IL29580A - A reaction product from chloral hydrate and 7-chloro-1-methyl-5-phenyl-1,4-3h-benzodiazepin-2(1h)-one and psychotropic compositions containing it - Google Patents
A reaction product from chloral hydrate and 7-chloro-1-methyl-5-phenyl-1,4-3h-benzodiazepin-2(1h)-one and psychotropic compositions containing itInfo
- Publication number
- IL29580A IL29580A IL2958068A IL2958068A IL29580A IL 29580 A IL29580 A IL 29580A IL 2958068 A IL2958068 A IL 2958068A IL 2958068 A IL2958068 A IL 2958068A IL 29580 A IL29580 A IL 29580A
- Authority
- IL
- Israel
- Prior art keywords
- chloro
- phenyl
- chloral hydrate
- solvent
- benzodiazepin
- Prior art date
Links
- 230000000506 psychotropic effect Effects 0.000 title claims description 3
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 title description 14
- 229960002327 chloral hydrate Drugs 0.000 title description 14
- 239000007795 chemical reaction product Substances 0.000 title description 5
- 239000000203 mixture Substances 0.000 title description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000000047 product Substances 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 239000000320 mechanical mixture Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- ZHYMGSPDEVXULU-UHFFFAOYSA-N 1,2-benzodiazepin-3-one Chemical class N1=NC(=O)C=CC2=CC=CC=C21 ZHYMGSPDEVXULU-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- -1 as for example Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- NALBLJLOBICXRH-UHFFFAOYSA-N dinitrogen monohydride Chemical compound N=[N] NALBLJLOBICXRH-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
-l-ni a-T oy ΒΚΤΊ*Π um a najina ^a nan nsia
n**-(1 Η)2-7»3ΤΚ»τητ33-3 H-4,1- * Js-5- 'na
A reaction product from chloral hydrate and
7-chloro-1 -methyl-5-phenyl-1 ,4-3H-benzodiazepin- 2(lH)-one and psychotropic compositions containing it.
DEL AR CHEMICALS LIMITED
C : 28004
ABSTRACT
A new substance having pharmaceu cal activity is prepared by reacting chloral hydrate and 7-chloro-l-rethyl-5-phenyl-l , -3H-ben2odiazepin-2 (1H) -one. The molecular formula of the new substance} which has a
β
m.p. of about 110 C, is C. ^H. -CI ,Ν.Ο, . I.R. spectrum (see drawing) shows absorption bands among others at about 3430 j and 1670 cm""1.
BACKGROUND OP THE Ii-]V.3NT∑QN
This invention relates to a new substance
and to a process for its preparation. More specifically, this invention relates to 7-chloro-l-mathyI-5-phenyl-l,4-3H-ben2odiasepin~2 (1H) -one chloral hydrate and to a process for its preparation.
SU?-S-IARY OF THE I INV EN IO
An object of the invention is to provide a new and useful substance. Another object is to provide a method for the preparation of said substance.
The product of the present invention is
represented by the general formula: cIQKI5C-^N2°3
has a melting point of about 110 C . It shov/s especially characteristic infra-red absorption bands at about 1670 cm' and at about 3430 cm""5". The complete infra-red spectrum, taken in potassium bromide is shown in the single figure of drawings .
The compound of this invention displays
valuable pharmacological properties. In particular, it exhibits tranquilizing, anti-convulsive and iruscle relaxant properties.
When tested on mice, the effect on the --■ central nervous system of the product of the present invention was found both qualitatively and quantitatively different from that of- 7-chloro-l-methyl-5-phenyl-l, 4- 3H-benzodiazepin-2 (1H) -one and from that of the physical mixtures of the latter with chloral hydrate in 1:1 and 1:2 molar proportions. The compound of the present invention was found to be a potent muscle relaxant as shown in Table I and also an anticonvulsant (against strychnine induced convulsions) as shown in Table II.
In both tables the product of the present invention is represented by A, whereas B represents 7-chloro-l-methyl-5-phenyl-l, 4-3H-benzodiazepin-2 (IK) -one, C represents chloral hydrate, D represents an equimolecular mechanical mixture of B and C and Ξ represents a mechanical mixture of B and C in 1:2 molecular ratio.
TABLE 1. MUSCLE RELAXANT DOSE OF VARIOUS COMPOUNDS IN TUB MOU
Range for 19/20 confidence limit
M.S. - not significant at 19/20 confidence limit
OF VARIOUS COMPOUNDS IN THE MOUSE (PER OS)
" Range for 19/20 confidence limit.
M.S. - not significant at 19/20 confidence limit.
As can be clearly seen from the above descrip tion the pharmacological activity of th . roduct of the present invention is qualitatively and quantitatively different from the activities of either of the starting materials and their mechanical mixtures. These high activities could not be foreseen from the activities of the components and the results obtained on testing are unexpected and surprising.
Equally surprising is the easy formation of the product of this invention, especially in. view of the fact that benzodiazepinones not substituted in position 1 or substituted with substituents such as a phenyl group in position 3 do not react with chloral hydrate under the conditions used for the preparation of our new product.
The compound of this invention may be
prepared for administration by formulation with the usual pharmaceutical carriers, for oral administration.
For example, an amount of the product of the invention ranging from about 2 milligrams to about 200 milligrams, individually selected according to the condition to be treated, may be formulated into dosage units with any of the usual pharmaceutical carriers, as for example, lactose, starch, gelatin, etc.
The product cf the invention is recdily obtained in excellent yields by reacting together
7-chloro-i-i^ethyl-5-phsnyl-i ,4-2H-ben.¾oeias i -2 {IE) -one and chloral hydrate. Best results are obtained by bringing the reactants together in approximately equi olar quantities". It is preferred to bring the reaction about by heating e.g. above room temperature bu j if a solvent is used, the reaction vili take place even at room temperature. A mere mechanical mixture of the two reactants in the absence of a solvent will not yield the desired product at room temperature. The reaction is preferably carried out - in a medium of a substantially non-polar organic solvent, e.g. benzene, toluene 3 xylene, or hexane. However, the product of the invention is also obtained v;hen the tv;o reactants are melted together in the absence cf a solvent. ' ,
The nature of the bond obtained in the reaction.is not clear. Possibly, the strong partial positive charge cf the carbon atom v;hich is substituted by three chlorine atoms in chloral hydrate is partially compensated by the partial negative charge of the imino nitrogen of the other reactant. Another hypothesis is that the- imino dipole is discharged by addition of a hydroxy! group from the chloral hydrate. Eovrever, the present invention is not restricted to any theoretical interpretation of the reaction.
In order that the nature of the present
invention be more fully understood, the following
examples are given for illustration, but they
should not be construed as limiting the scope of
the invention.
EXAMPLE 1
To a stirred solution of 6.8 g' of chloral
hydrate in 12 ml of benzene at a temperature of about
40°C were added 10 g of 7-chloro-l-roethyl-5-phenyl-l,4-3K-benzodiazepin-2 (1H) -one. The latter compound went immediately into solution and the reaction product
precipitated from the reaction mixture in a short time.
It was collected by filtration, washed with benzene and dried at room temperature. The yield was about 15 g.
An analytical sample was prepared by recrystallization from benzene and had a melting point of about 110 C.
Analysis: calculated for °ΐ8Η16014Ν203 : C 4δ·02? κ 3·5δ> CI 31.51, N 6.22%; found C 48.01, K 3.77, CI 31.52, N 6,10%.
EXAMPLE 2
The process was carried out as described in
Example 1, except that toluene was used instead of
benzene as solvent. The same product as in Example 1 was obtained in the amount of 13.2 g.
EXAMPLE 3
Using xylene instead of benzene as reaction medium, the otherwise same--process... as described in .
Example 1 was carried out. The same product as in
Examj^le 1 was obtained. The yield was 13 g.
EXAMPLE 4
To a boiling solution of 6.8 g of chloral
hydrate in 100 ml- of hexane were added 10 g of 7-chloro-l-methyl-5-phenyl-l , 4-3H-benzodiazepin-2 (IK) -one. The latter starting material dissolved immediately and the reaction product precipitated on cooling. The yield was 14.1 g and the product was found identical with that described in Example 1.
EXAMPLE 5
An intimate mixture of 1.4 g of chloral hydrate and 2 g of 7-chloro-l-methyl-5-phenyl-l , 4-3H-benzodiazepin-2(lH)-one was heated to 100°C and ke t at that temperature for 10 minutes. After cooling, the product was triturated with benzene and collected by filtration.
The yield was 2.25 g and the product was found identical with the one described in Example 1.
EXAMPLE 6
To a stirred. solution of 6.8 g of chloral hydrate in—15 ml. benzene, 10 g of 7-chloro-l-methyl-5-phenyl-l , 4-3H-benzodiazepin-2 (1H) -one- were added at room temperature. The latter compound went immediately into solution and the reaction product' precipitated from the reaction mixture in a short time. It was collected by filtration, washed with benzene and dried at room temperature. The yield was 14.3 g and the product was found identical with that described in Example 1.
29580/2
Claims (1)
- CLAIMS 1. A chemical substance having a molecular formula of C. QH. gCl. O-, further characterized by a melting point in potassium bromide of about 118 C and by infra-red absorption bands/at about -1 -1 3430 cm and 1670 cm , said substance resulting from are brought together in a medium of a \substantially non-polar organic solvent. 5. A process according to Claim 4t wherein the solvent is benzene. '{ 6. A process according to Claim 4, wherein the solvent is toluene. < 7. A process according to Claim 4, wherein the solvent A is xylene. ! \ 8. A process according to'( Claim 4, wherein the solvent is n-hexane. 29580/.Γ ( 9. A process according to Claim 4, wherein the reaction is carried out at a temperature higher than room temperature, 10. A pharmaceutical composition _having psychotropic activity comprising a pharmaceutical carrier and an effective amount of the product of Claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62079967A | 1967-03-06 | 1967-03-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL29580A true IL29580A (en) | 1971-12-29 |
Family
ID=24487444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL2958068A IL29580A (en) | 1967-03-06 | 1968-03-05 | A reaction product from chloral hydrate and 7-chloro-1-methyl-5-phenyl-1,4-3h-benzodiazepin-2(1h)-one and psychotropic compositions containing it |
Country Status (13)
| Country | Link |
|---|---|
| AT (1) | AT286991B (en) |
| BE (1) | BE711676A (en) |
| CH (1) | CH505117A (en) |
| DK (1) | DK121234B (en) |
| FI (1) | FI48351C (en) |
| FR (2) | FR1583753A (en) |
| GB (1) | GB1183060A (en) |
| IE (1) | IE31974B1 (en) |
| IL (1) | IL29580A (en) |
| LU (1) | LU55619A1 (en) |
| NL (2) | NL6803061A (en) |
| NO (1) | NO119841B (en) |
| SE (1) | SE342629B (en) |
-
0
- NL NL138681D patent/NL138681C/xx active
-
1968
- 1968-03-05 DK DK90368A patent/DK121234B/en unknown
- 1968-03-05 SE SE289068A patent/SE342629B/xx unknown
- 1968-03-05 NL NL6803061A patent/NL6803061A/xx unknown
- 1968-03-05 IL IL2958068A patent/IL29580A/en unknown
- 1968-03-05 CH CH324468A patent/CH505117A/en not_active IP Right Cessation
- 1968-03-05 LU LU55619D patent/LU55619A1/xx unknown
- 1968-03-05 BE BE711676D patent/BE711676A/xx unknown
- 1968-03-05 FR FR1583753D patent/FR1583753A/fr not_active Expired
- 1968-03-05 FI FI60168A patent/FI48351C/en active
- 1968-03-05 IE IE25668A patent/IE31974B1/en unknown
- 1968-03-05 NO NO82568A patent/NO119841B/no unknown
- 1968-03-06 AT AT219668A patent/AT286991B/en not_active IP Right Cessation
- 1968-03-06 GB GB1099268A patent/GB1183060A/en not_active Expired
- 1968-06-05 FR FR153796A patent/FR7640M/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FI48351B (en) | 1974-05-31 |
| NL138681C (en) | |
| DE1670593B2 (en) | 1975-12-04 |
| LU55619A1 (en) | 1969-10-02 |
| SE342629B (en) | 1972-02-14 |
| DE1670593A1 (en) | 1972-01-27 |
| GB1183060A (en) | 1970-03-04 |
| FR1583753A (en) | 1969-12-05 |
| FR7640M (en) | 1970-02-02 |
| NO119841B (en) | 1970-07-13 |
| BE711676A (en) | 1968-09-05 |
| FI48351C (en) | 1974-09-10 |
| DK121234B (en) | 1971-09-27 |
| AT286991B (en) | 1971-01-11 |
| NL6803061A (en) | 1968-09-09 |
| IE31974B1 (en) | 1973-03-07 |
| IE31974L (en) | 1968-09-06 |
| CH505117A (en) | 1971-03-31 |
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