US2786834A - Bicycloazaoctane derivatives - Google Patents
Bicycloazaoctane derivatives Download PDFInfo
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- US2786834A US2786834A US479872A US47987255A US2786834A US 2786834 A US2786834 A US 2786834A US 479872 A US479872 A US 479872A US 47987255 A US47987255 A US 47987255A US 2786834 A US2786834 A US 2786834A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/24—Camphidines
Definitions
- This invention relates to compositions of matter, particularly to chemo-therapeutic organic compounds and methods of their preparation, and more particularly to compounds of value in the treatment of cardio-vascular and other diseases.
- the invention relates to bicycloazaoctane and the simple salts and the monoand bis-quaternary salts of bicycloazaoctane.
- Another object is to provide novel, physiologically active compounds characterized by chemotherapeutic or medicinal properties, particularly hypotensive activity.
- a more specific object is to provide novel compounds, namely, bis-quaternary salts o'fbicycloazaoctane.
- Another and equally important object of the invention is the provision of methods of synthesizing the novel compounds referred to in the foregoing objects.
- novel chemotherapeutic compounds of the present invention are bis-quaternary salts of l-methyl-S-dimethyl- 3-azabicyclo (3,2,1) octane (camphidine) the base itself being shown in the formula following:
- the novel compounds discovered are obtained by forming the N-dialkylaminoalkyl 'imides of alkyl group with from 1 to 6 carbon atoms, an alkylene group containing 3 carbon atoms or, the structure may represent a heterocyclic ring namely, morpholine, piperidine, pyrrolidine or piperazine.
- A represents the parent bicycloaZo-octane nucleus and X" represents an anion namely, iodide, chloride, bromide, acetate or sulfate.
- R, R and n have the same meaning in all formulae as described above for Formula 1.
- the site of both simple and quaternary salt formation on the nucleus A is always the nitrogen at position 3.
- R" represents a simple alkyl group having one to three carbon atoms. R may be the same as,
- the free bases and simple salts possess antihistaminic and bronchiodilatory activity.
- the free bases, Formula I possess in varying degree a very discrete moldy or earthy odor which is of value in obtaining this rare type of odor in perfumery or other special preparations in which these particular odoriferous qualities are desired.
- EXAMPLE I N-dimethylaminoethyl-D-camphidine, simple salts and quaternary salts
- the free base has prepared as follows: grams of N-dimethylaminoethyl-D-camphorimide dissolved in 300 ml. of anhydrous ethyl ether was added dropwise to a rapidly stirred solution of 16 grams (0.44 mole) of lithium aluminum hydride (LAH) dissolved in 600 ml. of anhydrous ethyl ether. The addition was at such a rate as to just maintain a gentle reflux of the ether. After the addition was complete, the mixture was stirred under reflux for an additional 2 hours and allowed to stand over night.
- LAH lithium aluminum hydride
- the dihydrochloride a crystalline hygroscopic salt, was prepared by treating the free base dissolved in ethanol with a saturated ethanolic-I-ICl solution. It had a melting point 2634 C. On recrystallization from absolute methanol-anhydrous other it had a melting point of 265-266 C. and an experimentally determined chloride ion content of 23.41% as compared to 23.85% theoretically calculated.
- the dimethiodide could not be obtained by simple reaction of thefree base with methyl iodide in large excess in methanol or ethanol. only the monomethiodide obtained was prepared by adding the free base to pure methyl iodide. For this reason and on the basis of the following experiments, it is concluded that the monomethiodide described above must be the quaternary salt of the side chain nitrogen and not that of the ring nitrogen. Examination of a molecular model of this molecule showed that the ring nitrogen ofiered considerable hindrance to the formation of a quaternary salt here. The following experiments illustratethe difliculty of quaternizing the ring nitrogen and the manner in which this was finally accomplished.
- the dihydrochloride was prepared as described under Example I and had a melting point of 290292 C. Chloride ion calculated theoretically, 22.78%; chloride ion found by analysis, 22.92%.
- the dihydr0chl0ride The dihydrochloride of N-diethylaminoethyl-D-norcamphidine was also prepared as in Example I and was found to have a melting point of 254.5-255.5 C. and a chloride ion content of 21.77%
- the m0n0methiodide.-The salt was prepared as described under Example I. Its melting point is 196-198 C. and it has an iodide content of 31.13% as compared -with a theoretical value of 31.07%
- the dimethiodide-This compound was prepared as described under Experiment 4, Example I. Its melting point is 217219 C. and its iodide content is 45.88%
- novel compounds disclosed herein are highly efficacious in the treatment of physiological disorders requiring anti-histaminic, bronchiodilatory, and hypotensive etfects.
- milligrams of the quaternary salts in parenteral solution may be administered once a day or -250 milligrams may be given orally in the form of tablets, capsules or the like.
- the base compounds may be given orally or by injection in 50 milligram doses.
Description
BICYCLOAZAOCTANE DERIVATIVES Leonard M. Rice, Baltimore, Md., and Charles H. Grogan, Falls Church, Va., assignors to The Geschickter Fund for Medical Research, Inc., Washington, D. C., a cor-- poration of New York N Drawing. Application January 4, 1955, Serial No. 479,872
9 Claims. (Cl. 260-239) This invention relates to compositions of matter, particularly to chemo-therapeutic organic compounds and methods of their preparation, and more particularly to compounds of value in the treatment of cardio-vascular and other diseases.
Specifically the invention relates to bicycloazaoctane and the simple salts and the monoand bis-quaternary salts of bicycloazaoctane.
Accordingly, it is a basic object of the present invention to provide novel organic compounds and methods for the preparation thereof.
Another object is to provide novel, physiologically active compounds characterized by chemotherapeutic or medicinal properties, particularly hypotensive activity.
A more specific object is to provide novel compounds, namely, bis-quaternary salts o'fbicycloazaoctane.
Another and equally important object of the invention is the provision of methods of synthesizing the novel compounds referred to in the foregoing objects.
These and other objects and the manner in which they are accomplished will become apparent to those conversant with the art from the following description of the general class of compounds and certain specific examples of particular members thereof as well as general and specific methods of their synthesis.
The novel chemotherapeutic compounds of the present invention are bis-quaternary salts of l-methyl-S-dimethyl- 3-azabicyclo (3,2,1) octane (camphidine) the base itself being shown in the formula following:
Generally stated, the novel compounds discovered are obtained by forming the N-dialkylaminoalkyl 'imides of alkyl group with from 1 to 6 carbon atoms, an alkylene group containing 3 carbon atoms or, the structure may represent a heterocyclic ring namely, morpholine, piperidine, pyrrolidine or piperazine.
The simple salts of the bases illustrated by Formula 1 are shown by Formula 2.
X- X- R and the monoand bis-quaternary salts of these bases by Formulae 3(a) and 3(1)), respectively:
In Formulae 2, 3(a) and 3(5), A represents the parent bicycloaZo-octane nucleus and X" represents an anion namely, iodide, chloride, bromide, acetate or sulfate. R, R and n have the same meaning in all formulae as described above for Formula 1. In the three latter formulae, i. e., 2, 3(a) and 3(b), the site of both simple and quaternary salt formation on the nucleus A is always the nitrogen at position 3. In the. quaternary and bisquaternary salts, R" represents a simple alkyl group having one to three carbon atoms. R may be the same as,
'or'ditferent from, R and/or R in any of the formulae given. V
Of the compounds described above, the free bases and simple salts possess antihistaminic and bronchiodilatory activity. The quaternary salts of these bases, and particularly the bis-quaternary salts thereof, possess a marked hypotensive activity in mammals at a low dosage level and at the same time a favorable therapeutic ratio. In addition, the free bases, Formula I, possess in varying degree a very discrete moldy or earthy odor which is of value in obtaining this rare type of odor in perfumery or other special preparations in which these particular odoriferous qualities are desired.
The following examples of specific compounds and methods will illustrate the manner in the general synthesizing procedure which may be applied to obtain particular members of the class of compounds discovered. It will be understood, however, that the following examples are not nor are they intended to be exhaustive of all compounds embraced by the present invention.
EXAMPLE I N-dimethylaminoethyl-D-camphidine, simple salts and quaternary salts The free base. -The free base has prepared as follows: grams of N-dimethylaminoethyl-D-camphorimide dissolved in 300 ml. of anhydrous ethyl ether was added dropwise to a rapidly stirred solution of 16 grams (0.44 mole) of lithium aluminum hydride (LAH) dissolved in 600 ml. of anhydrous ethyl ether. The addition was at such a rate as to just maintain a gentle reflux of the ether. After the addition was complete, the mixture was stirred under reflux for an additional 2 hours and allowed to stand over night. The reaction mixture was then decomposed by the dropwise addition of water at such a rate as to just cause reflux of the ether. When the evolution of hydrogen ceased, a slight excess of water was added and the mixture stirred for several hours. The inorganic material was filtered oil? and the residue washed several -times with ether. The ethereal filtrate was dried over anhydrous sodium'sulphate, the ether was stripped E and the residue was vacuum distilled to yield 33 grams of N- dimethylaminoethyl-D-camphidine base having a boiling point of 64 C. at 0.4 mm.; N =1.478.
The dihydrochloride.The dihydrochloride, a crystalline hygroscopic salt, was prepared by treating the free base dissolved in ethanol with a saturated ethanolic-I-ICl solution. It had a melting point 2634 C. On recrystallization from absolute methanol-anhydrous other it had a melting point of 265-266 C. and an experimentally determined chloride ion content of 23.41% as compared to 23.85% theoretically calculated.
The m0n0methi0dide.-The monomethiodide was readily obtained in crystalline form by treatment of the free base dissolved in absolute isopropanol with an excess of methyl iodide in a closed system. It had a melting point of 239240 C. Recrystallization of the salt from anhydrous methanol-anhydrous ether gave the compound with a melting point'of 241 C. The iodide ion calculated theoretically was 34.65% and that found to be present in this compound was 34.46%.
The dimethiodide.The dimethiodide could not be obtained by simple reaction of thefree base with methyl iodide in large excess in methanol or ethanol. only the monomethiodide obtained was prepared by adding the free base to pure methyl iodide. For this reason and on the basis of the following experiments, it is concluded that the monomethiodide described above must be the quaternary salt of the side chain nitrogen and not that of the ring nitrogen. Examination of a molecular model of this molecule showed that the ring nitrogen ofiered considerable hindrance to the formation of a quaternary salt here. The following experiments illustratethe difliculty of quaternizing the ring nitrogen and the manner in which this was finally accomplished.
Experiment 1.4 grams of the free base plus 10 ml. of methyl iodide were refluxed for 2 hours in 50 ml. of
In fact,
anhydrous methanol and yielded a white crystalline solidhaving a melting point of 232-234 C. On analysis, the
percentage of iodide ion introduced was found to be 36.76% or only slightly higher than the 34.65% theoretically required for the monomethiodide.
Experiment 2.Repeating Experiment 1 and refluxing for 12 hours in isopropanol gave a crystalline product i with 38.95% iodide ion.
Experiment 3.Repeating Experiment 1 and refluxing .the free base in pure methyl iodide for 3 days gave a discolored crystalline material with 44% iodide ion. The
' theoretical iodide ion content for the dimethiodide is indicating therefore that the compound obtained by means of Experiment 4 is in the dimethiodide.
EXAMPLE II N-dimethylaminopropyl-DL-camphidine, simple salts and quaternary salts Free base.-The free base was prepared as described under Example I by reducting 40 grams of the corresponding imide with 16 grams of LAH in anhydrous ether medium. The free base was obtained in 31 grams yield and had a boiling point of 7072 C. at 0.1 mm.; n =1.4770.
The dihydrochloride.The dihydrochloride was prepared as described under Example I and had a melting point of 290292 C. Chloride ion calculated theoretically, 22.78%; chloride ion found by analysis, 22.92%.
The m0n0methi0dide.-The monomethiodide, melting point 237-238 C., was prepared by reaction of the free base with an excess of methyl iodide in anhydrous methanol. Its theoretical iodide content is 33.37% and in analysis of the compound so obtained was 33.55%.
The dimethiodide.-The dimethiodide was prepared above under Experiment 4, Example I, the heating at 250 F. being carried on for 8 hours. It had a melting point of 269271 C. and an iodide content of 48.63% as compared with a theoretical iodide content of 48.60%.
EXAMPLE IH N-diethylaminoethyl-D-camphidine, simple salts and quaternary salts The free base-The free base was prepared as described under Example I, above. Reduction of 40 grams of the imide yielded 29 grams of the base, which has a boiling point of 7074 C. at 0.1 mm.; n =1.4780.
The dihydr0chl0ride.The dihydrochloride of N-diethylaminoethyl-D-norcamphidine was also prepared as in Example I and was found to have a melting point of 254.5-255.5 C. and a chloride ion content of 21.77%
the manner described under Experiment 4, Example I,
above. 'It has a melting point of 235-236 C. An analysis showed an iodide content of 47.13% as compared to a 47.16% theoretical value.
EXAMPLE IV N-diethylaminopropyl-D-camphidine, simple salts and quaternary salts The free base-This base was prepared as described under Example I; 40 grams of imide yielded 32 grams of the base which had a boiling point of 8387 C. at 0.06 mm.; n =1.4778.
The dihydrochl0rz'de.This salt was prepared as described under Example I and has a melting point of 212- 214 C. The analysis of the salt for chloride ion resulted in a finding of 20.74% as compared with a theoretical content of 20.89%
The m0n0methiodide.-The salt was prepared as described under Example I. Its melting point is 196-198 C. and it has an iodide content of 31.13% as compared -with a theoretical value of 31.07%
The dimethiodide-This compound was prepared as described under Experiment 4, Example I. Its melting point is 217219 C. and its iodide content is 45.88%
compared with 46.12% theoretically calculated.
Other N-dialkylaminoalkyl substitutions have been prepared in similar fashion as shown by the following tables:
-,Table I shows the bases and Table II shows the various salts,
TABLE I Bases N-DIALKYLAMINOALKYL-l-METHYL-8,8-DIMETHYL-3-AZABICYCLO [3.2.1] OCTANES Analysis. Percent B. P., N-substltutlon Formula 0. mm. Carbon Hydrogen Nitrogen on Calcd Found Calcd. Found Caled. Found l-dimothylamiuoethyl CuHggNg 6-1- 66 0.4 74. 94 75.05 12.58 12.44 12.49 12. 79 1. 4781 2-diethylaminoethyl... CrsHsiNr 70- 74 O. 1 76.12 76. 28 12. 78 12.86 11.10 11.28 1. 4780 i e wam opmpr CrsHsoN-r 76- so 0.2 75.56 75. 21 12.68 12. 40 11.75 11.67 1.4772
4-dunethy1amin0pr0p3 OisHzoNz 70- 0. 1 75. 56 75. 30 12. 68 12.30 11. 75 11. 54 1. 4770 y opropyl. C11Ha4Nz 81- 89 '0. 05 76. 62 76.63 12.86 12.73 10.51 10.44 1.4778
fi-diethylarninobutyl CrsHaaNz 96-100 0. 1 77. 07 77. 06 12. 94 12. 92 9. 99 9. 67 1. 4771 7-diethylaminoamyl. CmHagNz 100-105 0. 1 77.48 77. 63 13. 01 13. 10 9. 51 9. 36 1.4766
8-dlbutylarninopropyl. CzrHqtNz 106-110 0. 1 78. 19 77. 94 l3. l2 12. 95 8. 69 8. 23 1. 4756 9-morpholinoethyl CwHsoNzO 102-105 0. 1 72. 13 71. 85 11. 35 11. 36 10. 52 10. 31 1. 4954 10-pyrrolidinoethyl CmHguNg 88- 93 0.2 76. 74 76. 49 12.08 12.42 11.19 10.79 1. 4960 TABLE II Derivatives of compounds in Table I H01 Ionic Chlorine Monomethiodide Dimethlodide lonic Iodine Ionic Iodine Formula M. R, C. Oalcd. Found Formula M. P., 0. Formula Calcd. Found Calcd. Found 1. OuHsnClzNa 263-264 23. 85 23. 41 C E 3 11921.. CmHarIaNz 244-245 49. 94 50. O5 2. CrsHarCltNi. 254. 5-255. 5 21. 66 21. 77 47. 16 47. 63 3. CH32C12N2. 290-291 22. 78 22.74 48.60 48. 32 4. laHazGlzNz. 290-291 22. 78 22.92 48. 60 48. 63 5. CuHasClzNz. 212-214 20. 89 20. 74 46.12 45. 88 lBHBzG12'N2. 286-286 20.07 19.97 44.98 44.46 7. CmHroClzNz. 274-275 19. 29 19.59 43. 89 44. 15 8. CzrHnClzNz. 138-140 17.93 17.94 41.86 41.57 9. CmHazCle 1 263-264 20. 90 20.72 46.13 45. 96 10. CmHmChNz. 263-265 21.93 22.10 O17H33LN2. CmHauIgN: 250-251 47. 51 47.85
As previously mentioned, the novel compounds disclosed herein are highly efficacious in the treatment of physiological disorders requiring anti-histaminic, bronchiodilatory, and hypotensive etfects. For relief of hypertension milligrams of the quaternary salts in parenteral solution may be administered once a day or -250 milligrams may be given orally in the form of tablets, capsules or the like.
As a respiratory stimulant, the base compounds may be given orally or by injection in 50 milligram doses.
From the foregoing description of a novel class of compounds, particular exemplary members of the class and methods of synthesizing same, it will be understood that, on the basis of the discovery and knowledge disclosed herein, other specific compounds can be made and variations in the methods of synthesis resorted to. Therefore, the specific compounds and methods disclosed herein are to be considered in all respects as illustrative and not restrictive, the scope of the discovery being indicated by the appended claims rather than the foregoing description, and all specific compounds and variations and methods which come within the meaning and range of equivalency of the claims are therefore intended to be embraced there- This application is a continuation-in-part of our application Serial No. 388,062, filed October 23, 1953, entitled Bicycloazaoctane Derivatives, now abandoned.
We claim:
1. A compound selected from the group consisting of (1) compounds having the formula where, in said formula, n is a number from 1 to 5 and R is a member of the group consisting of dialkyl groups each alkyl group having 1 to 6 carbon atoms and radicals forming, together with the nitrogen atom to which they are attached, heterocyclic groups consisting of morpholine,
' piperidine, piperazine and pyrrolidine, and (2) the acid References Cited in the file of this patent FOREIGN PATENTS Germany Nov. 12, 1921 OTHER REFERENCES Auwers: Chem. Abst., vol. 17, p. 1644 (1923).
Claims (1)
1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) COMPOUNDS HAVING THE FORMULA
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US479872A US2786834A (en) | 1955-01-04 | 1955-01-04 | Bicycloazaoctane derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US479872A US2786834A (en) | 1955-01-04 | 1955-01-04 | Bicycloazaoctane derivatives |
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| US2786834A true US2786834A (en) | 1957-03-26 |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2904548A (en) * | 1957-01-28 | 1959-09-15 | Geschickter Fund Med Res | N-substituted-3-azabicyclo [3:3:0] octane-2, 4-diones and salts thereof |
| US2962496A (en) * | 1957-01-28 | 1960-11-29 | Geschickter Fund Med Res | Nu-substituted-3-azabicyclooctanes [3: 3: 0] and salts thereof |
| US2973368A (en) * | 1957-01-28 | 1961-02-28 | Geschickter Fund Med Res | 3-azabicyclo [3:2:0] heptane and derivatives thereof |
| US2991288A (en) * | 1961-07-04 | Camphidine derivatives | ||
| DE1138396B (en) * | 1957-06-06 | 1962-10-25 | Aktieselskabet Pharmacia, Kopenhagen | Process for the preparation of quaternary and bisquaternary camphidinium salts. |
| US3092630A (en) * | 1958-12-19 | 1963-06-04 | Gen Aniline & Film Corp | Preparation of nu-substituted-3-morpholones |
| US3224861A (en) * | 1961-07-03 | 1965-12-21 | Monsanto Co | Controlling undesired vegetation with benzyl hexamethyleniminecarbothioates |
| US3268588A (en) * | 1962-11-16 | 1966-08-23 | Celanese Corp | Process for producing hexamethylenediamine from 1-6-hexanediol |
| US4066662A (en) * | 1973-12-14 | 1978-01-03 | Science Union Et Cie., Societe Francaise De Recherche Medicale | N-substituted-2-aminomethyl-3-azabicyclo(3,3,0)octane compounds |
| US4952559A (en) * | 1986-10-24 | 1990-08-28 | Gaf Chemicals Corporation | Fragrance additive |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE362379C (en) * | 1916-10-20 | 1922-10-27 | Margarete Freifrau Von Axter G | Process for the preparation of basic compounds of camphoric acid imide |
-
1955
- 1955-01-04 US US479872A patent/US2786834A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE362379C (en) * | 1916-10-20 | 1922-10-27 | Margarete Freifrau Von Axter G | Process for the preparation of basic compounds of camphoric acid imide |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2991288A (en) * | 1961-07-04 | Camphidine derivatives | ||
| US2904548A (en) * | 1957-01-28 | 1959-09-15 | Geschickter Fund Med Res | N-substituted-3-azabicyclo [3:3:0] octane-2, 4-diones and salts thereof |
| US2962496A (en) * | 1957-01-28 | 1960-11-29 | Geschickter Fund Med Res | Nu-substituted-3-azabicyclooctanes [3: 3: 0] and salts thereof |
| US2973368A (en) * | 1957-01-28 | 1961-02-28 | Geschickter Fund Med Res | 3-azabicyclo [3:2:0] heptane and derivatives thereof |
| DE1138396B (en) * | 1957-06-06 | 1962-10-25 | Aktieselskabet Pharmacia, Kopenhagen | Process for the preparation of quaternary and bisquaternary camphidinium salts. |
| US3092630A (en) * | 1958-12-19 | 1963-06-04 | Gen Aniline & Film Corp | Preparation of nu-substituted-3-morpholones |
| US3224861A (en) * | 1961-07-03 | 1965-12-21 | Monsanto Co | Controlling undesired vegetation with benzyl hexamethyleniminecarbothioates |
| US3268588A (en) * | 1962-11-16 | 1966-08-23 | Celanese Corp | Process for producing hexamethylenediamine from 1-6-hexanediol |
| US4066662A (en) * | 1973-12-14 | 1978-01-03 | Science Union Et Cie., Societe Francaise De Recherche Medicale | N-substituted-2-aminomethyl-3-azabicyclo(3,3,0)octane compounds |
| US4952559A (en) * | 1986-10-24 | 1990-08-28 | Gaf Chemicals Corporation | Fragrance additive |
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