US3746743A - 2 - (ethylpropylamine)ethyl-alpha,alpha-diphenyl-glycollate and the hydrochloride thereof - Google Patents

2 - (ethylpropylamine)ethyl-alpha,alpha-diphenyl-glycollate and the hydrochloride thereof Download PDF

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US3746743A
US3746743A US00187558A US3746743DA US3746743A US 3746743 A US3746743 A US 3746743A US 00187558 A US00187558 A US 00187558A US 3746743D A US3746743D A US 3746743DA US 3746743 A US3746743 A US 3746743A
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M Mehta
J Bainbridge
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Beecham Group PLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates

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  • R and R are difierent lower alkyl groups of 1 to 6 carbon atoms
  • X is divalent alkylene of 2 or 3 carbon atoms
  • the present invention relates to new basic esters useful for the palliative treatment of Parkinsonism and the present application is a continuation of application Ser. No. 732,517, filed May 28, 1968, now abandoned, which is a continuation-in-part of application Ser. No. 390,173, filed Aug. 17, 1964, now abandoned.
  • the new anti-Parkinson compounds of the present invention have the formula:
  • R and R are different lower alkyl groups of 1 to 6 carbon atoms
  • X is divalent alkylene of 2 or 3 carbon atoms
  • the dosage and route of administration of the new anti-Parkinson compounds are in general the same as with known anti-Parkinson compounds. It is well recognized, however, that the dosage of active drug used for the treatment of Parkinsonism varies considerably from patient to patient and depending upon the severity of the condition existing in each patient as well as the length of time during which the patient has been affected with Parkinsonism. It is thus not possible to make a general rule with respect to amount and frequency of dosage as the physician or clinician must use his own best judgment.
  • the reaction is preferably but not necessarily carried out int he presence of a catalyst which is an alkali or alkaline earth metal alkoxide. Sodium methoxide is a particularly good catalyst.
  • the reaction is preferably carried out by heating the reactants II and III in a solvent such as light petroleum or n-heptane and the catalyst may be and usually is dissolved in a suitable solvent such as a sodium alkoxide which is present in excess of the corresponding alkanol.
  • the substituted acetic acid esters of Formula II which are used as the starting materials for the new compounds I, are prepared according to methods known per se.
  • Tests for pharmacological activity have been carried out on two of the compounds of the present invention together with comparative tests on compounds of similar structure.
  • the compounds tested were the hydrochlorides R and R are identical Me 0(CH ),N
  • mice Initially, the toxicities of compounds I to VI were determined in mice. Groups of 5 mice were each injected subcutaneously with solutions of compounds I, II, IV, V and VI and intravenously with a solution of compound III, and they were observed for toxic symptoms over a period of 24 hours. The number of animals that died in each group was noted and the LD (the median lethal dose), in mg./ kg. body weight, was calculated. The results were as follows:
  • the anti-tremorine activity of compounds I to VI was determined by dosing groups of 5 mice subcutaneously with a solution of each compound. After 30 minutes the mice were challenged with 40 mg./ kg. of tremorine administered intraperitoneally and the mice were assessed after a further 30 minutes for tremor. The degree of inhibition of tremor due to the tremorine was used to calculate the ED (medium efiective dose), and the results were as The mydriatic activity of compounds I and VI in mice was determined by dosing groups of 5 mice subcutaneous- 1y with a solution of each compound. After 20 minutes the eyes of the mice were inspected under a binocular microscope and the degree of mydriasis was measured in orbitary units by using a scale in one eyepiece. The results were used to determine the ED and were as follows:
  • mice The effect of compounds I and VI on the central nervous system was determined by measuring their inhibiting action in preventing convulsions due to the application of a maximal electroshock (MES) to the brain of mice.
  • MES maximal electroshock
  • Groups of 10 mice were injected subcutaneously with solutions of the compounds, then subjected to an MES one hour later.
  • the mice used had been preselected for their ability to exhibit maximum seizure before the active compound was administered.
  • the ED values for compounds I and II were 6.8 and 50 mg./kg. respectively, whereas compounds III to VI showed no inhibition of the MES.
  • Atropine is not used in the regular treatment of Parkinsonism as the side elfects are such that it would cause undue distress and hospitalization of the patient if used in therapeutic doses for the treatment of this condition.
  • EXAMPLE 1 A methanolic solution of sodium methoxide (from sodium (0.2 g.) and dry methanol (3 ml.) was added dropwise during minutes to a boiling solution of methyl u,a-diphenylglycollate (11 g.) and Z-ethylpropylaminoethanol (6 g.) in light petroleum (150 ml., B.P. 80-100") and the methanol that separated was removed by using a Dean and Starke apparatus. At the end of 5 hours no further separation of methanol occurred and the reaction mixture after being washed with water (3X 20 ml.) was extracted with 1 N hydrochloric acid (3X ml.).
  • EXAMPLE 2 Preparation of 2-(ethylpropylamino)ethyl a-cyclohexyl-a-phenylglycollate hydrochloride
  • a methanolic solution of sodium methoxide [from sodium (0.2 g.) in dry methanol (3 ml.)] was added dropwise during 20 minutes to a boiling solution of methyl a-cyclohexyl-u-phenylglycollate (16 g.) and 2-ethylpropylaminoethanol (12.7 g.) in light petroleum (500 ml., B.P. -100").
  • Esters of the following formula were prepared similarly (Ph, Me, Et, Pr and Bu stand for phenyl, methyl, ethyl, propyl and butyl, respectively):
  • the parent alcohol 3-(ethylpropylamino)propan-l-ol was obtained as follows:
  • Ethyl acrylate was added dropwise with stirring to an excess of n-propylamine (600 g.) containing water (10 ml.) and allowed to stand at room temperature for 4 hours. After removal of excess of propylamine, the residual oil was dissolved in ether, dried (MgSO the solvent removed by evaporation and the liquid distilled under reduced pressure to give ethyl fi-n-propylaminopropionate (136 g., 86%) as a colorless liquid, B.P. 78 C./9 mm., n 1.4258.
  • R and R cannot be identical and it is of critical significance that they be difierent lower alkyl groups as exemplified by the foregoing examples. It is only when R and R are dilferent lower alkyl groups that the full benefit and utility of the new compounds is realized for the treatment of Parkinsonism.
  • Compounds are known of similar constitution to the compounds of this invention but where the dialkylamino moiety has two like alkyl groups such as diethylamino or dipropylamino. Such compounds do not have anti-Parkinson utility, but on the contrary, may have utility as mere tranquilizers.
  • the lower alkyl groups of the dialkylamino moiety of the new compounds of this invention have different lower alkyl groups and an important aspect of the present invention resides in the discovery that these alkyl groups must be diiferent, because it they are not different, the resulting compounds have properties and usefulness for purposes other than the treatment of Parkinsonism.
  • the efiective dose of the new compounds of the present invention is below that which causes mydriasis whereas such is not true of substances hereintofore used in the treatment of Parkinsonism and wherein some effectiveness can be attained only by the use of such large dosages as to cause adverse unpleasant and even serious side effects such as blurred vision, dry mouth and symptoms of mydriasis.

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Abstract

NEW BASIC ESTERS ARE PROVIDED WHICH ARE USFUL IN THE PALLIATIVE TREATMENT OF PARKINSONISM. THE NEW ESTERS HAVE THE FORMULA:

C6H5-C(-OH)(-R1)-COO-X-N(-R2)-R3

WHEREIN R1 IS PHENYL OR CYCLOPHEXYL, R2 AND R3 ARE DIFFERENT LOWER ALKYL GROUPS OF 1 TO 6 CARBON ATOMS, AND X IS DIVALENT ALKYLENE OF 2 OR 3 CARBON ATOMS, AND NON-TOXIC PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, AND ARE PRODUCED FROM A SUBSTITUTED ACETIC ACID ESTER OF THE FORMULA:

C6H5-C(-OH)(-R1)-COO-ALKYL

WHICH IS REACTED WITH AN N-DISUBSTITUTED AMINOALCOHOL OF THE FORMULA:

HO-X-N(-R2)-R3

WHEREIN R1, R2, R3, AND X HAVE THE ABOVE MEANINGS, TO PRODUCE THE NEW AND USEFUL COMPOUNDS OF FORMULA 1.

Description

U.S. Cl. 260-473 A 2 Claims ABSTRACT OF THE DISCLOSURE New basic esters are provided which are useful in the palliative treatment of Parkinsonism. The new esters have the formula:
CsHr OH wherein R is phenyl or cyclohexyl,
R and R are difierent lower alkyl groups of 1 to 6 carbon atoms, and
X is divalent alkylene of 2 or 3 carbon atoms,
and non-toxic pharmaceutically acceptable acid addition salts thereof, and are produced from a substituted acetic acid ester of the formula:
CsHs OH R1 0 o Alkyl (II) which is reacted with an N-disubstituted aminoalcohol of the formula:
H.0X.N.
R: (III) wherein R R R and X have the above meanings, to produce the new and useful compounds of Formula I.
The present invention relates to new basic esters useful for the palliative treatment of Parkinsonism and the present application is a continuation of application Ser. No. 732,517, filed May 28, 1968, now abandoned, which is a continuation-in-part of application Ser. No. 390,173, filed Aug. 17, 1964, now abandoned.
The new anti-Parkinson compounds of the present invention have the formula:
CtHr OH R: COO.X.N./
(I) wherein R is phenyl or cyclohexyl,
R and R are different lower alkyl groups of 1 to 6 carbon atoms, and
X is divalent alkylene of 2 or 3 carbon atoms,
United States Patent 0 3,746,743 Patented July 17, 1973 and non-toxic pharmaceutically acceptable acid addition salts thereof, and in particular the hydrochloride. These compounds exhibit a high anti-tremorine activity in tests on animals and in other tests as set forth below. Particularly good compounds are those wherein R is phenyl or cyclohexyl, R is ethyl and R is n-propyl with-X being --CH CH These compounds also are character ized by unexpectedly low anti-acetylcholine activity in contrast to what might have been predicted from existing knowledge in this art and consequently the new compounds are free from the adverse side effects usually associated with presently available commercially employed anti-Parkinson compounds.
The dosage and route of administration of the new anti-Parkinson compounds are in general the same as with known anti-Parkinson compounds. It is well recognized, however, that the dosage of active drug used for the treatment of Parkinsonism varies considerably from patient to patient and depending upon the severity of the condition existing in each patient as well as the length of time during which the patient has been affected with Parkinsonism. It is thus not possible to make a general rule with respect to amount and frequency of dosage as the physician or clinician must use his own best judgment. It is, however, customary to start a patient on a relatively small amount and then gradually or incrementally to increase the dosage until signs of toxicity begin to become apparent as the maximal dosage or maintenance dosage should thereafter be below that amount which causes toxic reactions and yet which is suflicient to be elfective in the treatment of the particular patient, it being noted that the present compounds are like other anti-Parkinson compounds intended only as palliative, because there is presently no known cure for Parkinsonism. The literature and scientific information readily provides dosages used for other and less desirable and less elfective anti-Parkinson compounds as compared with the present invention.
The new esters prepared by reacting a substituted acetic acid ester of the formula:
CeHr 0H R, 000 Alksu (II) with an N-disubstituted aminoalcohol of the formula:
HO.X. RI (H) wherein R R R and X have the meanings set forth above. The reaction is preferably but not necessarily carried out int he presence of a catalyst which is an alkali or alkaline earth metal alkoxide. Sodium methoxide is a particularly good catalyst. The reaction is preferably carried out by heating the reactants II and III in a solvent such as light petroleum or n-heptane and the catalyst may be and usually is dissolved in a suitable solvent such as a sodium alkoxide which is present in excess of the corresponding alkanol. The substituted acetic acid esters of Formula II, which are used as the starting materials for the new compounds I, are prepared according to methods known per se.
Tests for pharmacological activity have been carried out on two of the compounds of the present invention together with comparative tests on compounds of similar structure. The compounds tested were the hydrochlorides R and R are identical Me 0(CH ),N
(IV) Me Et 0 0 0(CH )aN C /nBu P coowmnN (VI) uBu Compounds I and II are the compounds of Examples 1 and 2, respectively, and compound V is described in US. Pat. No. 2,399,736. Compound III is the drug Benactyzine.
Initially, the toxicities of compounds I to VI were determined in mice. Groups of 5 mice were each injected subcutaneously with solutions of compounds I, II, IV, V and VI and intravenously with a solution of compound III, and they were observed for toxic symptoms over a period of 24 hours. The number of animals that died in each group was noted and the LD (the median lethal dose), in mg./ kg. body weight, was calculated. The results were as follows:
Compound: LD mg./kg. 200 1000 The anti-tremorine activity of compounds I to VI was determined by dosing groups of 5 mice subcutaneously with a solution of each compound. After 30 minutes the mice were challenged with 40 mg./ kg. of tremorine administered intraperitoneally and the mice were assessed after a further 30 minutes for tremor. The degree of inhibition of tremor due to the tremorine was used to calculate the ED (medium efiective dose), and the results were as The mydriatic activity of compounds I and VI in mice was determined by dosing groups of 5 mice subcutaneous- 1y with a solution of each compound. After 20 minutes the eyes of the mice were inspected under a binocular microscope and the degree of mydriasis was measured in orbitary units by using a scale in one eyepiece. The results were used to determine the ED and were as follows:
Compound: ED mg./kg. I 26 II 7.5 III 0.5
IV 0.6 V 0.25 VI 12.5
The effect of compounds I and VI on the central nervous system was determined by measuring their inhibiting action in preventing convulsions due to the application of a maximal electroshock (MES) to the brain of mice. Groups of 10 mice were injected subcutaneously with solutions of the compounds, then subjected to an MES one hour later. The mice used had been preselected for their ability to exhibit maximum seizure before the active compound was administered. The ED values for compounds I and II were 6.8 and 50 mg./kg. respectively, whereas compounds III to VI showed no inhibition of the MES.
From the results of the tests described above it is shown that useful anti-tremorine activity was exhibited in mice at doses below the mydriatic dose for compounds I and H, whereas for compounds III to VI the mydriatic activity was evidenced at doses well below anti-tremorine eifects. Furthermore, in the described tests, compounds I and II showed anti-convulsant activity, as evidenced by inhibition of MES seizures in mice, whereas compounds III to VI did not shown such activity. This distinguished compounds I and H from compounds III to VI and indicated the usefulness of compounds I and II in the treatment of Parkinson tremor and rigidity.
Further tests were made to compare compound I with Benzohexol, which is one of the main drugs used throughout the world in the treatment of Parkinsonism. Compound I and Benzhexolwere administered subcutaneously and perorally to groups of 20 mice, then after 20 minutes 2 mg./ kg. of oxotremorine was administered intraperitoneally.
The doses of both compounds required to prevent tremor were determined after a further 10 minutes, and the ED values were calculated. The mydriatic activities and toxicities for the two compounds were determined subcutaneously in mice as described previously and perorally by similar methods; groups of 10 mice were used for these determinations. The results were as follows:
In the tests oxotremorine was used since tremors are produced quickly, whereas if tremorine is used, it has to be converted in vivo to oxotremorine to produce tremors. The results of the tests indicated that Benzhexol could not be administered in sufficiently high dose to produce its full efiect without the onset of atropine-like side effects (mydri-atic activity, dryness of mouth, etc.), whereas compound I produced its full eifects at doses that did not cause these side effects.
Atropine is not used in the regular treatment of Parkinsonism as the side elfects are such that it would cause undue distress and hospitalization of the patient if used in therapeutic doses for the treatment of this condition.
tative examples.
EXAMPLE 1 A methanolic solution of sodium methoxide (from sodium (0.2 g.) and dry methanol (3 ml.) was added dropwise during minutes to a boiling solution of methyl u,a-diphenylglycollate (11 g.) and Z-ethylpropylaminoethanol (6 g.) in light petroleum (150 ml., B.P. 80-100") and the methanol that separated was removed by using a Dean and Starke apparatus. At the end of 5 hours no further separation of methanol occurred and the reaction mixture after being washed with water (3X 20 ml.) was extracted with 1 N hydrochloric acid (3X ml.).
The acid extracts (after washing with ether ml.) were made alkaline with aqueous 5 N sodium hydroxide solution, the liberated base was extracted into ether (4X 50 ml.) and the ether extracts were dried (MgSO Treatment of the extracts with hydrogen chloride gave the hydrochloride (11 g., which was obtained as rectangular plates, M.P. 164 to 166 C., after several 6 crystallizations from butanone (Found: C, 67.0; H, 7.6; C1, 9.4. C H ClNO requires: C, 66.7; H, 7.5; Cl, 9.4%).
EXAMPLE 2 Preparation of 2-(ethylpropylamino)ethyl a-cyclohexyl-a-phenylglycollate hydrochloride A methanolic solution of sodium methoxide [from sodium (0.2 g.) in dry methanol (3 ml.)] was added dropwise during 20 minutes to a boiling solution of methyl a-cyclohexyl-u-phenylglycollate (16 g.) and 2-ethylpropylaminoethanol (12.7 g.) in light petroleum (500 ml., B.P. -100"). The reaction mixture was then treated as described in Example 1 to give the hydrochloride (16.6 g., 67%), as colorless needles, M.P. 200 to 201 C., after crystallization from ethanol. (Found: C, 65.3; H, 9.0; Cl, 9.0. C H ClNO requires: C, 65.6; H, 8.9; Cl, 9.2%).
Esters of the following formula were prepared similarly (Ph, Me, Et, Pr and Bu stand for phenyl, methyl, ethyl, propyl and butyl, respectively):
Pli /OH /O\ .1101 R COO.CH .CHZ.Y
Example M.P. Yield,
0. 1 Y 0.) percent Analysis 3 Ph Me 148-150 73 CmH2ilC1NO3 349B:
Found:C=65.4;H=7.2;Ci-= 3%. N\ Requires: C=65.2; H= .9; C1-=10.1%
4 C clo-OH Same-.." 192-193 34 C1H3 ClNO@E355.9:
y Found: C=64.0;H=8.5; o1-= 1%.
Requires: =64 1, =85, 0 -=10.0%
5 Ph M6 151-153 62 CzoHaaClNOa -363B:
ound: C=65 7, H=7. Cl-=9.8 N\ Requires: C=66.05; H=7.2; O1=9.7%
6 0 010-0 H Same-.-.- 189-191 CzHzzC1NOa 3699:
y Found: o=e5.3; H=9.1; o1=e.e%.
Requires: C=64.9; =8.7; -=9.6%
7 Ph Me 154-156 56 CzrHzsClNOa WTQZ Found: C=66.5; H=7.6; (ll-=9. N Requires: O=66.7; =7.5; -=9.4%.
8 Pb El; 148 39 C21H2aC1NOa 377.9:
Found: C=66.5; H=7.8; C1-=9.6%. N\ Requires: O=66.7; =7.5; -=9.4%.-
9 0 10-011 Same-.. 185-186 73 C H C1NOa 384.02
ye tuna. o=e5.4;1=r=9. :o1=9.4%.
Requires =65.7; =8.9;C1-=9.2%
10 Ph Et 134-134 68 0 2H CINO3 392.0:
2 l and:o=e7.4;H=s05;ci-=9.3%. N\ Requires: =67.4; =7.7; Cl-=9.05%
11 Cyclo-CuHn Bame.. -171 05 C22HauC1NOa 398D2 I Found: C=66.7; H=9 35; Cl-9 05%. Requires: C=66.4; =91; Cl =8.9%.
12 P11 El; 161-163 80 C2zHsoC1NO3 392D2 Found: C=67.7; H=7.6; Cl=9. N Requires: G=67.4; =7.7; 1=9.05%.
13 C lo-CH Same- 181-182 74 CzzHaaC1NO=398.0t
ye Found: 0= .6;H=9.0; o1=s.s%.
Requires: =66.4; =9.1, l=8.9%i
14 Ph Et 143-145 67 CzzHsoClNOa 39Z0Z Found: C=67.1; H=7.9; Cl=9.05%. N\ Requires: C=67.4; =7.7; Cl=9.05%.'
C 010-0 H Same..... 151-153 23 CzzHasClNOs 8.0: 15 y Found: o=ee.1; H= 1; o1=9.oo%
Requires: C=66.4; =91; Cl=8.9%
7 EXAMPLE 16 Preparation of 3- (ethylpropylamino)propyl a,e-diphenylg1yco1late hydrochloride 3-(ethylpropylamino)propan-l-ol (6 g.) and methyl 5 EXAMPLE 17 Preparation of 3-(ethylpropylamino)propyl a-cyclohexyl-ot-phenylglycollate hydrochloride 3-(ethylpropylamino)propan-l-ol (6 g.) and methyl a-cyclohexyl-a-phenylglycollate (12.8 g.) in boiling heptane (250 ml.) were treated with a methanolic solution of sodium methoxide [from sodium (0.1 g.) and dry methanol (3 ml.)]. Treatment of the dried ethereal solution obtained as described in Example 16, with ethereal hydrogen chloride gave the hydrochloride (11.5 g., 70%), as colorless prisms, M.P. 145-146 C. after crystallization from isopropanol (Found: C, 66.4; H, 9.3; Cl, 9.1. C H ClNO requires: C, 66.4; H, 9.1; Cl, 8.9%.)
The parent alcohol 3-(ethylpropylamino)propan-l-ol was obtained as follows:
Ethyl acrylate was added dropwise with stirring to an excess of n-propylamine (600 g.) containing water (10 ml.) and allowed to stand at room temperature for 4 hours. After removal of excess of propylamine, the residual oil was dissolved in ether, dried (MgSO the solvent removed by evaporation and the liquid distilled under reduced pressure to give ethyl fi-n-propylaminopropionate (136 g., 86%) as a colorless liquid, B.P. 78 C./9 mm., n 1.4258. This was then acetylated with acetic anhydride to give ethyl fi-(n-propylacetylamino)propionate as a colorless oil (160 g.; 93%), B.P. 104 C./0.6 mm., 21 1.4526. The latter on reduction with lithium aluminum hydride in ether yielded the desired 3-(ethylpropylamino)propan-l-ol (77.5 g.; 67%), B.P. 82.5 C./10 mm., n 1.4422.
It is to be particularly noted that R and R cannot be identical and it is of critical significance that they be difierent lower alkyl groups as exemplified by the foregoing examples. It is only when R and R are dilferent lower alkyl groups that the full benefit and utility of the new compounds is realized for the treatment of Parkinsonism. Compounds are known of similar constitution to the compounds of this invention but where the dialkylamino moiety has two like alkyl groups such as diethylamino or dipropylamino. Such compounds do not have anti-Parkinson utility, but on the contrary, may have utility as mere tranquilizers. It is, therefore crucial with respect to the present invention that the lower alkyl groups of the dialkylamino moiety of the new compounds of this invention have different lower alkyl groups and an important aspect of the present invention resides in the discovery that these alkyl groups must be diiferent, because it they are not different, the resulting compounds have properties and usefulness for purposes other than the treatment of Parkinsonism. It is further vitally important that the efiective dose of the new compounds of the present invention is below that which causes mydriasis whereas such is not true of substances hereintofore used in the treatment of Parkinsonism and wherein some effectiveness can be attained only by the use of such large dosages as to cause adverse unpleasant and even serious side effects such as blurred vision, dry mouth and symptoms of mydriasis.
What is claimed is:
1. A compound selected from the group consisting of 2-(ethylpropylamino)ethyl-aa-diphenylglycollate and the hydrochloride thereof.
2. The hydrochloride of the compound of claim 1.
References Cited UNITED STATES PATENTS 2,784,141 8/ 1954 Iacobsen 26-473 A LORRAINE H. WEINBERGER, Primary Examiner E. J. SKELLY, Assistant Examiner US. Cl. X.R. 424-308
US00187558A 1963-08-22 1971-10-07 2 - (ethylpropylamine)ethyl-alpha,alpha-diphenyl-glycollate and the hydrochloride thereof Expired - Lifetime US3746743A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4212886A (en) * 1978-11-01 1980-07-15 Survival Technology, Inc. Stabilized benactyzine hydrochloride
US20080058350A1 (en) * 2006-08-28 2008-03-06 Forest Laboratories Holdings Limited Imidazopyridine and imidazopyrimidine derivatives
US10504496B1 (en) 2019-04-23 2019-12-10 Sensoplex, Inc. Music tempo adjustment apparatus and method based on gait analysis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2046659A1 (en) * 1970-01-28 1972-03-23

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4212886A (en) * 1978-11-01 1980-07-15 Survival Technology, Inc. Stabilized benactyzine hydrochloride
US20080058350A1 (en) * 2006-08-28 2008-03-06 Forest Laboratories Holdings Limited Imidazopyridine and imidazopyrimidine derivatives
US7563797B2 (en) 2006-08-28 2009-07-21 Forest Laboratories Holding Limited Substituted imidazo(1,2-A)pyrimidines and imidazo(1,2-A) pyridines as cannabinoid receptor ligands
US10504496B1 (en) 2019-04-23 2019-12-10 Sensoplex, Inc. Music tempo adjustment apparatus and method based on gait analysis

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