IL27785A - 5,11-methylenimino-10,11-dihydro-5h-dibenzo(a,d) cycloheptene derivatives - Google Patents
5,11-methylenimino-10,11-dihydro-5h-dibenzo(a,d) cycloheptene derivativesInfo
- Publication number
- IL27785A IL27785A IL2778567A IL2778567A IL27785A IL 27785 A IL27785 A IL 27785A IL 2778567 A IL2778567 A IL 2778567A IL 2778567 A IL2778567 A IL 2778567A IL 27785 A IL27785 A IL 27785A
- Authority
- IL
- Israel
- Prior art keywords
- dihydro
- dibenzo
- methylenimino
- addition salts
- acid addition
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
■γπ*π*ι-11·10-ν3·ο-»κ3>»ι¾¾ι11 ·5 η » ι , ll-Methvleneimino-10, ll-dihydro-5H- dibenzo /a,d cycloheptene derivatives DR. A. WANDER S.A.
C: 26367 This invention is generally concerned with new 5H-dibenzo[a,d]eycloheptene derivatives, and more specific- ally with 5,ll-methylenimino-10,ll-dihydro-5H-dibenzo[a,d]- cycloheptenes of the formula: as well as acid addition salts and quaternary ammonium. deriv-atives thereof. In formula I denotes a hydrogen atom or a lower alkyl group, and represents a hydrogen atom or a lower alkyl, alkenyl or alkynyl group, whereby, however, the residues R^ and cannot simultaneously denote hydrogen atoms. "Lower alkyl, alkenyl or alkynyl" is intended to indicate, throughout the specification and claims, an alkyl, alkenyl or alkynyl residue having at most 5 carbon atoms, These compounds possess pharmacological actions which indicate that they may be useful as therapeutic agents in the treatment of nervous diseases, especially as centrally active muscle relaxants and as anticonvulsants. Especially active are those compounds wherein is hydrogen and lower alkyl, alkenyl or alkynyl, and also those compounds, wherein R-^ is methyl and ^ hydrogen or methyl.
In the following table, the . pharmacological effects of compounds according to the invention are expressed quanti-tatively. For an estimate of central muscle relaxant effects, "the inability of the mouse to maintain its position on the in- is the dose which renders 50% of the animals unable to main- tain their position on the inclined screen. For the anticon- vulsant action, the results of the electroshock test [method of Goodmann et al. ; J. Pharmacol. 108, 168 (1953)] are given for the rat. The ED 50 is expressed as that dosage which protects 5Q¾ of the rats from tonic extensor seizures of the hind limbs. The oral LD 50 for the mouse is given so that the therapeutic index may be judged.
T a b l e : The new compounds of this invention can be administered in dosage unit form to patients suffering from nervous diseases, e.g. spinal spasticity , cerebral-spastic paralysis, cramps, and spasms produced by inflammation of nerves, muscles and joints, these pharmaceutical preparations containing, besides the active substance, organic or inorganic solid or liquid carriers suitable for enteral or parenteral administration. The pharmaceutical pre or solutions for injection, one dosage unit containing from 2.5 to 10 mg of active substance, depending on its nature,- on the route of administration and on the physician's prescription, the effective daily dose amounting from 5 to 60 mg of active substance.
The quaternary ammonium derivatives of the compounds according to formula I can further be used as intermediate products for the preparation of other pharmacologically active substances. By degradation of these quaternary ammonium deriv-atives by the method of A. W. Hofmann 5-aminomethylated 5H-di-benzo[a,d]cycloheptenes, which show a specific anticonvulsant action, are obtained.
Compounds according to formula I are obtained by ring closure through condensation of an aminoaldehyde of the formula: wherein and have the above-mentioned meaning, or of a re-active derivative thereof, especially an acetal, in the presence of a Lewis acid.
Suitable Lewis acids are phosphoric acid, sulphuric acid, hydrochloric acid, phosphorous pentoxide, phosphorous oxychloride, polyphosphoric acid, boron trifluoride, zinc chloride and the like. The ring closure is preferably carried out by warming the starting material in the presence of the Lewis acid. materials, are produced , for example, by treating an amine of the formula: R, wherein R, and R have the above-mentioned meaning, with bromo- acetal.
Acetals of aldehydes of formula II, wherein re- presents hydrogen, are also obtained by reacting a Schiff base of the formula: wherein R^ has the meaning indicated above, with a G-rignard compound of the formula: Compounds according to formula I, wherein ^ denotes a lower alkyl, alkenyl or alkynyl group, are also obtained by alkylation, alkenylation or alkynylation of a compound of the formula: wherein R, has the meaning mentioned earlier, performed by treating the compounds of formula VI with re- active esters, especially the hydrohalic acid esters, of alcohols of the formula I^-OH. The alkylation can also be carried out by reacting the compounds of formula VI with corresponding aldehydes in the presence of a reducing agent, such as formic acid.
The 5 ,ll-methylenimino-10,ll-dihydro-5H-dibenzo[a,d]- cycloheptenes according to formula I can be obtained and used as free bases or in the form of their acid addition salts with suitable acids, e.g. hydrohalic acid, toluene-sulphonic acids, sulphuric, nitric, phosphoric, acetic, oxalic, malonic, succinic, malic, maleic, or tartaric acid.
The quaternary ammonium derivatives of the compounds of formula I can be produced simultaneously with the alkylation of the compounds of formula VI or by direct quaternization of the compounds of formula I in a way known per se, for instance by treating with dialkyl sulphates, sulphonic acid alkyl esters or alkyl halides.
Example 1 6.5 gm of β-[N-(l-phenyl-l-benzyl)ethyl]amino-acetalde-hyde-diethylacetal oxalate (m.p. 145-146°C) in 50 ml of 15 sulphuric acid are heated for 1 hour at 100°C under a nitrogen atmosphere. After cooling the reaction mixture is diluted with 20 ml of water, made alkaline with 30?S sodium hydroxide solution and shaken out 6 times with chloroform. The chloroform extracts are dried over sodium sulphate and evaporated. 3.62 gm (99?£ of the theory) of 5,ll-methylenimino-10,ll-dihydro-ll-methyl-5H- 4.17 gm of the corresponding hydrochloride salt which after crystallization from methanol/ether give colourless needles with melting point >350°C.
Example 2 2.5 gm of p-[N-a-dibenzyl-N-methyl]amino-acetaldehyde diethylacetal oxalate (m.p. 190-192°C) in 25 ml of 75% sulphuric acid are heated at 100°C for 1 hour. After cooling the reaction mixture is diluted with 20 ml of water, made alkaline with 30% sodium hydroxide solution and shaken out times with ether.
The ether extracts are dried over sodium sulphate and then evaporated to give an oily residue which on treatment with al- coholic hydrochloric acid yields 3.3 gm (94 of the theory) of N-methyl-5 ,ll-methylenimino-10,ll-dihydro-5H-dibenzo[a , d ]-cycloheptene hydrochloride. After crystallization from methanol/ ether colourless needles of melting point 221-222°C are obtained.
Example 3 6.5 gm of 5 , ll-methylenimino-10, ll-dihydro-5H-dibenzo- [a, dJcycloheptene together with 4.2 ml of 30 formaldehyde solution and 2.8 gm of formic acid are heated at reflux for 2 hours. The reaction mixture is cooled, diluted with 10 ml of water, then made alkaline with 30 sodium hydroxide solution and shaken out 5 times with chloroform. The chloroform extracts are dried over sodium sulphate and evaporated. The residue is converted to the hydrochloride salt in the usual manner whereby 7.6 gm (95% of the theory) of N-methyl- , ll-methylenimino-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene hydrochloride of melting Example 4 4 gm of 5 ,ll-methylenimino-10,ll-dihydro-5H-dibenzo- [a,d]cycloheptene in 50 ml of benzene are refluxed with 2.2 gm of allyl bromide and 3.6 gm of triethylamine for 4 hours. After cooling the reaction mixture is filtered and the filtrate eva- porated. The residue is converted in the usual manner to the hydrochloride salt whereby 4.96 gm (92 of the theory) of N-allyl-5 , 11-methylenimino-10, ll-dihydro-5H-dibenzo[a, d]- cycloheptene hydrochloride are obtained as colourless needles of melting point 210-214°C (from methanol/ether) .
Example 5 3.1 gm of N-methyl-5 ,ll-methylenimino-10,ll-dihydro-5H- dibenzo[a,d]cycloheptene (hydrochloride: m.p. 221-222°C) and 5 ml methyliodide are refluxed in 50 ml methanol for 5 hours. The reaction mixture is then evaporated and the residue is taken up in acetone and cooled. After a short time crystallization takes place and 4.7 gm (94% of the theory) of N-methyl- ,11-methylenimino-10, ll-dihydro-5H-dibenzo[a , d] cycloheptene methiodide in the form of colourless needles of melting point 236-237°C are obtained.
In analogous manner as in the above Examples there are further obtained from the corresponding starting materials e.g. the following compounds: N-ethyl-5 , 11-methylenimino-10,ll-dihydro-5H-dibenzo[a , d]-cycloheptene hydrochloride of melting point 216-217°C; N-n-propyl- ,ll-methylenimino-10, ll-dihydro-5H-dibenzo[a , d ]- N- ( 2-propynyl ) - , ll-methylenimino-10 , ll-dihydro-5H-dibenzo-[a , d]-cycloheptene hydrochloride of melting point 207-208°C; N-methyl-5 , ll-methylenimino-10, ll-dihydro-ll-methyl-5H-dibenzo-[a,d]cycloheptene hydrochloride of melting point 211-214°C; N-methyl-5,ll-methylenimino-10,ll-dihydro-ll-methyl-5H-dibenzo-[a,d]cycloheptene methiodide of melting point 203-206°C, and N-n-butyl-5 , ll-methylenimino-10 ,ll-dihydro-5H-dibenzo[a , d]-cycloheptene hydrochloride of double melting point 155°C and 217-222°C.
Production of tablets For the manufacture of tablets, the products of this invention can, for instance, be mixed with lactose and granulated with water, paraffin oil, 0.5 sodium alginate or 5 gelatine solution. The dried granulate is compressed into tablets in the presence of the usual auxiliary agents for tabletting, such as talcum, corn starch, colloidal silicic acid, or magnesium stearate. In this way, there are obtained, e.g. tablets of the following composition: A ) 5 , ll- ethylenimino-10 , 11-dihydro-ll-methyl- 5H-dibenzo[a, d] cycloheptene hydrochloride 5 mg Lactose 90 mg Colloidal silicic acid 2 mg Paraffin oil 2 mg Gelatine 0.5 mg Magnesium stearate 0.1 mg Corn starch 5 mg 1 B ) 5 ,ll-Methylenimino-10 , 11-dihydro-ll-methyl- 5H-dibenzo[a,d]cycloheptene hydrochloride 10 mg (t • Lactose 85 mg 3 Colloidal silicic acid 2 mg 4 Paraffin oil 2 mg Gelatine 0.5 mg 6. Magnesiumt stearate 0.1 mg 7 Corn starch 5 mg 8 Talcum 5.4 mg 9 These 110 mg tablets A) or B), respectively, which are 11 provided with a crack-line, can be administered orally in a 12 dosage of half a tablet to one tablet two to six times per day ]_3 in the treatment of patients suffering from spinal spasticity, 14. cerebral-spastic paralysis, cramps, and spasms produced by inflammation of nerves, muscles and joints. 16 17 18 19 21 22 23 24 26 27 28 :
Claims (12)
1. A compound selected from the class consisting of 5 ,11-methylenimino-10,ll-dihydro-5H-dibenzo[a,d]cyclo- enes of the formula: wherein R^ is a member of the group consisting of hydrogen and lower alkyl, and is a member of the group consisting of hydrogen, lower alkyl, alkenyl and alkynyl, whereby, however, R^ and ^ cannot simultaneously denote hydrogen atoms; (B): acid addition salts of (A); and (C): quaternary ammonium derivatives of (A).
2. A compound selected from the class consisting of (A): 5,ll-methylenimino-10,ll-dihydro-5H-dibenzofa,d]cyclo-heptenes of the formula: wherein is a member of the group consisting of lower alkyl, · alkenyl and alkynyl; (B): acid addition salts of (A); and
3. (C): quaternary ammonium derivatives of (A).
4. N-Ethyl-5,ll-methylenimino-10,ll-dihydro-5H-dibenzo- [a, djcycloheptene and its pharmaceutically acceptable acid addition salts.
5. N-n-Propyl-5 ,ll-methylenimino-10,ll-dihydro-5H-dibenzo [a,djcycloheptene and its pharmaceutically acceptable acid addition salts.
6. N-n-Butyl-5 ,ll-methylenimino-10, ll-dihydro-5H-dibenzo- [a, djcycloheptene and its pharmaceutically acceptable acid addition salts.
7. N-Allyl-5 ,ll-methylenimino-10,ll-dihydro-5H-dibenzo- [a, djcycloheptene and its pharmaceutically acceptable acid addition salts.
8. N-( 2-Propynyl )-5 » 11-methylenimino-10, ll-dihydro-5H-dibenzo[a,djcycloheptene and its pharmaceutically acceptable acid addition salts.
9. A compound selected from the class consisting of (A) : 5,H-niethylenimino-10,ll-dihydro-5H-dibenzo[afdjcyclo-heptenes of the formula: wherein is a member of the group consisting of hydrogen and methyl; (B): acid addition salts of (A); and (C): quaternary ammonium derivatives of (A).
10. 5 , 11-Methylenimino-10,ll-dihydro-ll-methyl-5H-dibenzo-[a,d]cycloheptene and its pharmaceutically acceptable acid addition salts.
11. N-Me h l-5,ll-methylenimino-10,ll-dihydro-ll-methyl-5H-dibenzo[a,d]cycloheptene and its pharmaceutically acceptable acid addition salts.
12. A process for the preparation of 5,11-methylenimino-10,ll-dihydro-5H-dibenzo[a,d]cycloheptenes of the formula: wherein R^ denotes hydrogen or lower alkyl, and R,, represents hydrogen or lower alkyl, alkenyl or alkynyl, whereby, however, R^ and cannot simultaneously denote hydrogen atoms; as well as acid addition salts and quaternary ammonium derivatives thereof, comprising either: a) ring closure through condensation of an aminoaldehyde of the formula: wherein R-^ and R^ have the above-mentioned meaning, or a reactive derivative thereof, in the presence of a Lewis acid; or for the preparation of compounds, in which R^ denotes lower alkyl, alkenyl or alkynyl, alkylation, alkenylation or alkynylation of compounds of the formula: R-. wherein has the meaning indicated above, whereby the reaction products are isolated as free bases or in the form of their acid addition salts or converted to the quaternary ammonium derivatives. \ Dated this 12th day of April, 1967 For the Applicants DR. REINHOLD GOHN
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH589866A CH496716A (en) | 1966-04-22 | 1966-04-22 | 5h-dibenzo a d-cycloheptene derivs centrally active |
Publications (1)
Publication Number | Publication Date |
---|---|
IL27785A true IL27785A (en) | 1971-03-24 |
Family
ID=4301185
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL2778567A IL27785A (en) | 1966-04-22 | 1967-04-13 | 5,11-methylenimino-10,11-dihydro-5h-dibenzo(a,d) cycloheptene derivatives |
Country Status (12)
Country | Link |
---|---|
AT (2) | AT275540B (en) |
BE (1) | BE697369A (en) |
CH (1) | CH496716A (en) |
DE (1) | DE1720016A1 (en) |
DK (1) | DK115116B (en) |
ES (1) | ES339452A1 (en) |
FR (1) | FR6143M (en) |
GB (1) | GB1146109A (en) |
GR (1) | GR36289B (en) |
IL (1) | IL27785A (en) |
NL (1) | NL6705570A (en) |
SE (1) | SE326962B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4950030A (en) * | 1986-05-30 | 1990-08-21 | Motor Wheel Corporation | Wheel for a track laying vehicle |
US5011834A (en) * | 1989-04-14 | 1991-04-30 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
US6017910A (en) * | 1989-04-14 | 2000-01-25 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon | PCP receptor ligands and the use thereof |
-
1966
- 1966-04-22 CH CH589866A patent/CH496716A/en not_active IP Right Cessation
-
1967
- 1967-04-13 GB GB1697067A patent/GB1146109A/en not_active Expired
- 1967-04-13 IL IL2778567A patent/IL27785A/en unknown
- 1967-04-13 DE DE19671720016 patent/DE1720016A1/en active Pending
- 1967-04-17 FR FR102958A patent/FR6143M/fr not_active Expired
- 1967-04-18 ES ES339452A patent/ES339452A1/en not_active Expired
- 1967-04-19 DK DK212167A patent/DK115116B/en unknown
- 1967-04-20 SE SE559267A patent/SE326962B/xx unknown
- 1967-04-20 NL NL6705570A patent/NL6705570A/xx unknown
- 1967-04-21 BE BE697369D patent/BE697369A/xx unknown
- 1967-04-21 AT AT1035368A patent/AT275540B/en active
- 1967-04-21 AT AT379967A patent/AT275538B/en active
- 1967-04-22 GR GR670136289A patent/GR36289B/en unknown
Also Published As
Publication number | Publication date |
---|---|
SE326962B (en) | 1970-08-10 |
CH496716A (en) | 1970-09-30 |
GB1146109A (en) | 1969-03-19 |
DE1720016A1 (en) | 1971-05-19 |
DK115116B (en) | 1969-09-08 |
BE697369A (en) | 1967-10-23 |
GR36289B (en) | 1969-01-20 |
AT275540B (en) | 1969-10-27 |
FR6143M (en) | 1968-06-24 |
AT275538B (en) | 1969-10-27 |
ES339452A1 (en) | 1968-05-16 |
NL6705570A (en) | 1967-10-23 |
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