US2780577A - Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives - Google Patents
Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives Download PDFInfo
- Publication number
- US2780577A US2780577A US228543A US22854351A US2780577A US 2780577 A US2780577 A US 2780577A US 228543 A US228543 A US 228543A US 22854351 A US22854351 A US 22854351A US 2780577 A US2780577 A US 2780577A
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- US
- United States
- Prior art keywords
- diquaternary
- activity
- stilbazoline
- curariform
- polymethylene
- 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
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- -1 polymethylene Polymers 0.000 title claims description 11
- 230000002401 inhibitory effect Effects 0.000 title description 5
- 230000000694 effects Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 239000000842 neuromuscular blocking agent Substances 0.000 claims description 3
- 150000003839 salts Chemical group 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229950000405 decamethonium Drugs 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- HLXQFVXURMXRPU-UHFFFAOYSA-L trimethyl-[10-(trimethylazaniumyl)decyl]azanium;dibromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCCCCCCC[N+](C)(C)C HLXQFVXURMXRPU-UHFFFAOYSA-L 0.000 description 2
- GXFZCDMWGMFGFL-KKXMJGKMSA-N (+)-Tubocurarine chloride hydrochloride Chemical compound [Cl-].[Cl-].C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CC[NH+]3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 GXFZCDMWGMFGFL-KKXMJGKMSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- RKVCIHSKQLKLDQ-UHFFFAOYSA-N [Br-].[Br-].C[NH+](C)C.C[NH+](C)C Chemical compound [Br-].[Br-].C[NH+](C)C.C[NH+](C)C RKVCIHSKQLKLDQ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- IUKQLMGVFMDQDP-UHFFFAOYSA-N azane;piperidine Chemical compound N.C1CCNCC1 IUKQLMGVFMDQDP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003156 neuromuscular nondepolarizing agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940045681 other alkylating agent in atc Drugs 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a new class of derivatives having the property of inhibiting the action of certain curariform drugs. These compounds comprise a family of diquaternary salts having the formula:
- R and R are radicals selected from the class consisting of the methyl and ethyl radicals and R is a lower alkyl radical of not over four carbon atoms, and X- is the anion of a non-toxic acid.
- the compounds of the present invention are conveniently prepared by a sequence of reactions parallel to that shown in our co-pending patent application No. 218,279, now Pat. No. 2,655,503, on the -y-stilbazoline diquaternary salts.
- X- is 1'.
- the iodides can readily be converted into other salts by conventional methods. In the doses to be used in practice the nature of the anion is of no consequence and therefore we consider all anions of acids possessing low inherent toxicity to be equivalent and comprehended in our invention.
- EXAMPLE 1 1 methyl 2 (4' dimethylaminophenethyl) piperidine bis methiodide (compound 49-204)
- the base obtained from 12.5 g. (0.033 mole) of 1 methyl 2 (4 dimethylaminophenethyl) piperidine hydroiodide (or 1 methyl 4 dimethylamino a stilbazoline hydroiodide) was taken up in ether and dried over potassium carbonate. The solution was filtered from the desiccant and evaporated. The residual base (8.3 g.) was dissolved in methanol, 8 cc. of methyliodide was added, and the solution was refluxed 8 hours on the steam bath.
- the second portion of the solution of the precursor base was converted to the his ethiodide.
- This like the bis propiodide and his butiodide of Example 2 could not be crystallized but was obtained as a pseudo solid of correct composition.
- a method of checking the curate-like activity of a polymethylene.diquaternary curariform drug which comprises the administration to a human being of a salt of the bivalent cation:
- a method of checking the curare-like activity of a polymethylene diquaternary curariform drug which comprises the administration to a human being of a salt of the bivalent cation:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent 4 Claims. (Cl. 167-65) The present invention relates to a new class of derivatives having the property of inhibiting the action of certain curariform drugs. These compounds comprise a family of diquaternary salts having the formula:
wherein R and R are radicals selected from the class consisting of the methyl and ethyl radicals and R is a lower alkyl radical of not over four carbon atoms, and X- is the anion of a non-toxic acid.
The inhibiting action of these compounds which are derived from alpha-stilbazoline is entirely unexpected in view of the very potent curare-like activity of the closely related diquaternary salts of the 'y-stilbazoline system such as While the present derivatives show only very minor curate-like activity, they possess the surprising property of inhibiting the action of their 'y-analogs. This inhibitory action, however, does not extend to natural d-tubocurarine chloride but it does afiect the powerful polymethylene diquaternary salts of which thebest known is decarn'ethylene bis-trimethylammonium bromide (Decamethonium Bromide, Syncurine, Ceeten,. C-lO). Since these latter compounds which are already in clinical use suffer from the disadvantage of having no direct antidote, the protective utility of our a-stilbazoline diquaternary salts in medicine is considerable.
The compounds of the present invention are conveniently prepared by a sequence of reactions parallel to that shown in our co-pending patent application No. 218,279, now Pat. No. 2,655,503, on the -y-stilbazoline diquaternary salts.
2,780,577 A, Patented Feb. 5, 1957 base Steps land 11 have already been described (Phillips, J. Org. Chem, 12, 333 (1947), and J. Amer. Chem. Soc., 72, 1850 (1950) wherefore the present application discloses only those processes involved in the third step and the preparation of certain intermediates not specifically reported before.
In the general formula of these diquaternary salts the III nature of the alkyl groups (R, R and R appears not 7 to be especially critical; however, the simplest compound in which all are methyl groups is at least as active as any of the others. Further, with increasing size of the alkyl groups the respiration is afiected unfavorably and the synthetic operations become more difficult so that the given limits cover the substances that are believed to be of practical utility. The compounds having R =n-propyl and n-butyl with R=R =methyl were not obtained in crystalline form though analytically pure. In part this may be due to the general tendency of larger alkyl groups to lower melting points; however, other influences may be at work. When all-alkyl groups are the same these substances have one asymmetric atom and exist as racemic mixtures, but when R and R are ditferent a second point of asymmetry is created at the piperidine nitrogen. Such substances can exist in four stereo-isomeric forms or as two different racemic modifications. It is very likely that the lower and unsharp melting points correspond to the presence of such isomeric mixtures. Further separation of isomers will doubtless reveal variations in physiological activity, but it is not believed that such separation will be of commercial value.
According to the given scheme of synthesis X- is 1'. However, other anions can be present. such as Br, SO4= etc. through the use of other alkylating agents in place of methyl or ethyl iodide. Furthermore, the iodides can readily be converted into other salts by conventional methods. In the doses to be used in practice the nature of the anion is of no consequence and therefore we consider all anions of acids possessing low inherent toxicity to be equivalent and comprehended in our invention.
EXAMPLE 1 1 methyl 2 (4' dimethylaminophenethyl) piperidine bis methiodide (compound 49-204) The base obtained from 12.5 g. (0.033 mole) of 1 methyl 2 (4 dimethylaminophenethyl) piperidine hydroiodide (or 1 methyl 4 dimethylamino a stilbazoline hydroiodide) was taken up in ether and dried over potassium carbonate. The solution was filtered from the desiccant and evaporated. The residual base (8.3 g.) was dissolved in methanol, 8 cc. of methyliodide was added, and the solution was refluxed 8 hours on the steam bath. The solvent and excess methyliodide were then evaporated and the diquaternary salt was crystallized from a methanol ethyl acetate mixture, M. P., 188- 189 C. Conversion to the chloride was accomplished by shaking with silver chloride in aqueous solution.
3 EXAMPLE 2 N methyl 2 (4 dimethylaminophenethyl) piperidine bis ethiodide (compound 49-241) By the method of Example 1, 1 methyl 2 (4 di methylaminophenethyl) piperidine was converted to its bis-ethiodide which melts at. 205-6.
The corresponding bis n-propiodide and bis n-butiodide were also prepared by the same procedure. Although they could not be obtained crystalline, they were precipitated a number of times as oils which hardened on rubbing with ether to apparent solids. These gave correct analysis for carbon, hydrogen, and iodine and may be regarded as analytically pure. They may be mixtures of stereoisomers. These solids softened over the ranges of 145-l50, and 115-120 C'. respectively EXAMPLE. 3
1' methyl 2 (4 diethylaminophenethyl) piperidine bismethiodide The base was liberated from 6 g. (0.015 mole) of 1 methyl 2 (4 diethylaminophenethyl) piperidine, taken into ether and dried over potassium carbonate. After evaporation of the solvent ether the residue was dissolved in 15 cc. of methanol and the solution was divided into two equal portions. To one of these was added cc. of methyl iodide and the solution was refluxed 18 hours. The solvent was evaporated and the residue was crystallized from ethanol-ether mixtures. The product (3.5 g.) melted with decomposition at 191- 192 C.
The second portion of the solution of the precursor base was converted to the his ethiodide. This, like the bis propiodide and his butiodide of Example 2 could not be crystallized but was obtained as a pseudo solid of correct composition.
omorn-Q-mnnw 2X- N 7 3. A method of checking the curate-like activity of a polymethylene.diquaternary curariform drug which comprises the administration to a human being of a salt of the bivalent cation:
4. emeraQarwmncm.
4. A method of checking the curare-like activity of a polymethylene diquaternary curariform drug which comprises the administration to a human being of a salt of the bivalent cation:
omcmQ-mcnmum References Cited in the file of this patent Phillips. (1): J. Org. Chem., vol. 14, pp. 302-5 (1949).
Phillips (II): J. Am. Chem. Soc., vol. 72, pp. 1850-2, April 1950.
Claims (1)
1. A METHOD OF CHECKING THE CURARE-LIKE ACTIVITY OF A POLYMETHYLENE DIQUATERNARY CURARIFORM DRUG WHICH COMPRISES THE ADMINISTRATION TO A HUMAN BEING OF A COMPOUND OF THE FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US228543A US2780577A (en) | 1951-05-26 | 1951-05-26 | Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US228543A US2780577A (en) | 1951-05-26 | 1951-05-26 | Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2780577A true US2780577A (en) | 1957-02-05 |
Family
ID=22857612
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US228543A Expired - Lifetime US2780577A (en) | 1951-05-26 | 1951-05-26 | Inhibiting polymethylene diquaternary curariform activity by alpha-stilbazoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2780577A (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3119824A (en) * | 1964-01-28 | L-substituted-l | ||
| US3135659A (en) * | 1962-05-02 | 1964-06-02 | Wallace & Tiernan Inc | Hydroxy and alkoxy aryl quinazolinones |
| US3161653A (en) * | 1960-11-23 | 1964-12-15 | Merck Ag E | 2-[(2'-methyl-benzo-thienyl-3')-methyl]-delta2-imidazoline and its pharmaceutically aceptable acid addition salts |
| US3169090A (en) * | 1961-01-23 | 1965-02-09 | Upjohn Co | Thiazoline analgesics |
| US3209025A (en) * | 1960-10-29 | 1965-09-28 | Hoechst Ag | Bis-(beta-carbhydrazido-ethyl)-sulfone |
| US3222365A (en) * | 1962-01-15 | 1965-12-07 | Lilly Co Eli | 4-halophenyl-2-alkyl-1(2)-phthalazinones |
| US3235566A (en) * | 1966-02-15 | Benzofuran-j-carboxylic acids and esters | ||
| US3271398A (en) * | 1962-03-05 | 1966-09-06 | Fujisawa Pharmaceutical Co | Orotic acid salt of 4-amino-5-imidazolecarboxamide |
| US3931195A (en) * | 1971-03-03 | 1976-01-06 | Mead Johnson & Company | Substituted piperidines |
| US4000143A (en) * | 1971-03-03 | 1976-12-28 | Mead Johnson & Company | Substituted piperidines |
| US4064254A (en) * | 1971-03-03 | 1977-12-20 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| USRE30811E (en) * | 1971-03-03 | 1981-12-01 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| USRE30812E (en) * | 1971-03-03 | 1981-12-01 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| US4558133A (en) * | 1979-08-08 | 1985-12-10 | Bayer Aktiengesellschaft | p-(Pyridinium-vinyl)-N,N-(disubstituted-aniline salts for dyeing paper and their preparation |
-
1951
- 1951-05-26 US US228543A patent/US2780577A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3235566A (en) * | 1966-02-15 | Benzofuran-j-carboxylic acids and esters | ||
| US3119824A (en) * | 1964-01-28 | L-substituted-l | ||
| US3209025A (en) * | 1960-10-29 | 1965-09-28 | Hoechst Ag | Bis-(beta-carbhydrazido-ethyl)-sulfone |
| US3238101A (en) * | 1960-11-23 | 1966-03-01 | Merck Ag E | Blood vessel constricting compositions and methods of using same |
| US3161653A (en) * | 1960-11-23 | 1964-12-15 | Merck Ag E | 2-[(2'-methyl-benzo-thienyl-3')-methyl]-delta2-imidazoline and its pharmaceutically aceptable acid addition salts |
| US3169090A (en) * | 1961-01-23 | 1965-02-09 | Upjohn Co | Thiazoline analgesics |
| US3222365A (en) * | 1962-01-15 | 1965-12-07 | Lilly Co Eli | 4-halophenyl-2-alkyl-1(2)-phthalazinones |
| US3271398A (en) * | 1962-03-05 | 1966-09-06 | Fujisawa Pharmaceutical Co | Orotic acid salt of 4-amino-5-imidazolecarboxamide |
| US3135659A (en) * | 1962-05-02 | 1964-06-02 | Wallace & Tiernan Inc | Hydroxy and alkoxy aryl quinazolinones |
| US3931195A (en) * | 1971-03-03 | 1976-01-06 | Mead Johnson & Company | Substituted piperidines |
| US4000143A (en) * | 1971-03-03 | 1976-12-28 | Mead Johnson & Company | Substituted piperidines |
| US4064254A (en) * | 1971-03-03 | 1977-12-20 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| USRE30811E (en) * | 1971-03-03 | 1981-12-01 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| USRE30812E (en) * | 1971-03-03 | 1981-12-01 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| US4558133A (en) * | 1979-08-08 | 1985-12-10 | Bayer Aktiengesellschaft | p-(Pyridinium-vinyl)-N,N-(disubstituted-aniline salts for dyeing paper and their preparation |
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