US2900415A - Synthesized antispasmodic compounds - Google Patents
Synthesized antispasmodic compounds Download PDFInfo
- Publication number
- US2900415A US2900415A US475302A US47530254A US2900415A US 2900415 A US2900415 A US 2900415A US 475302 A US475302 A US 475302A US 47530254 A US47530254 A US 47530254A US 2900415 A US2900415 A US 2900415A
- Authority
- US
- United States
- Prior art keywords
- compounds
- mole
- antispasmodic
- formula
- synthesized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/66—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
Definitions
- antispasmodic compounds such as epinephrine to relieve the spasms of smooth muscles in the gastro-intestinal tract and the bronchial tubes.
- five inter-related factors need to be considered, (1) bronchodilator activity, (2) general antispasmodic activity, (3) period of effectiveness, i.e., whether the action is fleeting or prolonged, (4) deleterious side effects, and (5) the modes in which the substance may be elfectively administered.
- the clinical usefulness of these compounds is greatly limited in that they have a weak and fleeting action, a high incidence of undesirable and sometimes deleterious side efiects, and/or are limited by the mode in which they can be administered.
- R is an alkyl group containing a minimum of six (6) and a maximum of nine (9) carbon atoms, a hydroxyalkyl group, acycloalkyl alkyl group, an aryl-alkyl group, or a heterocyclic-alkyl group.
- NorE.Antispasmodic activity is measured by the relaxation of spasm produced by acetyl choline in an isolated strip of guinea pig ileum (intestine) and is expressed. in the dilution in millions which will produce 50% relaxation.
- the figures given represent 1 to 22 millions, i.e., the number 2 represents a dilution of one'part compound in 2 million parts of water; therefore, the higher the number, the more active is the compound.
- R is an aryl-alkyl group
- R is an aryl-alkyl group
- bronchodilator and peripheral vasodilator activity as is aptly illustrated in the Biological Activity table of some of the compounds, below.
- salts may be prepared by any of the well-known standard methods. While the salt normally employed is the hydrochloride, I have prepared the. compounds in the form of other salts such as acetate, sulfate and tartrate.
Description
United States Patent 2,900,415 SYNTHESIZED ANTISPASMODIC COMPOUNDS John H. Biel, Milwaukee, Wis., assignor to Lakeside Laboratories, Inc., a corporation of Wisconsin No Drawing. Application December 14, 1954 Serial No. 475,302
2 Claims. (Cl. 260-5706) This invention relates to antispasmodic compounds which relieve the spasms of smooth mucles, particularly those of the gastro-intestinal tract, the lung, and the vascular system and to the new ketones from which they are produced.
A great deal of work has been done in developing antispasmodic compounds such as epinephrine to relieve the spasms of smooth muscles in the gastro-intestinal tract and the bronchial tubes. In evaluating the usefulness of these antispasmodics, five inter-related factors need to be considered, (1) bronchodilator activity, (2) general antispasmodic activity, (3) period of effectiveness, i.e., whether the action is fleeting or prolonged, (4) deleterious side effects, and (5) the modes in which the substance may be elfectively administered. The clinical usefulness of these compounds is greatly limited in that they have a weak and fleeting action, a high incidence of undesirable and sometimes deleterious side efiects, and/or are limited by the mode in which they can be administered.
I have discovered and synthesized a group of new, superior antispasmodic compounds and the compounds from which they are produced having the structural formula:
and R is an alkyl group containing a minimum of six (6) and a maximum of nine (9) carbon atoms, a hydroxyalkyl group, acycloalkyl alkyl group, an aryl-alkyl group, or a heterocyclic-alkyl group. Experiments indicate that they have strong, lengthy bronchodilator and general antispasmodic action, little or no incidence of undesiflble side efiects enabling the administration of much greater amounts than heretofore possible, and can be innocuously injected.
ice
wherein R is:
[2-hexyl] [2 (5-methy1) -hexyl] [l-nonyl] H H'H 'H 'H HOOCC-CCCCGH H H H H H H [2-nonyl] The biological activitiesof some of the new antispasmodic alkyl compounds are compiled in the table below together with the three most potent known alkyl com- My new compounds wherein R is an alkyl containing erty as evidenced by an immediate drop in animal blood pressure upon injection, yet their cardiac stimulant propcities are less than those of epinephrine and Isuprel.
Examples of the new alkyl compounds which I have synthesized are:
OH H H I I HO gg-N\ R pounds having less than six (6) carbon atoms.
Antispasmodic Biological Activity,
dilution in millions methyl (epinephrine) isoprolpyl (Isuprel) Known lower homologs The new alkyl radical compounds.
.*NorE.Antispasmodic activity is measured by the relaxation of spasm produced by acetyl choline in an isolated strip of guinea pig ileum (intestine) and is expressed. in the dilution in millions which will produce 50% relaxation. Thus the figures given represent 1 to 22 millions, i.e., the number 2 represents a dilution of one'part compound in 2 million parts of water; therefore, the higher the number, the more active is the compound.
Experiments with the new group of compounds wherein R is a hydroxy-alkyl indicate that they are of the same order of biological activity as epinephrine in the test for bronchial relaxation. However, unlike both epinephrine and Isuprel, they cause very little action on the heart and blood pressure of the cat or dog. For example, it requires 1000 times as much of my antispasmodic compound m which R isa hydroxyethyl to produce a blood pressure 1ncrease equal to that given by epinephrine (1000 Isopropyl arterennl rate of flow of perfusion fluid through an excised guinea pig lung.
whereinRis:
(hydroxyethyl) l l H HCCCH H H 1-(2-hydroxy-propyl) The group of compounds wherein R is a cycloalkyl-alkyl are quite diiferent from Isuprel in structure but have several times its bronchodilator and peripheral vasodilator activity.
Examples of the cycloalkyl-alkyl compounds which have been synthesized are:
(cyclohexyI-methyl) 6 HC-C H H (cyclohexyl-ethyl) l H CH (cyclohexyl-lsopropyl) wherein R is:
The compounds wherein R is an aryl-alkyl group are also quite different from Isuprel in structure but have greater bronchodilator and peripheral vasodilator activity, as is aptly illustrated in the Biological Activity table of some of the compounds, below.
Broncho: dilator Activity The new aryl-alkyl compoun s.
2-(4-phenyl-bu 2-(1-p-metho Isupr {z-h-phenyl-propyl) Norm-The starred compounds are of interest in that they are more active as bronchodilator agents than would first appear from the table. According to the data listed here these compounds have about X, the bronchodilator activity of Isuprel; however, when tested at lower concentration and when compared at 25% relaxation of the bronchial musculature, as measured by perfusion flow, they are equally as potent and perhaps even more potent than Isuprel. They cause less depression of blood pressure in the cat than does Isuprel, and protect the intact guinea pig from asthma induced by histamine spray.
**NOTE.The bronchodilator activity is evaluated by measuring Tthe e lung is constricted with histamine to simulate what occurs in an asthmatic attack. 0n perfusion of fluid containing the substance to be tested, the lung is relaxed. The figures in the table give the amount of compound in gammas (one gamma is Mono mg.) required to restore the how to normal. Therefore, the lower the figure, the more active is thedrug.
Examples of the compounds in this group which have been synthesized are:
l-(l-phenyl-ethyl) e-EQ 1-(2 phenyl-ethyl) 2-(4-pheny1-butyl) l H BIO-C OCH;
2-(1-p-methoxyphenyl-propy1) z-(l-ochlorophenyl-propyl) 2-(1-m,p-methylened1oxy-phenyl) CC OCH CHa Experiments on compounds wherein R is a heterocyclicalkyl indicate that they are as active as epinephrine in bronchodilator tests. However, they produce blood pressure lowering in animals whereas epinephrine raises the blood pressure. Thus, they do not have this undesirable side eficct of epinephrine. An example of this group of compounds which I have synthesized is:
Preparation of a-(3,4-dihydroxyphenyl)-p-(N-(4-methyl-2 pentyl)-aminoethanol) hydrochloride having the structural formula:
H CH-CHz-C -CH;
CH3 a 57g. (0.48 mole) of 4-methyl 2- aminopentane was dissolved in 125 cc. of 60% ethylalcohol. '150 cc. of ethyl alcohol containing 30 g. (.16 mole) of chloracetyl catechol was slowly added to this solution over a two hour period while stirring at reflux temperature- An inert atmosphere was maintained by bubbling nitrogen through the solution. The reaction mixture was stirred and refluxed for an additional four hours, cooled and acidified with HCl-gas to pH=2. "On standing, acrystalline amino ketone precipitate formed which was filtered in an atmosphere of carbon dioxide and washed repeatedly with acetone. .An alcoholic solution of. 6.2g. (0.2 mole) of this amino ketone precipitate was reduced with 1.0 g. of a 10% palladium-on-charcoal catalyst .at a pressure of 60 lbs. of hydrogen. The reaction mixture was clarified by filtration in an atmosphere of carbon dioxide and concentrated to dryness by distillation in vacuo. The residual oil crystallized when suspended in anhydrous ethyl ether and 5.0 g. of a white precipitate was collected by filtration. This solid was purified by suspending it in 10 cc. of ice cold acetone and then collected by filtration, giving a yield of the desired compound of 3.1 g. (74%) and having a melting point of 123125 dec.
EXAMPLE II Preparation of a-(3,4-dihydroxyphenyl)-B-N-(4-methyl-2-hexyl)-aminoethanol hydrochloride having the structural formula:
n11 n HO1\ /E E0 -oo N CHCH CHOH2-OH HO acid and then concentrated to viscous consistency .by.
distillation in vacuo. The residue was dissolved in 250 cc. of methylethylketone and allowed to stand The amino-ketone crystalline .precipitate which formed was filtered, washed with methylethylketone, resuspendedfin 100 cc. of fresh methylethylketone, filtered and then recrystallized from 120 cc. of isopropyl alcohol. .Analcoholic solution containing 8 g. (0.25 mole) of'these aminoketone crystals was then reduced with .lgm. of platinum oxide (PtO at a pressure of 60 lbs. of hydro gen. The reaction mixture was filtered and the filtrate concentrated to dryness in vacuo. The oily residue was dissolved in water and the aqueous solution neutralized with 4 g. of sodium bicarbonate. The resultant gummy precipitate was extracted from the aqueous phase with n-butyl alcohol and then acidified with glacial vacetica'cid, (about 3 cc.). This solution was then concentrated to dryness in vacuo and the residue crystallized from 60 cc.
v 6 v of acetone giving a yield ofthe desired compound of 6 g. which has a melting point of 136137 dec.
EXAMPLE- n1 Preparation r o t- 3,4 dihydrOXyphenyD-fl-(N-Z hydroxyethyl) aniinoethanol hydrochloride having the structural formulaz: H a
A mixture of 2-hydroxyethylamine [18.3 g. (0.30 mole)] chloracetylcatechol [18.5 'g. (0.10 mole)] and 60% ethanol cc.) was" stirred at 'room temperaturefor three hours, cooled, acidified with 20 cc. of concentrated-HCl and then concentrated in vacuo until crystals formed. The residual mixture was cooled, filtered and immediately suspended in boiling isopropylalcohol (60 cc.). After cooling and filtering, the 7.5 g. of this aminoketone of the desired antispasmodic compound was dissolved in Water and subjected to hydrogenation with .2 g. of PtO at 60 lbs. of hydrogen. The hydrogenation mixture was filtered, concentrated to dryness in vacuo and crystallized from acetone-isopropanol'. Recrystallization from abso lute ethanol gave a yield of the desired anti-spasmodic compound of 2.7 g. which melted at 116-117 dec.
0 EXAMPLE. 1v
Preparation of aP(3,4-dihydroxyphenyl)-/3-N-(cyclohexylmethyl)-aminoethanol hydrochloride having the structural formula:
V V 1 H HO \N/ ao s A mixture of chloracetylcatechol [13.0 g. (0.07 mole)], cyclohexylmethylamine [22.0 g. (0.20 mole)], and cc. of 60% ethanol was stirred and refluxed for two hours, cooled, acidified with 15 cc. of concentrated aqueous hydrochloric acid and then allowed to stand at room temperature for three days. The crystalline aminoketone precipitate which formed was filtered, washed with 1:1 acetone: ethanol and then acetone. A 50% alcoholic solution of 8 g. (.027 mole), of this aminoketone precipitate was reduced with .2 g. PtO at 60 lbs. of hydrogen, clarified by filtration and concentrated to dryness in vacuo. The residue was dissolved in 60 cc. of hot acetone and the solution allowed to stand for approximately two days. The antispasmodic crystalline precipitate which formed was filtered giving a yield of 5.8 g. (72%) and had a melting point of 151-152 dec.
EXAMPLE V 0 Preparation of a-(3,4-dihydroxyphenyl) -5-(N-2 phenyL isopropyl) aminoethanol hydrochloride halving the structural formula:
at reflux temperature and with continual stirring. Stirring and refluxing were continued for another five hours after which the reaction mixture was cooled and then 75 acidified with 20 cc. of concentrated aqueous HCl. The
EXAMPLE VI Preparation of a (3,4 dihydroxyphenyl) 43 (N- 2 p methoxyphenyl isopropyl) aminoethanol hydrochloride having the structural formula:
A mixture of, p-methoxyphenylisopropylamine [50.0 g. (0.30 mole) chloroacetylcatechol [18.5 g. (0.10 mole) and 80 cc. of 60% ethanol was stirred and heated at 60 for 6 hours. The reaction mixture was acidified with concentrated HC1 and concentrated to a viscous consistency in vacuo. The aminoketone residue was suspended in hot isopropyl alcohol and filtered. This aminoketone filtrate was then reduced with platinum oxide in the same manner as that employed in the previous examples. The residue after concentration was crystallized from acetone giving a 60% yield of the desired compound which had a melting point of 122123 dec.
'8 EXAMl LE vn Preparation of a.-'-(3,4 dihydroxyphenyl) B N- -2-furylisopropyl) -aminoethanol hydrochloride having 'the structural formula:
24.0 g. (0.13 mole) of chloracetylcatechol was added to 50.0 g. (0.40 mole) of Z-furylisopropylanfine dissolved in 80 cc. of ethanol over a period of two hours while stirring continually and maintaining a temperature of 60". Stirring at a temperature of 60 was continued for another two hours. The reaction mixture was then cooled and the pH adjusted to 4 with 21 cc. of concentrated HCl. The acid solution was concentrated to dryness in vacuo and the residue crystallized from 800 cc. of isopropyl alcohol. Five gm. of these aminoketone crystals was reduced in absolute alcohol with platinum oxide at 60 lbs. of hydrogen, concentrated to dryness in vacuo and the residue rubbed under anhydrous ether until crystalline. The desired product was filtered under anhydrous conditions giving a yield of 4.3 g. (86%) which had a melting point of dec.
In the above examples hydrochlorides of the desired compounds were produced. Those skilled in the art can usewell known standard techniques for reducing these chlorides.
Listed in the two following tables are the compounds and their accompanying ketones which I have synthesized.
Table! Analyses Molecular M.P., R Formula degrees Galcd. Found n-hexyl. CuHuClNOs 203-204 4. 87 5.04 2-hexy CuHnGlNO: 195-196 12. 39 4.87 12.75 4.92 n-hepty CuHmOlNOz 213-215 11. 4. 64 11. 62 4. 2-heptyl- CXEHZOINO! 201-203 4. 64 4. 43 3-heptyl C H CINO; 191-193 4. 64 4. 64 4-n1ethyl- OusHnClNO: 204-206 11. 80 4. 64 11.83 4. 71 iso-heptyl ounucuvo. 204-206 11. 80 4. 64 11. 88 4. 63 n-nonyl CuHzaGlNO; 230-233 10. 80 4. 24 10. 82 4. 30 2-nonyl 011111.80 0; 198-199 10.80 10.47 2-hydroxyethyl.-- .OwHnClNOi -196 14. 33 6. 05 14. 30 5. 50 Oyclohexylmethyl 01511210 0: 184-185 12.35 4.87 12. 47. 4. 93 a-Oyclohexylethyl CmHuOINO; 226-228 11.30 11.08 (2-Gyclohexyl) isopropyl 0 E203 0; 216-218 10.82 4. 28 10.78 4.25 1-(a-phenyl)-ethy CuHmClNO: 206-208 11.54 4. 55 11.33 4.54 fl-phenylethyl uHraCl 03 220-221 11.54 4.55 11. 30 4.51 -y-phenylpropyl OnHzoClNO: 218-220 11. 03 4. 36 10.88 4. 33 B -phenylpropyl CrrHzoClNOs 219-220 11. 03 4. 36 11. 02 4 34 B-phenylisopropy OnHzuC 0: 206-208 11. 03 4.30 10.99 4. 35 4-pheny1-2butyl OrnHnClNOa 223-225 10.59 4.17 10.54 4.20 2-(p-methoxyphenyl)- CisHnClNO 203-205 10.11 3. 99 9.89 3.97
iso ropyl.
2-(o-clalorophenyD-isopropyl (l HnClzNou 201-203 19. 92 3. 93 20. 00 4. 02 B (3, 4 methylenedioxy- CisHaoClNO: 232-234 9.70 3. 84 9. 59 3. 84
henyD-isopropyl. 2- a-furyD-isopropyl- GnHuOlNO 181-182 11.41 4.49 11.33 4.5:)
Table H H H -%N\ Analyses Molecular M.P., R Formula degrees Oalcd. Found 166-167 4. 74 4. 98 135-136 4. 32 4. 14 106-108 11 70 4.62 11.70 4. 83 Oi'lHnNOe 126-126. 4. 28 4. OnHnNO; 106-109 4.28 3.70 OuHnNO: 136-137 4. 28 4. 32 OgHnNOn 126-127 4. 28 4. 31 O HggOlNO; 128-129 10. 72 4. 24 11. 14 4. 46 2-nouy1. CflHasClNOa 81-83 10.72 10. 17 2-hydroxyethyl CmHmOlNOq 116-117 14.25 5.62 14. 29 5.50 Oyclohexylmethyl CmHnOlNO: 152 11. 78 4. 11. 77 4. 74 a-oyclohexylethyl OmHnOlNO: 162-163 11.24 4.42 11.53 (2-Oyelohexy1)-isopropy OflHzsClNO: 140-141 10.79 4.25 10.78 4. 34 l-(a-pheuyh-ethyl CmHuNOs 153-153. 5 4. 24 4. 20 B-phenylethyl OlUHlOClNOl 141-142 11.45 4.52 11.60 4.57 'y-phenylpropyl--- C11 120 a 131-132 10.99 4. 33 10.82 4.47 B- henylpropyl--- OnHnOlNO: 65-70 10.99 4.33 10.58 4.20 B -phenylisopropy 011E110 139-140 10. 99 4. 33 11. 00 4. 31 4-phenyl-2-butyl. CroHuNOu 3.88 3.92 2 i-s (p niethoxyphenyl) OXBHHOINO 122-123 10.05 3. 97 9. 86 .3. 97
opropy 2-(o-ch1oropheny1)lsopropyl. OnHnOhNO; 19.82 3.91 B (3, 4 methylenedioxy- OmHnUlNOI 126-127 9. 68 3.81 9. 60 3.76
henyD-isopropyl. 2- a-iuryD-lsopropyl 015H OlN04 70 11.32 4.47 11.20 4. 42
1 Too hygroscoplc.
In normal clinical use, the compounds will be employed in salt form and it is to be understood that the claims hereof cover the salts as well as the fundamental compounds. The activity of the compounds is independent of whether they are in salt form or otherwise. Salts may be prepared by any of the well-known standard methods. While the salt normally employed is the hydrochloride, I have prepared the. compounds in the form of other salts such as acetate, sulfate and tartrate.
This application is related to my application Serial No. 469,305, filed November 16, 1954, and is a continuationin-part of my application Serial No. 230,249, filed June 6, 1951, both of which applications are now abandoned.
Having described my invention as related to the embodiment described herein, it is my intention that the invention be not limited by any of the details of description unless otherwise specified, but rather be construed broadly within its spirit and scope as set out in the accompanying claims.
I claim:
1. A composition of the formula wherein R is a hydroxyethyl group of the formula CH CH 0H 2. A composition of the formula II HQ oHoH-(JHr-N wherein R is a hydroxypropyl group of the formula CH CHOHCH References Cited in the file of this patent UNITED STATES PATENTS Switzerland Dec. 16, 1949 UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,900,415 August 18, 1959 John H. Biel It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 1, line 13, for mucles read muscles; column 2, lines 50 to 55 in the table, second column thereof, the first three compounds should be in the upper bracket and the l-hexyl compound should be bracketed with The new alkyl radical compounds; column 3, lines 23 to 25, the formula should appear as shown below instead of as in the patent:
t H n -GHOH H H lines 46 to 48, for that portion of the formula reading it n read f E CHa CH:
column 4, lines 55 to 57, the formula should appear as shown below instead of as in the patent:
OH: lines 59 to 61, the formula should appear as shown below instead of as in the patent:
same column 4, lines 73 to 75, for the right-hand portion of the formula reading column 5, lines 26 and 27, for (0.2 mole) read (.02 mole)-; line 65, for (0.25 mole) read (.025 mole)-' column 6, lines 63 to 68, Example V, the formula should appear as shown below instead of as in the patent:
on n 1101 E E0 1 B[ 1|C1 II\I 11 no ZZZ-1C3} column 7, lines 20 to 23, for that portion of the formula reading on n column 8, lines 43 to 47, Table I, the formula should appear as shown below instead of as in the patent:
column 10, line 43, the formula should read as shown below instead of as in the patent: -OH OHOHCH Signed and sealed this 12th day of April 1960.
Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Oficer. Oowwm'ssz'oner of Patents,
Claims (1)
1. A COMPOSITION OF THE FORMULA
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US475302A US2900415A (en) | 1954-12-14 | 1954-12-14 | Synthesized antispasmodic compounds |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US475302A US2900415A (en) | 1954-12-14 | 1954-12-14 | Synthesized antispasmodic compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
US2900415A true US2900415A (en) | 1959-08-18 |
Family
ID=23887000
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US475302A Expired - Lifetime US2900415A (en) | 1954-12-14 | 1954-12-14 | Synthesized antispasmodic compounds |
Country Status (1)
Country | Link |
---|---|
US (1) | US2900415A (en) |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3197507A (en) * | 1963-03-21 | 1965-07-27 | American Home Prod | Substituted 3-p-fluorobenzoylpropylphenylalkylamines and method for making the same |
US3207788A (en) * | 1963-10-17 | 1965-09-21 | Upjohn Co | Tertiaryaminoalkoxy derivatives of 2, 2-diphenylacetophenone |
US3211792A (en) * | 1963-01-24 | 1965-10-12 | Hoffmann La Roche | 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof |
US3215732A (en) * | 1960-05-04 | 1965-11-02 | Ici Ltd | Naphthalene derivatives |
US3215739A (en) * | 1960-10-12 | 1965-11-02 | Kefalas As | Method of producing dibenzo (a, d) cyclohepta (1, 4) dienes |
US3215738A (en) * | 1962-01-24 | 1965-11-02 | Hoffmann La Roche | N-(substituted-phenethyl)-1-hydroxy-1-cycloalkyl-ethylamines |
US3225096A (en) * | 1964-03-02 | 1965-12-21 | Lilly Co Eli | N-cyclopropylamine aralkanone and aralkanol amine derivatives |
US3225095A (en) * | 1962-03-31 | 1965-12-21 | Degussa | N-aryl-substituted-propan-(1)-ones and -ols of arylaminoalkanols and salts thereof |
US3253034A (en) * | 1961-12-22 | 1966-05-24 | Ici Ltd | Amino-phenylethanols |
US3312733A (en) * | 1961-09-15 | 1967-04-04 | Ici Ltd | Optically active naphthylethanolamines and the salts thereof |
FR2085683A1 (en) * | 1970-03-07 | 1971-12-31 | Troponwerke Dinklage & Co | |
US3869474A (en) * | 1970-08-07 | 1975-03-04 | Tanabe Seiyaku Co | 3,4-dihydroxy-benzylalcohol amino derivatives |
US3952021A (en) * | 1973-04-28 | 1976-04-20 | Tanabe Seiyaku Co., Ltd. | α-(3,4-Dimethoxyphenethylaminomethyl)-3,4 or 3,5-dihydroxybenzylalcohols and salts thereof |
US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
US4853381A (en) * | 1984-04-17 | 1989-08-01 | Glaxo Group Limited | Ethanolamine compounds |
US5066678A (en) * | 1989-04-24 | 1991-11-19 | Glaxo Group Limited | Phenethandamine derivatives and pharmaceutical use thereof |
US20080045502A1 (en) * | 2003-06-17 | 2008-02-21 | Arena Pharmaceuticals, Inc. | Processes for Preparing 3-Benzazepines |
JP2009529519A (en) * | 2006-03-09 | 2009-08-20 | ソーセイ アールアンドディ リミテッド | Use of β-aminoalcohol in the treatment of inflammatory diseases and pain |
US20100076068A1 (en) * | 2006-12-12 | 2010-03-25 | Andrea Walmsley | Aminoalcohol Derivatives and Their Therapeutic Use |
US20100305316A1 (en) * | 2006-12-05 | 2010-12-02 | Tawfik Gharbaoui | Processes for preparing (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates thereof |
US20110015438A1 (en) * | 2008-03-04 | 2011-01-20 | Carlos Marlon V | Process for the preparation of intermediates related tothe 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5,-tetrahydro-1h-3-benzazepine |
US8501935B2 (en) | 2006-04-03 | 2013-08-06 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto |
US8952197B2 (en) | 2009-06-18 | 2015-02-10 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-HT2C receptor agonists |
US8999970B2 (en) | 2010-09-01 | 2015-04-07 | Arena Pharmaceuticals, Inc. | Administration of an anti-obesity compound to individuals with renal impairment |
US9045431B2 (en) | 2010-06-02 | 2015-06-02 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-HT2C receptor agonists |
US9169213B2 (en) | 2012-10-09 | 2015-10-27 | Arena Pharmaceuticals, Inc. | Method of weight management |
US9248133B2 (en) | 2010-09-01 | 2016-02-02 | Arena Pharmaceuticals, Inc. | Salts of lorcaserin with optically active acids |
US9365521B2 (en) | 2010-09-01 | 2016-06-14 | Arena Pharmaceuticals, Inc. | Non-hygroscopic salts of 5-HT2C agonists |
US10226471B2 (en) | 2010-09-01 | 2019-03-12 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-HT2C agonists useful for weight management |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1913520A (en) * | 1927-10-29 | 1933-06-13 | Winthrop Chem Co Inc | Process of preparing amino alcohols |
US2046946A (en) * | 1933-01-12 | 1936-07-07 | Chemische Fabriken Dr Joachim | Process for the production of diaminoalcohols of the aromatic series |
US2151459A (en) * | 1935-07-14 | 1939-03-21 | Winthrop Chem Co Inc | Derivatives of 3,4-dihydroxyphenylaminopropanols |
US2460144A (en) * | 1946-04-11 | 1949-01-25 | Sterling Drug Inc | Hydroxyphenyl alkanolamines |
CH263801A (en) * | 1948-04-02 | 1949-09-15 | Hoffmann La Roche | Process for the preparation of a tertiary alkyl amine salt. |
US2493471A (en) * | 1945-06-04 | 1950-01-03 | Parke Davis & Co | Stabilized organic compounds and methods of obtaining the same |
BE497436A (en) * | 1949-08-09 | 1950-12-01 | Troponwerke Dinklage & Co | PROCESS FOR THE PREPARATION OF ALCOYL-AROMATIC DIOXYPHENYLETHANOLAMINES. |
BE497437A (en) * | 1949-08-09 | 1950-12-01 | Troponwerke Dinklage & Co | PROCESS FOR PREPARING DIOXYPHENYL-PROPANOL-ARALKYL AMINES. |
US2661373A (en) * | 1953-03-02 | 1953-12-01 | Kulz Ida | Certain amino alcohols and ketones |
-
1954
- 1954-12-14 US US475302A patent/US2900415A/en not_active Expired - Lifetime
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1913520A (en) * | 1927-10-29 | 1933-06-13 | Winthrop Chem Co Inc | Process of preparing amino alcohols |
US2046946A (en) * | 1933-01-12 | 1936-07-07 | Chemische Fabriken Dr Joachim | Process for the production of diaminoalcohols of the aromatic series |
US2151459A (en) * | 1935-07-14 | 1939-03-21 | Winthrop Chem Co Inc | Derivatives of 3,4-dihydroxyphenylaminopropanols |
US2493471A (en) * | 1945-06-04 | 1950-01-03 | Parke Davis & Co | Stabilized organic compounds and methods of obtaining the same |
US2460144A (en) * | 1946-04-11 | 1949-01-25 | Sterling Drug Inc | Hydroxyphenyl alkanolamines |
CH263801A (en) * | 1948-04-02 | 1949-09-15 | Hoffmann La Roche | Process for the preparation of a tertiary alkyl amine salt. |
BE497436A (en) * | 1949-08-09 | 1950-12-01 | Troponwerke Dinklage & Co | PROCESS FOR THE PREPARATION OF ALCOYL-AROMATIC DIOXYPHENYLETHANOLAMINES. |
BE497437A (en) * | 1949-08-09 | 1950-12-01 | Troponwerke Dinklage & Co | PROCESS FOR PREPARING DIOXYPHENYL-PROPANOL-ARALKYL AMINES. |
US2661373A (en) * | 1953-03-02 | 1953-12-01 | Kulz Ida | Certain amino alcohols and ketones |
Cited By (39)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3215732A (en) * | 1960-05-04 | 1965-11-02 | Ici Ltd | Naphthalene derivatives |
US3215739A (en) * | 1960-10-12 | 1965-11-02 | Kefalas As | Method of producing dibenzo (a, d) cyclohepta (1, 4) dienes |
US3312733A (en) * | 1961-09-15 | 1967-04-04 | Ici Ltd | Optically active naphthylethanolamines and the salts thereof |
US3253034A (en) * | 1961-12-22 | 1966-05-24 | Ici Ltd | Amino-phenylethanols |
US3215738A (en) * | 1962-01-24 | 1965-11-02 | Hoffmann La Roche | N-(substituted-phenethyl)-1-hydroxy-1-cycloalkyl-ethylamines |
US3225095A (en) * | 1962-03-31 | 1965-12-21 | Degussa | N-aryl-substituted-propan-(1)-ones and -ols of arylaminoalkanols and salts thereof |
US3211792A (en) * | 1963-01-24 | 1965-10-12 | Hoffmann La Roche | 1-(phenyl)-or 1-(alkyl-substitutedphenyl)-5-(substituted-phenyl)-3-aza penta-(1)-ols and salts thereof |
US3197507A (en) * | 1963-03-21 | 1965-07-27 | American Home Prod | Substituted 3-p-fluorobenzoylpropylphenylalkylamines and method for making the same |
US3207788A (en) * | 1963-10-17 | 1965-09-21 | Upjohn Co | Tertiaryaminoalkoxy derivatives of 2, 2-diphenylacetophenone |
US3225096A (en) * | 1964-03-02 | 1965-12-21 | Lilly Co Eli | N-cyclopropylamine aralkanone and aralkanol amine derivatives |
FR2085683A1 (en) * | 1970-03-07 | 1971-12-31 | Troponwerke Dinklage & Co | |
US3869474A (en) * | 1970-08-07 | 1975-03-04 | Tanabe Seiyaku Co | 3,4-dihydroxy-benzylalcohol amino derivatives |
US3952021A (en) * | 1973-04-28 | 1976-04-20 | Tanabe Seiyaku Co., Ltd. | α-(3,4-Dimethoxyphenethylaminomethyl)-3,4 or 3,5-dihydroxybenzylalcohols and salts thereof |
US4314082A (en) * | 1978-07-14 | 1982-02-02 | American Hospital Supply Corporation | Derivatives of 2-amino-6,7-dihydroxytetrahydro naphthalene (ADTN) |
US4853381A (en) * | 1984-04-17 | 1989-08-01 | Glaxo Group Limited | Ethanolamine compounds |
US5066678A (en) * | 1989-04-24 | 1991-11-19 | Glaxo Group Limited | Phenethandamine derivatives and pharmaceutical use thereof |
US8946207B2 (en) | 2003-06-17 | 2015-02-03 | Arena Pharmaceuticals, Inc. | Processes for preparing 3-benzazepines |
US20080045502A1 (en) * | 2003-06-17 | 2008-02-21 | Arena Pharmaceuticals, Inc. | Processes for Preparing 3-Benzazepines |
US9102627B2 (en) | 2003-06-17 | 2015-08-11 | Arena Pharmaceuticals, Inc. | Processes for preparing 3-benzazepines |
AU2004267016B2 (en) * | 2003-06-17 | 2011-11-24 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases |
US8367657B2 (en) | 2003-06-17 | 2013-02-05 | Arena Pharmaceuticals, Inc. | Processes for preparing 3-benzazepines |
JP2009529519A (en) * | 2006-03-09 | 2009-08-20 | ソーセイ アールアンドディ リミテッド | Use of β-aminoalcohol in the treatment of inflammatory diseases and pain |
JP2013049680A (en) * | 2006-03-09 | 2013-03-14 | Biocopea Ltd | Use of beta-aminoalcohol in treatment of inflammatory disease and pain |
US8501935B2 (en) | 2006-04-03 | 2013-08-06 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto |
US8802845B2 (en) | 2006-04-03 | 2014-08-12 | Arena Phamaceuticals, Inc. | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto |
US20100305316A1 (en) * | 2006-12-05 | 2010-12-02 | Tawfik Gharbaoui | Processes for preparing (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates thereof |
US8299241B2 (en) | 2006-12-05 | 2012-10-30 | Arena Pharmaceuticals, Inc. | Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereof |
US20100076068A1 (en) * | 2006-12-12 | 2010-03-25 | Andrea Walmsley | Aminoalcohol Derivatives and Their Therapeutic Use |
US8822727B2 (en) | 2008-03-04 | 2014-09-02 | Arena Pharmaceuticals, Inc. | Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine |
US20110015438A1 (en) * | 2008-03-04 | 2011-01-20 | Carlos Marlon V | Process for the preparation of intermediates related tothe 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5,-tetrahydro-1h-3-benzazepine |
US8952197B2 (en) | 2009-06-18 | 2015-02-10 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-HT2C receptor agonists |
US9045431B2 (en) | 2010-06-02 | 2015-06-02 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-HT2C receptor agonists |
US8999970B2 (en) | 2010-09-01 | 2015-04-07 | Arena Pharmaceuticals, Inc. | Administration of an anti-obesity compound to individuals with renal impairment |
US9248133B2 (en) | 2010-09-01 | 2016-02-02 | Arena Pharmaceuticals, Inc. | Salts of lorcaserin with optically active acids |
US9365521B2 (en) | 2010-09-01 | 2016-06-14 | Arena Pharmaceuticals, Inc. | Non-hygroscopic salts of 5-HT2C agonists |
US9770455B2 (en) | 2010-09-01 | 2017-09-26 | Arena Pharmaceuticals, Inc. | Administration of an anti-obesity compound to individuals with renal impairment |
US10226471B2 (en) | 2010-09-01 | 2019-03-12 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-HT2C agonists useful for weight management |
US10463676B2 (en) | 2010-09-01 | 2019-11-05 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-HT2C agonists useful for weight management |
US9169213B2 (en) | 2012-10-09 | 2015-10-27 | Arena Pharmaceuticals, Inc. | Method of weight management |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US2900415A (en) | Synthesized antispasmodic compounds | |
AU2006261327B2 (en) | Sphingosine kinase inhibitors | |
SE448730B (en) | NEW 1- (4,4-DIPHENYL BUTYL) PIPERAZINE CARBOXAMIDES AND CARBOTIOAMIDES AND USE OF THESE COMPOUNDS FOR THE PREPARATION OF MEDICINES FOR TREATING CERTAIN DISEASES | |
US3341594A (en) | 1-(3, 5-dihydroxy-phenyl)-1-hydroxy-2-isopropylamino-ethane and salts thereof | |
US2846437A (en) | Lower alkyl 4-phenyl-1-(substituted-alkyl) piperidine-4-carboxylates and preparationthereof | |
EP0363061A1 (en) | Imidazoline derivative and preparation thereof | |
DE69636048T2 (en) | INHIBITORS OF CELL ADHESION AND CELL INFILTRATION | |
Wright et al. | Antidiabetic agents. N4-arylsulfonylsemicarbazides | |
CA1115703A (en) | Piperidinopropyl derivatives | |
DE2503136A1 (en) | 5-METHYLTHIOPYRIMIDINE SUITABLE AS ANTIDIABETIC AND HYPOCHOLESTERINAEMIC DRUGS | |
JP2883970B2 (en) | New 1,4- (diphenylalkyl) piperazine derivatives | |
US2978454A (en) | Lower alkyl-4-phenyl-1-[(diloweralkoxy phenyl)-aliphatic] piperidine-4-carboxylates | |
US4086234A (en) | Process for the preparation of tertiary amines | |
US4478838A (en) | 1-(3,4,5-Trimethoxycinnamoyl)-4-alkylaminocarbonylethyl piperazines | |
DE3228992A1 (en) | SPIROTHIAZOLIDINDION DERIVATIVES, PRODUCTION OF THESE COMPOUNDS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM | |
DE2513865A1 (en) | 1,2-DIPHENYLAETHANOLAMINE DERIVATIVES | |
AU637670B2 (en) | Piperazine compound, production thereof, and medicinal use thereof | |
DE2825407C3 (en) | Piperazine dithiocarboxylic acid derivatives, process for their preparation and pharmaceuticals containing them | |
US4259257A (en) | 1-Phenyl-2-amino-1,3-propanediol-N-aryloxyalkyl derivatives | |
JPS63227570A (en) | Isoquinoline derivative | |
US2824111A (en) | Pyrrolidines | |
Lourie et al. | The Syntheses and Hypotensive Activities of Some Substituted 1, 4-Diazabicyclo [4.4. 0] decanes | |
US3651232A (en) | Compositions and methods for lowering blood sugar levels | |
DE4300696A1 (en) | Substituted N-aminoalkyl methanesulfanilides as antispasmodics | |
US4221814A (en) | Terephthalic acid monoamide derivatives, process for preparing the same, and an anti-allergic agent prepared from the same |