US3040049A - Method of producing pharmaceutic ally - Google Patents
Method of producing pharmaceutic ally Download PDFInfo
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- US3040049A US3040049A US3040049DA US3040049A US 3040049 A US3040049 A US 3040049A US 3040049D A US3040049D A US 3040049DA US 3040049 A US3040049 A US 3040049A
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- 150000001875 compounds Chemical class 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 230000000694 effects Effects 0.000 description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 10
- -1 methyl compound Chemical class 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000005712 crystallization Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- JKPALQVXINOOER-SFYZADRCSA-N C1CC[C@@]2(Cl)CC[C@]1([H])N2C Chemical compound C1CC[C@@]2(Cl)CC[C@]1([H])N2C JKPALQVXINOOER-SFYZADRCSA-N 0.000 description 4
- 210000004940 Nucleus Anatomy 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004432 carbon atoms Chemical group C* 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MXHXXJOHFRHBFB-UHFFFAOYSA-N (2-methylphenyl)-phenylmethanol Chemical compound CC1=CC=CC=C1C(O)C1=CC=CC=C1 MXHXXJOHFRHBFB-UHFFFAOYSA-N 0.000 description 2
- BYCIIIBJGCLCGB-UHFFFAOYSA-N (6,6-dimethylcyclohexa-2,4-dien-1-yl)-phenylmethanol Chemical compound CC1(C)C=CC=CC1C(O)C1=CC=CC=C1 BYCIIIBJGCLCGB-UHFFFAOYSA-N 0.000 description 2
- FXBOKASTQKMONI-UHFFFAOYSA-N 2-methyl-5-(2-methylphenoxy)benzenesulfonic acid Chemical compound CC1=CC=CC=C1OC1=CC=C(C)C(S(O)(=O)=O)=C1 FXBOKASTQKMONI-UHFFFAOYSA-N 0.000 description 2
- 229930006677 A03BA01 - Atropine Natural products 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N Atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960000396 Atropine Drugs 0.000 description 2
- 241000700190 Caviidae Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N Sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002048 spasmolytic Effects 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
Definitions
- the para halogen substituted compounds are considered of importance. I have found that particularly the monoortho-methyl substituted compound has a very pronounced atropine-like activity, which many times exceeds the activity of the corresponding unsubstituted compound as Well as the activity of the mono-meta and mono-para methyl-substituted compound.
- the toxicity is of the same order of magnitude or even smaller than that of the isomeric compounds or that of the unsubstituted compound, so that the therapeutic width of the mono-ortho-methyl compound is appreciably larger than that of the corresponding compounds not having the methyl group or having it in a different position in the phenyl nucleus.
- mice 25 mg./kg. 1,4-dipyrrolidinobutyn-2 was injected the effective dose in at least 50% of the mice (ED in the case of a subcutaneous injection amounted to 2.5 mg./kg. mouse for the 2 methyl compound and to 21 mg./kg. mouse for the 2 tertiary butyl compound.
- A represents a halogen atom and Ban OH group or A an OH group and B a halogen atom or an OH group. If one of the symbols A and B represents a halogen atom and the other an OH group the reaction is generally carried out with the addition of an oxygen binding sub stance. If A is the halogen atom it is also possible to carry out the reaction with an excess of the amino alcohol without the addition of another oxygen binding substance. It is possible, for example, to obtain the compounds according to the application by heating one equivalent of the desired substituted benzhydryl with two equivalents of the amino alcohol, the addition of a solvent being not necessary.
- Example I 21.6 grams of Z-methylbenzhydrylchloride (0.1 mol) are heated with 25.8 grams of tropinol (0.2 mol) at a temperature of from 100150 C. for 15-30 minutes. A two layer system will form, the lower layer of which solidifies upon slight cooling. After cooling of the reaction mixture 100-15O cc. of ether are added, in which the liquid upper layer will dissolve. After separating the ether layer 150 cc. of water and subsequently 25 cc. of 40% hydrobromic acid are added thereto. The precipitate consisting of 2 methylbenzhydryl tropinyl ether hydrobromide is separated by filtration, washed with ether and subsequently with water and is thereupon dried.
- the yield of the said product amounts to 14 grams (45%). After purification by crystallization the compound melts at 222224 C.
- Example ll Tropinolis converted into chlorotropane by means of thionyl chloride. "One mol of chlorotropane together with one mol of 2 methylbenzhydrol is heated in the presence of sodamide as an acid binding substance at a temperature-of from IOU-150 C. for 15-30 minutes.
- Example III To 1.0 mol of orthomethylbenzhydrol 1.1 mol of tropinol are added. The mixture is heated to 50-60 C. until a homogeneous melt is obtained. To this melt 1.15 mol of p-toluenesulphonic acid are added owing to which the temperature rises to 90100 C. Subsequently the mixture is heated at a temperature of 130-150 C. under reduced pressure for 4 to 5 hours. After cooling the mixture is taken up in a mixture of diluted lye and ether. The layer of ether is separated out and treated with a dilute aqueous HBr-solution. The hydrobromide of 2- methylbenzhydryltropinylether separates out as an oil which soon solidifies.
- the solid substance is isolated and crystallized from acetone or from a mixture of acetone and ether. The yield is 75%. Melting point is 223224 C.
- Example IV In the same manner as described in Example III the hydrobromide of Z-ethylbenzhydryl tropinyl ether is prepared from ortho-ethyl benzhydrol, tropinol and p-toluene sulphonic acid. Melting point after crystallization is 180 C. Yield 67%.
- Example V In the same manner as described in Example III the tropinyl 2,2'-dimethyl benzhydryl tropinyl ether is prepared from 2,2-dimethylbenzhydrol. The melting point of the hydrobromide is 194 C. The yield is Example VI formula Al; CH2-CH--CH HC'3-O(
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
United States Patent 3,040,049 METHOD OF PRODUCING PHARMACEUTICALLY ACTIVE TROPINYLETHERS August F. Harms, Amsterdam, Netherlands, assignor to N.V. Koninklijke Pharmaceutische Fabrieken v/h Brocades-Stheeman & Pharmacia, Meppel, Netherlands, a corporation of the Netherlands No Drawing. Filed June 2, 1958, Ser. No. 738,956 Claims priority, application Netherlands May 31, 1957 1 Claim. (Cl. 260-292) This invention relates to the production of pharmaceutically active tropinylethers of the general formula Ar; CHz-CH CH2 A1: CH CH CHg in which Ar and Ar are substituted or unsubstituted phenyl groups as well as salts and quaternary ammonium compounds thereof. Examples of salts are the hydrobromide, the hydrochloride, the sulphate and the methane sulphonate.
Various compounds of the above mentioned structure are known. Thus U.S. *Patent 2,595,405 describes the unsubstituted compound, while US. Patent 2,706,198 and British Patents 708,911, 769,282 and 773,290 describe a number of compounds substituted in a phenyl group. The said patents likewise mention a number of methods of preparing said compounds. Substances having the above formula have pronounced atropine-like properties as well as a strong antihistaminic activity.
I have now found that compounds having an appreciably stronger activity can be obtained if at least one of the phenyl nuclei possesses an alkyl substituent in at least one of the ortho positions. According to the invention, therefore, compounds of the above general formula are prepared in a manner known for similar compounds, in which compounds at least one of the groups Ar or Ar is substituted in at least one of the ortho positions by an alkyl group having at most 6 carbon atoms, the two groups containing no other substituents.
It is true that US. Patent 2,706,198 discloses compounds of the general formula:
in which R and R may represent i.=a. low 'alkyl groups, but the alkyl substituted compounds described in said patent all contain one or more substituents in the paraor meta-position in the phenyl nuclei. In addition it appears from the patent that primarily the para halogen substituted compounds are considered of importance. I have found that particularly the monoortho-methyl substituted compound has a very pronounced atropine-like activity, which many times exceeds the activity of the corresponding unsubstituted compound as Well as the activity of the mono-meta and mono-para methyl-substituted compound. In addition the toxicity is of the same order of magnitude or even smaller than that of the isomeric compounds or that of the unsubstituted compound, so that the therapeutic width of the mono-ortho-methyl compound is appreciably larger than that of the corresponding compounds not having the methyl group or having it in a different position in the phenyl nucleus.
The subjoined table lists the pharmacological test results obtained in comparative experiments applied to the isolated intestine of cavies by means of compounds sub- Spasmolytic activity Toxicity 50 in mg. per kg. of mouse in the ease of an intravenous injection) Substituent HZ Anti BaOlz Anti Acetylch, activity HBr sulphateatropine In addition to the strong atropine-like activity described above the compounds according to the invention have the property that they entirely eliminate tremors created by the administration of 1,4-dipyrrolidinobutyn-2, as does atropine (C. M. Everett, Nature 177, 1238 (1956)).
If in mice 25 mg./kg. 1,4-dipyrrolidinobutyn-2 was injected the effective dose in at least 50% of the mice (ED in the case of a subcutaneous injection amounted to 2.5 mg./kg. mouse for the 2 methyl compound and to 21 mg./kg. mouse for the 2 tertiary butyl compound.
Also in this respect the 2 methyl benzhydryltropinylother again appears to have exceptional properties.
The compounds according to the application can be prepared in various Ways. According to the most usual method a compound of the formula:
is reacted with a compound of the formula:
CH2'CHCH2 B-OH NCH GH2-CH-OH2 in which A represents a halogen atom and Ban OH group or A an OH group and B a halogen atom or an OH group. If one of the symbols A and B represents a halogen atom and the other an OH group the reaction is generally carried out with the addition of an oxygen binding sub stance. If A is the halogen atom it is also possible to carry out the reaction with an excess of the amino alcohol without the addition of another oxygen binding substance. It is possible, for example, to obtain the compounds according to the application by heating one equivalent of the desired substituted benzhydryl with two equivalents of the amino alcohol, the addition of a solvent being not necessary.
Preferably, however, a compound is reacted with a compound CHz-CHCH2 HO-OH NCH3 CH2CH OH: in the presence of an organic sulphonic acid such as ptoluenesulphonic acid the reaction mixture being heated. The invention will be elucidated with reference to the following examples:
Example I 21.6 grams of Z-methylbenzhydrylchloride (0.1 mol) are heated with 25.8 grams of tropinol (0.2 mol) at a temperature of from 100150 C. for 15-30 minutes. A two layer system will form, the lower layer of which solidifies upon slight cooling. After cooling of the reaction mixture 100-15O cc. of ether are added, in which the liquid upper layer will dissolve. After separating the ether layer 150 cc. of water and subsequently 25 cc. of 40% hydrobromic acid are added thereto. The precipitate consisting of 2 methylbenzhydryl tropinyl ether hydrobromide is separated by filtration, washed with ether and subsequently with water and is thereupon dried.
The yield of the said product amounts to 14 grams (45%). After purification by crystallization the compound melts at 222224 C.
Example ll Tropinolis converted into chlorotropane by means of thionyl chloride. "One mol of chlorotropane together with one mol of 2 methylbenzhydrol is heated in the presence of sodamide as an acid binding substance at a temperature-of from IOU-150 C. for 15-30 minutes.
The reaction mixture is Worked up as described in Example I. Since the chance of quaternary salts forming is much slighter here than in the preceding method the yield is appreciably larger; it amounts to 60%. Melting point after crystallization is 221-223 'C.
Example III To 1.0 mol of orthomethylbenzhydrol 1.1 mol of tropinol are added. The mixture is heated to 50-60 C. until a homogeneous melt is obtained. To this melt 1.15 mol of p-toluenesulphonic acid are added owing to which the temperature rises to 90100 C. Subsequently the mixture is heated at a temperature of 130-150 C. under reduced pressure for 4 to 5 hours. After cooling the mixture is taken up in a mixture of diluted lye and ether. The layer of ether is separated out and treated with a dilute aqueous HBr-solution. The hydrobromide of 2- methylbenzhydryltropinylether separates out as an oil which soon solidifies.
The solid substance is isolated and crystallized from acetone or from a mixture of acetone and ether. The yield is 75%. Melting point is 223224 C.
Example IV In the same manner as described in Example III the hydrobromide of Z-ethylbenzhydryl tropinyl ether is prepared from ortho-ethyl benzhydrol, tropinol and p-toluene sulphonic acid. Melting point after crystallization is 180 C. Yield 67%.
4 Example V In the same manner as described in Example III the tropinyl 2,2'-dimethyl benzhydryl tropinyl ether is prepared from 2,2-dimethylbenzhydrol. The melting point of the hydrobromide is 194 C. The yield is Example VI formula Al; CH2-CH--CH HC'3-O(|3H N-CH Al: H2- H 0112 which comprises reacting a compound of the general formula Al1 I-I( 7A with a compound of the general formula CH2CH-OHq BCH N-CHQ Hr-CH wherein Ar; and Ar are phenyl groups of which at least one is substituted in at least one of the ortho-positions by an alkyl group containing at most 6 carbon atoms, while both groups Ar and Ar are free from other substituents in an ortho-position and are free from substituents in any position other than the ortho-position, A is a hydroxyl group, B is a hydroxyl group, and the reaction is carried out in the presence of toluene sulphonic acid.
References Cited in the file of this patent UNITED STATES PATENTS Weijlard et al Apr. 12, 1955 Nield et al. Feb. 19, 1957
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3040049A true US3040049A (en) | 1962-06-19 |
Family
ID=3450743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US3040049D Expired - Lifetime US3040049A (en) | Method of producing pharmaceutic ally |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3040049A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994004146A1 (en) * | 1992-08-24 | 1994-03-03 | President And Fellows Of Harvard College | Cocaine analogues and their use as cocaine drug therapies and therapeutic and imaging agents for neurodegenerative disorders |
| US5770180A (en) * | 1992-08-24 | 1998-06-23 | Organix, Inc. | Bridge-substituted tropanes for methods of imaging and therapy |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2706198A (en) * | 1952-03-29 | 1955-04-12 | Merck & Co Inc | Benzhydryl ethers of tropine and processes of preparation |
| US2782200A (en) * | 1957-02-19 | Process for preparing j- |
-
0
- US US3040049D patent/US3040049A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2782200A (en) * | 1957-02-19 | Process for preparing j- | ||
| US2706198A (en) * | 1952-03-29 | 1955-04-12 | Merck & Co Inc | Benzhydryl ethers of tropine and processes of preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994004146A1 (en) * | 1992-08-24 | 1994-03-03 | President And Fellows Of Harvard College | Cocaine analogues and their use as cocaine drug therapies and therapeutic and imaging agents for neurodegenerative disorders |
| US5770180A (en) * | 1992-08-24 | 1998-06-23 | Organix, Inc. | Bridge-substituted tropanes for methods of imaging and therapy |
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