GB2029830A - Alkyl o oxybenzylamine derivatives their preparation and pharmaceutical compisitions containing them - Google Patents
Alkyl o oxybenzylamine derivatives their preparation and pharmaceutical compisitions containing them Download PDFInfo
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- C07C247/00—Compounds containing azido groups
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/20—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms using aldehydes or ketones
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Abstract
The new //c-alkyl-O-oxy-benzylamin derivatives, which have in the phenylic cycle as substituants one or at most two halogen atoms of a number in the periodic system from 17 to 53, the atom(s) of halogen being in the meta position with respect to the amino-alkyl rests, have salidiuretic and antihypertensive properties. They are obtained, for example, by chlorination, halogenation or iodization.
Description
SPECIFICATION -alkyl-o-oxybenzylamine derivatives, their preparation and pharmaceutical compositions containing them
The present invention relates to a-alkyl-o-oxybenzylamine derivatives, their preparation and pharmaceutical compositions containing them.
In particular, the invention provides a-alkyl-o-oxybenzylamines having the phenyl ring substituted by one or at most t , I halogen atoms of atomic number of from 17 to 53, the halogen atom or atoms being in a position meta to the aminoalkyl moiety, hereinafter referred to as the compounds of the invention.
It is to be understood that the compounds of the invention include derivatives substituted in the amino moiety. The oxy substituent may e.g. by hydroxy or acyloxy.
In accordance with the invention, there are especially provided compounds of formula I,
wherein
R, is alkyl of 1 to 4 carbon atoms,
R2 to R4 independently are hydrogen or alkyl of 1 to 4 carbon atoms and either Z is hydrogen or alkyl of 1 to 7 carbon atoms and W is halogen of atomic number of from 17
to 53 or Z is halogen of atomic number of from 17 to 53 and W is hydrogen or alkyl of 1 to 7 carbon
atoms, or Z and Ware halogen of atomic number of from 9 to 53 with the proviso that they are not
both fluorine, and 0- and/or N-acyl derivatives thereof.
It is to be appreciated that N-acyl derivatives are only contemplated when in formula I at least one of R2 and R4 is hydrogen.
0-and N-acyl derivatives of the compounds of formula I are those derivatives wherein the hydroxy and/or amino moiety is in acylated form. The compounds of formula l are preferred to their derivatives.
The derivatives are preferably acylated at the nitrogen atom only.
When R1, R2, R3 a id/or R4 is alkyl, it preferably is of 1 or 2, especially 1 carbon atom. It preferably is straight-chained. When Z orW is alkyl, it preferably is of 3 to 5, especially 3 or 4 carbon atoms. It preferably is branched in the position a to the phenyl ring carbon atom, as in isopropyl or tert-butyl.
Halogen preferably is bromine or iodine, especially bromine.
R3 preferably is hydrogen. When it is alkyl, it preferably is identical to R,. R2 and/or R4 preferably is hydrogen. When R2 and R4 are alkyl, they preferably are identical. When one or both of R2 and R4 are alkyl, R3 preferably is hydrogen.
Z preferably is alkyl or halogen, especially alkyl. W preferably is halogen or alkyl, especially halogen.
A group of compounds of formula I is the compounds of formula Ipa
wherein
R, and R2 are as defined above, zPa is alkyl of 1 to 7 carbon atoms and WPa is halogen of atomic number of from 17 to 53.
Another group of compounds of formula I is the compounds of formula Ipb
wherein
R, and R2 are as defined above,
Zpb is halogen of atomic number of from 17 to 53,
Wpb is alkyl of 1 to 7 carbon atoms.
Another group of compounds of formula I is the compounds of formula Ipc
wherein
R, and R2 are as defined above, zpc is halogen of atomic number of from 9 to 53 and wpc is halogen of atomic number of from 17 to 53.
Another group of compounds of formula I is the compounds of formula Ipd
wherein
R, and R2 are as defined above,
RPd3 is alkyl of 1 to 4 carbon atoms and either ZPd iS alkyl of 1 to 7 carbon atoms and WPd is halogen of atomic number of from 17 to 53 or Zpd iS halogen of atomic number of from 17 to 53 and WPd iS alkyl of 1 to 7 carbon atoms, or ZPd iS halogen of atomic number of from 9 to 53 and WPd is halogen of atomic number of from
17to53.
A compound of the invention may be obtained in conventional manner, e.g. by appropriately chlorinating, brominating or iodinating a corresponding c-alkyl-O-oxybenzylamine having the phenyl ring substituted by at most one halogen atom.
In particular, a compound of formula I or an 0- and/or N-acyl derivative thereof may be obtained by a process comprising appropriately chlorinating, brominating or iodinating a corresponding compound formula II
wherein R1 to R4 are as defined above and
either Z' is hydrogen or alkyl of 1 to 7 carbon atoms and W' is hydrogen,
or Z' is hydrogen and W' is alkyl of 1 to 7 carbon atoms,
or Z' is halogen of atomic number of from 9 to 53, W' is hydrogen
or Z' is hydrogen and W' is halogen of atomic number of from 9 to 53, with the proviso that
A) when Z and W are halogen of atomic number of from 17 to 53 and are different, one of Z' and W' is
halogen of atomic number of from 17 to 53, and
B) when Z or W is fluorine, accordingly Z' orW' is fluorine,
or an 0- and/or N-acyl derivative thereof.
The halogenation process may be effected in conventional mannerforthe production of analogous o-oxy-halobenzylimines by mono- or dihalogenation.
Suitable reaction temperatures may be from about --1 to about +50 C, preferably from about OOC to room temperature.
Chlorination or bromination may be effected by directly reacting with chlorine gas or bromine.
Conveniently a catalyst such as iron or iron (III) chloride is used. The reaction is preferably effected in an
inert solvent such as methylene chloride, chloroform, carbon tetrachloride or acetic acid.
lodination may be effected with iodine chloride. The reaction may be effected in water, preferably
using an additional hydrophilic solvent such as dioxan. Conveniently acidic conditions are used.
When Z' and Ware hydrogen, a mixture of compounds may be obtained, which can be separated
using conventional methods such as chromatography or fractional crystallization.
The compounds may be isolated from the reaction mixture and purified in accordance with known
methods.
Free base forms of the compounds of the invention may be converted into salt forms in conventional manner and vice versa. Suitable acids for acid addition salt formation include maleic, fumaric, malonic, tartaric and hydrochloric acid. When the oxy group is a hydroxy group, salts may also be formed with strong bases, e.g. sodium hydroxide.
When R1 and R3 are different, the carbon atom carrying these substituents is asymmetrically substituted. These compounds may therefore exist in racemic form or in optically active form. The optically active forms may be prepared in conventional manner, e.g. from the corresponding racemic form by using conventional separation methods such as fractional crystallization of a corresponding diastereoisomeric salt of an optically active acid such as tartaric, malic or madelic acid.
The starting materials may be obtained in conventional manner.
An 0- and/or N-acyl derivative of a compound of formula II may e.g. be obtained by 0- and/or Nacylating a corresponding compound of formula II, if required using selective conditions.
A compound of formula Ila, llb or llc may e.g. be obtained using the methods outlined in the following diagram, wherein
R, to R4 are as defined above, R3 is alkyl of 1 to 4 carbon atoms and either Z" is hydrogen, fluorine or alkyl of 1 to 7 carbon atoms and W" is hydrogen or Z" is hydrogen and W" is alkyl of 1 to 7 carbon atoms or fluorine:
Z" Zl zoo ZI. W10)/R,,,,,l W t Cp / R2 No t::i1 1IN OH OH R3 N/ H R3 R4 OH R4 IIa IIb 110 reactio catalytic hydrogenation Ifoilowed by R optional mono or dialkylation zoo W 9 \ W' @;X\,R1 OH | Cl ClW 1 reaction with' Vimine reaction Ireaction with azidel followed reaction 'Iby z y optional z aK mono- or thionyl or WI'0 o /R1 We + -OH > OH YIÌ39O1 LI juctioftl V s4 ~~ x o \ ~{ h introduction of COR1 in the 2 position I. by by Friedel-Crafts Xf A r4~~~ Z acylation ant 6if g + multaneous ethero U l n |; WI 4 F Y < . ON < S NR CORI IX > VI R2 ~ NH2 | of -COR /I1 iintroduction of -COR1 k'" I in the 2-position by O-acylation followed by OH Fries rearrangement in the VIII presence of a Lewis acid II ~
Insofar as the preparation of any particular starting material is not particularly described, this may be effected in conventional manner or in analogous manner to that described herein.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
.EXAMPLE 1:2-(1-aminoethyl)-6-bromo-4-tert-butyi-phenol 5.8 g of bromine are added dropwise and under stirring at room temperature to a solution of 5.0 g
of 2-(1 -aminoethyl)-4-tert-butylphenol dissolved in 100 ml of acetic acid. After one hour of further
stirring the solvent is evaporated under a vacuum, the residue is dissolved in water and the title
compound made to precipitate by dropwise addition of dilute ammonia solution (M.P. 92--940 -- from exa.- S-etro.eum anther; M.P. of the hydrochloride 1 96--1 980 -- from ethanol/ether).
he starting material is obtained as follows:
a) 70 g of aluminium chloride in 350 ml carbon disulfide are slowly reacted at 100 with 40 g of acetyl
chloride. After one hour 70 g of 4-tert-butylanisole are added dropwise over 1 5 minutes and the
reaction mixture stirred for 15 hours at room temperature. After working up of the reaction mixture
in conventional manner 5-tert-butyl-2-hydroxy-aceto-phenone is obtained (B.P. o o, mm Hg = 1300).
b) 10 g of 5 tert-butyl-2-hydroxyacetophenone are reacted overnight at room temperature with 70 ml
ethanol saturated with ammonia. 5-tert-butyl-2-hydroxyacetophenone imine is obtained (M.P.
121-1 220 from hexane).
c) A solution of 44 g of 5 tert-butyl-2-hydroxy-acetophenone imine in 250 ml of methanol is reacted
in portions at room temperature with 10 g of sodium borohydride. After 45 minutes the reaction
mixture is evaporated to dryness, the residue dissolved in dilute aqueous hydrochloric acid and
extracted with ether. The acid aqueous solution is made alkaline with conc. ammonia and extracted
with ether. 2-(1 -Aminoethyl)-4-tert-butylphenol is obtained (M.P. 78--7900- from hexane/petroleum ether; M.P. of the hydrogen maleate 1641650).
EXAMPLE 2: 2-( l-a mi noethyl)-4,6-dibromophe nol a) In racemicform
11.0 g of bromine are added dropwise over 30 minutes and under stirring at room temperature to a solution of 4.7 g of 2-(1 -aminoethyl-phenol dissolved in 100 ml of acetic acid. After one hour of further stirring the solvent is evaporated under a vacuum, the residue is dissolved in water and the title compound made to precipitate by dropwise addition of dilute ammonia solution (M.P. 187--1890).
The starting material is obtained as follows:
22.4 g of 2-hydroxyacetophenone imine are partially dissolved in 300 ml absolute tetrahydrofuran
and then 24 ml of borane dimethylsulfide are slowly added dropwise under an argon atmosphere. After reaction has taken place the mixture is heated under reflux for 2 hours. The solvent is then evaporated under a vacuum from the so obtained solution and the residue extracted with a mixture of ether and dilute aqueous hydrochloric acid. The acid aqueous phase is made alkaline with ammonia and extracted with ether. After the solvent has been dried and then evaporated 2-(1-aminoethyl)-phenol is obtained
(M.P. of the hydrochloride form 1 7 770-from isopropanol/hydrochloric acid).
b) In optically active form
30 g of recemic 2-(l-aminoethyl)-4,6-dibromo-phenoi and 1 7 g of L(+)-tartaric acid are dissolved simultaneously in 300 ml of hot water. During cooling off to room temperature a tartrate crystallizes slowly out ([a] 2g of the free base form: 60).
This salt is then repeatedly recrystallized until the free base form liberated with ammonia
possesses a constant optical rotation. The (-)-antipode of 2-(1 -aminoethyl)-4,6-dibromophenol is obtained: [a] 2g ~ 120 (c=1:0.1 N HC1); M.P. 165--1660 (from ethanol).
The same procedure is repeated with D( -- )-tartaric acid. The ( + )-antipode of 2-( 1 -aminoethyl)- 4,6-di-bromophenol is obtained: [a] 2g + 11.80 (c = 1; 0.1 N HC1); M.P. 166--1670 (from ethanol).
EXAMPLE 3: 2-(1-amino-1-methylethyl)-4-tert-butyl-6-iodophenol
1.6 g of 2-(1 -amino-1 methylethyl)-4-tert-butylphenol hydrochloride are dissolved in a mixture of
15 ml of water and 5 ml of 1 N hydrochloric acid. 2.8 g of iodine chloride are slowly added dropwise,
under stirring and at room temperature. Stirring is maintained for a further hour. The reaction mixture is then made alkaline with dilute aqueous ammonia solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate, filtered off and evaporated. The title compound is obtained (M.P. 136-1370-from hexane).
The starting material is obtained as follows: a) 30 g of 2-acetyl-4-tert-butylphenol are dissolved in 250 ml of dry ether and then reacted under
stirring at room temperature and within 30 minutes with 300 ml of a 1 M solution of methyl lithium
in dry ether. Stirring is maintained for a further 2 hours. After working up of the reaction mixture in
conventional manner 4-tert-butyl-2-(1 -hydroxy- 1 -methylethyl)phenol is obtained (M.P. 66--67 ).
b) A mixture of 23 g of 4-tert-butyl-2-(1 -hydroxy-1-methyl-ethyl)phenol and 14.4 sodium azide in
250 ml of chloroform is cooled to -100 and a mixture of 45 ml of trifluoroacetic acid and 100 ml of
chloroform added dropwise. The reaction mixture is stirred furtherfor3 hours at room temperature.
After working up of the reaction mixture in conventional manner 2-(1-azido-1-methylethyl)-4-tert- butylphenol is obtained (light brown oil).
c) A solution of 2-(1-azido-1-methylethyl)-4-tert-butylphenol in 250 ml ethanol is hydrogenated at
500 and 5 atm. in presence of 900 mg Put02. The catalyst is separated by filtration and the filtrate
concentrated to dryness in a vacuum. After working up of the reaction mixture in conventional
manner 2-(1 -amino-1 -methylethyl)-4-tert-butylphenol is obtained (M.P. 89--90 - from hexane).
In analogous manner the following compounds of formula I are obtained by chlorinating, brominating or iodinating corresponding compounds of formula II:
Example Analogous R1 R3 R2 R4 Z W M.P.
No. to Ex. No.
4 3 Me H H H tBu I hml 183-1 84' 6 1,2 Et H H H tBu Br b 69- 69 7 3 Et H H H Me I hml 133-135- 8 3 Me H Me H tBu I hcl 183-184- 9 3 ipr H H H tBu I hcl 131-135- 10 1,2 Me H H H Me Br b 169-170- 11 1,2 Me H H H Br tBu ns > 3004 12 1,2 Me Me H H tBu Br b 128-129- 13 3 Me Me H H Me I ns > 3104 (dec.) 14 1,2d) Me Me H H Br Br b 140-142 15 1,2b);3c) Me H H H Br I b 158-159- 16 1,2d) Me H H H C1 C1 b 185-1864 17 1,2b)c) Me H H H C1 Br b 179-180- 18 1,2b);;3o) Me H - H H C1 I b 150-151a 19 3c) Me H H H F I b 115-116- 20 1,2c) Me H H H F Br b 161-162- 21 1,2d) Et H H H Br Br hol 204-205- 22 3d) Me H H H I I ns > 250 (dec.) 23 1,2d) Me H Me Me Br Br 24 - 1,2d) Me Me Me H Br Br 25 1,2d) Me Et H H Br Br 26 1,2d) Et H H H Br Br hol 204-205@ 27 1,2d) Me H Me H Br Br b 165-166' 28 1 ,2a) Me H H -l I Br H hol 226-228' 29 1,2a) d Me H H H- H Br hol 179-180' 30 1,2a) Me H H H C1 H b 135-136' 31 1,2a) Me H H H H C1 32 3a) Me H H H H 33 1,2a) Et H H H Br H
Example . Analogous R1 R3 R2 R4 Z W . M.P.
No. to Ex. No.
34 1,2a) Et H H H H Br 35 3a) Me H H H I H 36 1,2a) Me Me H H Br H 37 1,2a) Me Me H H H Br 38 1,2a) Me H Me Me Br H 39 1,2a\ Me H Me Me H Br 40 1,2a) Me Me Me H Br H 41 1,2a) Me Me Me H H Br 42 1,2a) Me Et H H Br H 43 1,2a) Me Et H H H Br 44 1,2a) Me H Me H Br H 45 1,2a) Me H Me H H Br The product of the reaction is a mixture of compounds of formula I, wherein the halogen atom is in the 4 position with respect to the hydroxy group, of compounds of formula I, wherein the halogen atom is in the 6 position with respect to the hydroxy group, b =in free form and of compounds of formula I halogenated in the 4 hcl = in hydrochloride form and 6 positions. The mixture is separated in known hml = in hydrogen maleate manner either by fractional crystallization or by form chromatography using silicagel as absorbant and chloroform plus increasing amounts of methanol as ns = in naphtalene-1, 5 eluent. disulfonate form b) Starting from a corresponding compound of formula 11, Et = ethyl wherein Z' is hydrogen and W' is not hydrogen. Pr = isopropyl Me = methyl Starting from a corresponding compound of formula II, tBu = tert-butyl wherein W' is hydrogen and Z' is not hydrogen.
d) Starting from the corresponding compounds of formula II, wherein either Z' only or W' only or both a) Z' and W' are hydrogen.
The compounds of the invention possess pharmacological activity in arrivals.
The compounds exhibit salidiuretic activity, as indicated in standard tests, for example in vivo in rats treated in accordance with the principles of E. Flückiger et al., Schwe4.med Wachenschrift 93 (1963) 1232--1 237, at a dosage of about 1 to about 100 mg/kg p.o.
The compounds are therefore indicated for use as salidiuretics, e.g. for the treatment of oedema and hypertension.
The compounds also exhibit antihypertensive activity, as indicated in standard tests, for example, in the Grollman rat test [A. Groliman, Proc.Soc.Exp. Biol. and Med. 57 (1944) 02] on administration of from 1 to 100 mg/kg p.o.
The compounds are therefore indicated for use as antihypertensive agents,-eig. for the treatment of hypertension.
Preferred are the compounds of Examples 1, 2, 3 and 12, especially Examples 1 and 2.
An indicated daily dose is from about 1 to about 50 mg, and dosage forms suitable for oral administration comprise from about 0.25 to about 20 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.
The compounds may be administered in pharmaceutically acceptable salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner. The present invention also provides a pharmaceutical composition comprising a compound of the invention on free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.
Claims (75)
1. A process for the production of an a-alkyl-o-oxybenzylamine having the phenyl ring substituted by one or at most two halogen atoms of atomic number of from 17 to 53, the halogen atom or atoms being in a position meta to the aminoalkyl moiety, which comprises appropriately chlorinating, brominating or iodinating a corresponding a-alkyl-o-oxybenzylamine derivative having the phenyl ring substituted by at most on halogen atom.
2. A process for the production of a compound of formula I,
wherein R1 is alkyl of 1 to 4 carbon atoms,
R2 to R4 independently are hydrogen or alkyl of 1 to 4 carbon atoms and either Z is hydrogen or alkyl of 1 to 7 carbon atoms and W is halogen of atomic number of from 17 to53 or Z is halogen of atomic number of from 17 to 53 and W is hydrogen or alkyl of 1 to 7 carbon
atoms, or Z and Ware hologen of atomic number of from 9 to 53 with the proviso that they are not
both fluorine, or an 0- and/or N-acyl derivative thereof, which comprises appropriately chlorinating, brominating or iodinating a corresponding compound of formula II,
wherein R1 to Ra are as defined above and either Z' is hydrogen or alkyl of 1 to 7 carbon atoms and W' is hydrogen, or Z' is hydrogen and W is alkyl of 1 to 7 carbon atoms, or Z' is halogen of atomic number of from 9 to 53, W is hydrogen or Z' is hydrogen and W' is halogen of atonic number of from 9 to 53, with the provisos that
A) when Z and W are halogen of atomic number of from 17 to 53 and are different, one of Z' and W' is
halogen of atomic number of from 17 to 53, and
B) when Z orW is fluorine, accordingly Z' orW' is fluorine, or an 0- and/or N-acyl derivative thereof.
3. A process for the production of a compound as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples.
4. A compound as defined in claim 1, whenever produced by a process according to claim 1.
5. An a-alkyl-o-oxybenzylamine having the phenyl ring substituted by one or at most two halogen atoms of atomic number of from 17 to 53, the halogen atom or atoms being in a position meta to the aminoalkyl moiety.
6. A compound of formula I, as defined in claim 2, or an 0-and/or N-acyl derivative thereof.
7. A compound of formula I, as defined in claim 2.
8. A compound of claim 6. wherein R3 is hydrogen.
9. A compound of claim 6, wherein R3is identical to F.
10. A compound of claim 6, wherein R2 is hydrogen.
11. A compound of claim 6, wherein R4 is hydrogen.
12. A compound of claim 6, wherein R2 and R4 are alkyl and are identical.
13. A compound of claim 6, wherein one of R2 and R4is alkyl and R3is hydrogen.
14. A compound of claim 6, wherein R2 and R4 are alkyl and R3is hydrogen.
15. A compound of claim 6, wherein Z is alkyl.
16. A compound of claim 6. wherein Z is halogen.
17. A compound of claim 6, wherein W is halogen.
1 8. A compound of claim 6, wherein W is alkyl.
1 9. A compound of claim 6, wherein W and Z are both halogen.
20. A compound of claim 7 of formula Ipa,
wherein
R, and R2 are as defined in claim 2, Zpa is alkyl of 1 to 7 carbon atoms and WPB is halogen of atomic number of from 17 to 53.
21. A compound of claim 7 of formula Ipb,
wherein
R1 and R2 are as defined in claim 2,
ZPb is halogen of atomic number of from 17 to 53 and WPb is alkyl of 1 to 7 carbon atoms.
22. A compound of claim 7 of formula Ipc,
wherein
R, and R2 are as defined in claim 2,
ZPC is halogen of atomic number of from 9 to 53 and WPC is halogen of atomic number of from 17 to 53.
23. A compound of claim 7 of formula Ipd,
wherein
R, and R2 are as defined in claim 2, RP3 is alkyl of 1 to 4 carbon atoms and either ZPd is alkyl of 1 to 7 carbon atoms and WPd is halogen of atomic number of from 1 7 to 53 or ZPd is halogen of atomic number of from 17 to 53 and Wpd is alkyl of 1 to 7 carbon atoms, or ZPd is halogen of atomic number of from 9 to 53 and WPd is halogen of atomic number of
from 17 to 53.
24. The compound of claim 7, which is 2-(1 -amino-ethyl)-6-bromo-4-tert-butylphenol
25. The compound of claim 7, which is 2-(1 -amino-ethyl)-4,6-dibromophenol.
26. The compound of claim 7, which is 2-(1-amino-1-methylethyl)-4-tert-butyl-6-iodophenol.
27. The compound of claim 7, wherein P1, R3,R2,R4,Z and W are, respectively, Me, H, H, H, tBu,
28. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, H, H, H, iPr, I.
29. The compound of claim 7, wherein R1,R3,R2,R4,Z and Ware, respectively, Et, H, H, H, tBu, Br.
30. The compound of claim 7, wherein P1, R3,R2,R4,Z and Ware, respectively, Et, H, H, H, Me,
31. The compound of claim 7, wherein P1, R3,R2,R4,Z and Ware, respectively, Me, H, Me, H, tBu,
I.
32. The compound of claim 7, wherein P1, R3,R2,R4,Z and Ware, respectively, iPr, H, H, H, tBu, I.
33. The compound of claim 7, wherein P1, R3,R2,R4,Z and W are, respectively, Me, H, H, H, Me,
Br.
34. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, H, H, H, Br, tBu.
35. The compound of claim 7, wherein R1, R3, R2, R4, Z and W are, respectively, Me, Me, H, H, tBu,
Br.
36. The compound of claim 7, wherein R1, R3, R2, R4,Z and Ware, respectively, Me, Me, H, H, Me,
I.
37. The compound of claim 7, wherein R1, R3, R2, R4,Z and Ware, respectively, Me, Me, H, H, Br,
Br.
38. The compound of claim 7, wherein R1, R3, R2, R4,Z and W are, respectively, Me, H, H, H, Br, I.
39. The compound of claim 7, wherein R1, R3, R2, R4, Z and W are, respectively, Me, H, H, H, CI, CI.
40. The compound of claim 7, wherein R1, R3, R2, B4, Z and W are, respectively, Me, H, H, H, Cl, Br.
41.The compound of claim 7, wherein R1,R3,R2,R4,Z and Ware, respectively, Me, H, H, H, CI,
42. The compound of claim 7, wherein R1, B3, R2, Rd, Z and Ware, respectively, Me, H, H, H, F, I.
43. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, H, H, H, F, Br.
44. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Et, H, H, H, Br, Br.
45. The compound of claim 7, wherein R1,R3,R2,R4,Z and Ware, respectively, Me, H, H, H, I,
46. The compound of claim 7, wherein R1, R3, R2,R4, Z and Ware, respectively, Me, H, Me, Me, Br,
Br.
47. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, Me, Me, H, Br,
Br.
48. The compound of claim 7, wherein R1, R3, R2,R4,Z and W are, respectively, Me, Et, H, H, Br, Br.
49. The compound of claim 7, wherein R,, R3,R2,R4,Z and W are, respectively, Et, H, H, H, Br, Br.
50. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, H, Me, H, Br,
Br.
51.The compound of claim 7, wherein R1,R3,R2,R4,Z and Ware, respectively, Me, H, H, H, Br, H.
52. The compound of claim 7, wherein R,, R3,R2,R4,Z and Ware, respectively, Me, H, H, H, H, Br.
53. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, H, H, H, CI, H.
54. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, H, H, H, H, Cl.
55. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, H, H, H, H, I.
56. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Et, H, H, H, Br, H.
57. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Et, H, H, H, H, Br.
58. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, H, H, H, I, H.
59. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, Me, H, H, Br,
H.
60. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, Me, H, H, H,
Br.
61.The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, H, Me, Me, Br,
H.
62. The compound of claim 7, wherein R1, R3, R2, R4, Z and Ware, respectively, Me, H, Me, Me, H,
Br.
63. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, Me, Me, H, Br,
H.
64. The compound of claim 7, wherein R1, R1,R3, R2, R4,Z and Ware, respectively, Me, Me, Me, H, H,
Br.
65. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, Et, H, H, Br, H.
66. The compound of claim 7, wherein R1, R1,R3, R2, R4, Z and Ware, respectively, Me, Et, H, H, H, Br.
67. The compound of claim 7, wherein R1, R3,R2,R4,Z and W are, respectively, Me, H, Me, H, Br,
H.
68. The compound of claim 7, wherein R1, R3,R2,R4,Z and Ware, respectively, Me, H, Me, H, H,
Br.
69. A compound according to any one of claims 4 to 68, in racemic form.
70. A compound according to any one of claims 4 to 68, in (+) optically active form.
71. A compound according to any one of claims 4 to 68, in (-) optically active form.
72. A compound according to any one of claims 4 to 71 in free base form.
73. A compound according to any one of claims 4 to 71 is salt form.
74. A compound according to any one of claims 4 to 71 in acid addition salt form.
75. A pharmaceutical composition comprising a compound of any one of claims 4 to 71 in free base form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH937078 | 1978-09-06 | ||
CH437779 | 1979-05-10 | ||
CH437579 | 1979-05-10 | ||
CH557679 | 1979-06-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB2029830A true GB2029830A (en) | 1980-03-26 |
Family
ID=27428769
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7930423A Withdrawn GB2029830A (en) | 1978-09-06 | 1979-09-03 | Alkyl o oxybenzylamine derivatives their preparation and pharmaceutical compisitions containing them |
Country Status (14)
Country | Link |
---|---|
AU (1) | AU5056579A (en) |
DE (1) | DE2934508A1 (en) |
DK (1) | DK362379A (en) |
ES (1) | ES483865A1 (en) |
FI (1) | FI792676A (en) |
FR (1) | FR2435461A1 (en) |
GB (1) | GB2029830A (en) |
IL (1) | IL58169A0 (en) |
NL (1) | NL7906557A (en) |
PT (1) | PT70142A (en) |
SE (1) | SE7907185L (en) |
SU (1) | SU895283A3 (en) |
WO (1) | WO1980000561A1 (en) |
YU (1) | YU215279A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0311385A2 (en) * | 1987-10-09 | 1989-04-12 | Sumitomo Chemical Company, Limited | Optically active hydroxybenzylamine derivative, optically active amine-boron compound containing said derivative, and process for producing optically active compound by using said compound |
US5231227A (en) * | 1987-10-09 | 1993-07-27 | Sumitomo Chemical Company, Limited | Optically active hydroxybenzylamine derivative and process for producing said compound |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL8100078A (en) * | 1980-01-14 | 1981-08-17 | Sandoz Ag | NEW 2-AMINOMETHYL-6-HALOGEN-PHENOLS, AND METHODS FOR PREPARING THESE PHENOLS AND MEDICINAL PRODUCTS CONTAINING THEM. |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1493949A1 (en) * | 1962-05-30 | 1969-07-10 | Merck Ag E | Process for the preparation of primary amines |
NL149783B (en) * | 1970-12-23 | 1976-06-15 | Merck & Co Inc | PROCESS FOR THE PREPARATION OF SUBSTITUTED AMINOMETHYLPHENOLS, OF THE NON-TOXIC PHARMACOLOGICALLY ACCEPTABLE SALTS DERIVED FROM THIS, PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL PREPARATIONS AND THE PREPARED PREPARATIONS. |
NL180978C (en) * | 1972-10-23 | 1987-06-01 | Thomae Gmbh Dr K | METHOD FOR MANUFACTURING A PHARMACEUTICAL PREPARATION WITH SECRETORIC AND / OR ANTI-COUGHTING ACTION, AND A METHOD FOR PREPARING A COMPOUND SUITABLE FOR USE IN THE FOREGOING METHOD |
AT332863B (en) * | 1973-01-02 | 1976-10-25 | Gerot Pharmazeutika | PROCESS FOR THE PREPARATION OF NEW 2-AMINOMETHYL-4,6-DIHALOGENPHENOL DERIVATIVES AND THEIR ADDITIONAL SALTS WITH ACIDS |
-
1979
- 1979-08-27 DE DE2934508A patent/DE2934508A1/en not_active Withdrawn
- 1979-08-27 WO PCT/CH1979/000113 patent/WO1980000561A1/en unknown
- 1979-08-28 FI FI792676A patent/FI792676A/en not_active Application Discontinuation
- 1979-08-29 SE SE7907185A patent/SE7907185L/en not_active Application Discontinuation
- 1979-08-29 DK DK362379A patent/DK362379A/en not_active Application Discontinuation
- 1979-08-31 NL NL7906557A patent/NL7906557A/en not_active Application Discontinuation
- 1979-09-03 GB GB7930423A patent/GB2029830A/en not_active Withdrawn
- 1979-09-04 IL IL58169A patent/IL58169A0/en unknown
- 1979-09-04 ES ES483865A patent/ES483865A1/en not_active Expired
- 1979-09-04 PT PT70142A patent/PT70142A/en unknown
- 1979-09-04 AU AU50565/79A patent/AU5056579A/en not_active Abandoned
- 1979-09-05 FR FR7922168A patent/FR2435461A1/en not_active Withdrawn
- 1979-09-05 YU YU02152/79A patent/YU215279A/en unknown
- 1979-09-05 SU SU792808553A patent/SU895283A3/en active
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0311385A2 (en) * | 1987-10-09 | 1989-04-12 | Sumitomo Chemical Company, Limited | Optically active hydroxybenzylamine derivative, optically active amine-boron compound containing said derivative, and process for producing optically active compound by using said compound |
EP0311385A3 (en) * | 1987-10-09 | 1990-06-27 | Sumitomo Chemical Company, Limited | Optically active hydroxybenzylamine derivative, optically active amine-boron compound containing said derivative, and process for producing optically active compound by using said compound |
US5011989A (en) * | 1987-10-09 | 1991-04-30 | Sumitomo Chemical Company, Limited | Optically active hydroxybenzylamine |
US5231227A (en) * | 1987-10-09 | 1993-07-27 | Sumitomo Chemical Company, Limited | Optically active hydroxybenzylamine derivative and process for producing said compound |
Also Published As
Publication number | Publication date |
---|---|
FI792676A (en) | 1980-03-07 |
YU215279A (en) | 1983-04-30 |
ES483865A1 (en) | 1980-04-16 |
AU5056579A (en) | 1980-03-13 |
IL58169A0 (en) | 1979-12-30 |
SU895283A3 (en) | 1981-12-30 |
DE2934508A1 (en) | 1980-03-20 |
PT70142A (en) | 1979-10-01 |
SE7907185L (en) | 1980-03-07 |
FR2435461A1 (en) | 1980-04-04 |
WO1980000561A1 (en) | 1980-04-03 |
NL7906557A (en) | 1980-03-10 |
DK362379A (en) | 1980-03-07 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |