 20 cc. of acetonitrile. The total reaction time was eight days. The yield was 8.2 gm. (69.2% of theory).

EXAMPLE 54 Using a procedure analogous to that described in Example 53, ()-N-n-propyl-norscopolamine bromoallylate, white crystals (from methanol/ether), M.P. 154- 155 C. (decomp.), specific rotation [u] 23.8 (c.=2.0), was prepared from ()-n-propyl-norscopolamine and allyl bromide. The yield was 70.3% of theory.

EXAMPLE 55 Preparation of -N-n-heptyl-norscopolamine methomethanesulfonate 13.5 gm. (0.035 mol) of (--)-N-n-heptyl-norscopolamine were dissolved in 20 cc. of acetonitrile, 4.4 gm. (0.04 mol) of methyl methanesulfonate were added to the solution, and the mixture was allowed to stand for six days at 60 C. The precipitate formed thereby was collected and recrystallized from a mixture of acetone and ether. 10.2 gm. (59.0% of theory) of white crystalline -N-n-heptyl-norscopolamine methometh- 'anesulfonate, M.P. 135- C., specific rotation [:1 20 C. (c.=2.0), were obtained.

EXAMPLE 56 Using a procedure analogous to thtt described in Example 55, (-)N-n-octyl-norscopolamine methomethanesulfonate, white crystals (from acetone/ ether), M.P. l66.5167.5 C., specific rotation [a] =22.5 (c.= 2.0), was prepared from ()-N-n-octyl-norscopolamine and methyl methanesulfonate. The yield was 44.6% of theory.

EXAMPLE 57 Using a procedure analogous to that described in Example 55, (-)N-n-nonyl-norscopolamine methomethanesulfonate, white crystals (from acetone/ether), M.P. 131132 C., specific rotation [u] =-Z3.75 (0.: 2.0), was prepared from ()-N-nnonyl-norscopolamine and methyl methanesulfonate. The total reaction time was four weeks. The yield was 59.2% of theory.

EXAMPLE 58 Using a procedure analogous to that described in Example 55, ()-N-n-decyl-norscopolamine methomethanesulfonate, white crystals (from acetone), M.P. 119- 120 C., specific rotation [a] =25.0 (c.=2.0), was prepared from N n decyl norscopolamine and methyl methanesulfonate. The yield was 70.8% of theory.

EXAMPLE 59 Using a procedure analogous to that described in Example 55, ()-N-n-dodecyl-norscopolamine methomethanesulfonate, white crystals (from acetone), M.P. 110- 111 C., specific rotation [oz] =22.5 (c.=2.0), was prepared from N n dodecyl norscopolamine and methyl methanesulfonate. The yield was 57.7% of theory.

EXAMPLE 60 In the quaternary salts of the Formula Ia the spasmolytic activity predominates; especially active in this respect are the levorotatory quaternary salts of the Formula Ia wherein R is an acyclic, saturated or unsaturated hydrocarbon, such as ()-N-ethyl-norscopolamine methobromide or (-)-N-allyl-norscopolamine methobromide.

For pharmaceutical purposes the compounds of the instant invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one dosage unit of the active ingredient, such as tablets, coated pills, solutions, suspensions, emulsions, wettable powders, syrups, capsules, wafers suppositories and the like. One dosage unit of the compound according to the present invention is from 0.08 to 5.0 mgm./kg. body weight, preferably from 0.16 to 3.3 mgm./kg. body weight. If desired, a dosage unit composition according to the present invention may also comprise one or more other active ingredients, such as analgesics, antiphlogistics, psychotherapeutics, sedatives and tranquilizers.

The following examples illustrate a few dosage unit compositions comprising a compound of the invention as an active ingredient. The parts are parts by weight unless otherwise specified.

EXAMPLE 61 Hypodermic solution The solution is compounded from the following ingredients:

Parts ()-N-ethyl-norscopolamine methobromide 10.0 Dextrose 47.0

Tartaric acid 0.012 Double-distilled water, q.s. ad. 2000.0 parts by vol.

Suppositories The suppository composition is compounded from the following ingredients:

Parts -N-n-propyl-norscopolamine methomethanesulfonate 10.0

Lactose 100.0 Cocoa butter 1630.0

Total 1740.0

Compounding pr0cedure.-The norscopolamine compound is admixed with the lactose, and the mixture is homogeneously distributed in the molten cocoa butter. The composition is then poured into cooled suppository molds, each holding 1740 mgm. of the composition. Each finished suppository contains 10 mgm. of the active ingredient.

EXAMPLE 63 Coated pills The pill core composition is compounded from the following ingredients:

Parts (--)-N-ethyl-norscopolamine hydrochloride 10.0 Dicalcium phosphate 20.0 Lactose 13.9

Corn starch 30.0

Colloidal silicic acid 3.0

Tartaric acid 0.5

Soluble starch 2.0

Stearic acid 0.5

Food coloring 0.1

Total 80.0

Compounding procedutra-The n-orscopolamine compound is intimately admixed with about one-half the indicated amount of each of the other ingredients except the soluble starch, and the mixture is moistened with an aqueous solution of the soluble starch. The moist mass is granulated by forcing it through a fine-mesh screen, the granulate is dried and then admixed with the remaining half of the ingredients, and the composition is pressed into 80 mgm.-pill cores, which are subsequently coated with a thin shell of a customary pill-coating composition consisting essentially of titanium dioxide, sugar, gum arabic, polyvinylpyrrolidone and talcum. Each finished coated pill contain mgm. of the norscopolamine compound.

EXAMPLE 64 Enteric-coated pills The pill core composition is compounded from the Compounding procedure.-The pill cores are prepared in a manner analogous to that described in Example 63, except that the composition is pressed into 365 mgm.-pill cores. The latter are then coated with a thin enteric shell with the aid of a solution of 43.0 parts of cellulose acetate phthalate in an organic solvent. The enteric-coated pills are thereafter provided with an additional coating as in Example 63. Each coated pill contains 100 mgm. of the norscopolam'me compound.

EXAMPLE 65 Suppositories with additional active ingredient The suppository composition is compounded from the following ingredients:

Parts 1 -N-n-propyl-norscopolamine maleate 3 0.0 Metamizol 10.0 Lechithin 2.0 Cocoa butter 179.0

Total 221.0

The compounding procedure is the same as in Example 62, except that each suppository mold holds 221 mgm. of the composition. Each suppository contains 30 mgm. of

the norscopolarnine compound and 10 mgm. of metamizol an antipyrctic and analgesic.

EXAMPLE 66 Compounding procedure.-The quaternary norscopol amine compound is dissolved in the demineralized water, and the solution is admixed with a solution of the p-hydroxybenzoic acid esters in the ethanol. 1 cc. of the finished solution (20 drops) contains 0.03 mgm. of the norscopolamine compound.

EXAMPLE 67 Coated pills with additional active ingredient The pill core composition is compounded from the following ingredients:

The compounding procedure is analogous to that of Example 63, except that mgm.-pill cores are formed. Each coated pill contains 10 mgm. of the quaternary norscopolamine compound and 10 mgm. of the benzo diazepinone compound.

Although the above dosage unit composition examples illustrate only seven specific compounds of the instant generic invention as active ingredients, it should be undersood that any other compounds embraced by Formula I or a nontoxic, pharmacologically acceptable acid addition salt thereof, or any other quaternary salt embraced by Formula Ia may be substituted for the particular norscopolamine compound illustrated in Examples 61 through 67. Moreover, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. The levorotatory compound of the formula [0/' l ICHiCH=CHz (JHo(":-oH-cHi]- H01 OH--( JH 0H3 CHiOH 2. The levorotatory compound of the formula CH GH CH1 0 [o I N3o1 I+0H2-oH=oH2 H'OC i---CHO0H5 Br- \CH-- H (311i 011,011 3. The levorotatory compound of the formula CH-0H CH 0 [o I HzC=CHOH I I+n-OaH IEf-Oi'J-CH-Cgldiil- Br- CH H CH1 0111011 References Cited UNITED STATES PATENTS 2,814,623 11/1957 Moifett 260292 HENRY R. JILES, Primary Examiner ALAN L. ROTMAN, Assistant Examiner US. Cl. X.R. 260256; 424253, 26 5 3 35 UNITED STATES PATENT OFFICE CERTIFICATE OF CCRRECTION Patent No. 31L7286l Dated October 9 9 a mm ZEILE ROLF BAimoLzER gERHARD WALTHER,

It is certified that error appears in the ebove-identified patent and that sziid Letters Patent are hereby corrected as shown below:

Colur m' 9, line 43 "20D" should read 2 0--.

Column 11,. line'25 "-20" should read -25 Column 13, 1: ne 5 correct the spelling of "Lecithin" Column- 1 line 58 in the formu la of Claim 2 r N C" should read --H C-- Bibni-QD AND."

- r S'EALEB FEB 171970 Atpaf:

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