This invention provides new compounds of formula I, ##STR1## wherein R.sub.1 is hydrogen, halogen of an atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms,R.sub.2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, in which the multiple bond is located in a position other than the .alpha.,.beta. position, hydroxyalkyl of 2 to 5 carbon atoms in which the hydroxy group is separated from the nitrogen atom of the tricyclic ring system by at least 2 carbon atoms, alkanoylalkyl of 3 to 5 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, andEitherR.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, andR.sub.4 is hydrogen,OrR.sub.3 and R.sub.4 together with the nitrogen atom toWhich they are bound form a 1-pyrrolyl ring,Useful as anti-aggressive and C.N.S. depressants. SUThe present invention relates to 1,2,3,4-tetrahydrobenzoisoquinolines.The present invention provides compounds of formula I, ##STR2## wherein R.sub.1 is hydrogen, halogen of an atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms,R.sub.2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, in which the multiple bond is located in a position other than the .alpha.,.beta. position, hydroxyalkyl of 2 to 5 carbon atoms in which the hydroxy group is separated from the nitrogen atom of the tricyclic ring system by at least 2 carbon atoms, alkanoylalkyl of 3 to 5 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, andEitherR.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, andR.sub.4 is hydrogen,OrR.sub.3 and R.sub.4 together with the nitrogen atom to which they are bound form a 1-pyrrolyl ring.The alkyl and alkoxy moieties (except when R.sub.2 is alkyl) preferably have 1 or 2 carbon atoms, especially 1 carbon atom.R.sub.1 is preferably hydrogen. Otherwise R.sub.1 is preferably in the 7 or 8 position.R.sub.2 is preferably hydrogen, or alkyl. When R.sub.2 is alkyl, it preferably has 1 to 3 carbon atoms, and is especially methyl or isopropyl. When R.sub.2 is alkenyl or alkynyl, it preferably has 3 or 4 carbon atoms. When R.sub.2 is hydroxyalkyl, it preferably has 2 or 3 carbon atoms. When R.sub.2 is alkanoylalkyl it preferably contains an acetyl moiety, and preferably signifies acetonyl. When R.sub.2 is phenylalkyl, this is preferably benzyl. When the phenyl ring is substituted this is preferably substituted by halogen, especially chlorine.R.sub.3 is preferably hydrogen or methyl. A preferred alternative is when R.sub.3, R.sub.4 and the nitrogen atom to which they are bound form a 1-pyrrolyl ring. R.sub.3 when phenylalkyl is preferably an optionally substituted benzyl or phenylethyl group.The present invention further provides a process for the production of a compound of formula I which comprisesa. for the production of a compound of formula Ia, ##STR3## wherein R.sub.1, R.sub.3 and R.sub.4 are as defined above, andR.sub.2.sup.i is as defined for R.sub.2 above with the proviso that R.sub.2.sup.I is other than hydrogen,alkylating a compound of formula Ib, ##STR4## wherein R.sub.1, R.sub.3 and R.sub.4 are as defined above, orb. for the production of a compound of formula Ic, ##STR5## wherein R.sub.1, R.sub.3 and R.sub.4 are as defined above, andR.sub.2.sup.ii is a primary alkyl group of 1 to 4 carbon atoms, or a primary unsubstituted or mono-substituted phenylalkyl as defined above for R.sub.2,reducing a compound of formula II, ##STR6## wherein R.sub.1, R.sub.3 and R.sub.4 are as defined above, andR.sub.5 is (i) alkanoyl of 2 to 4 carbon atoms, (ii) benzoyl or phenylalkanoyl of 8 to 10 carbon atoms in which benzoyl or phenylalkanoyl the phenyl ring is unsubstituted or mono-substituted by halogen or alkyl or alkoxy of 1 to 4 carbon atoms, or (iii) lower alkoxycarbonyl, or aryloxycarbonyl, orc. for the production of a compound of formula Ib, as defined above, splitting off a radical R.sub.5.sup.I from a compound of formula III, ##STR7## wherein R.sub.1, R.sub.3 and R.sub.4 are as defined above, andR.sub.5.sup.i is a group capable of being split off by solvolysis.The introduction of the R.sub.2.sup.I group as defined above according to process a) is a mono-alkylation in the 2 position of the tetrahydrobenzo[g] isoindoline residue and may be effected in known manner for such alkylations of analogous ring systems bearing in mind the other groups present. For example the compound of formula Ib may be reacted with a compound of formula IV,r.sub.2.sup.i -x ivwhereinR.sub.2.sup.i is as defined above, andX is chlorine, bromine or iodine.An inert organic solvent may be used. Preferably there is present a medium-strong basic condensation agent, or an excess of the compound of formula Ib. As condensation agents are preferably used medium-strong organic bases such as triethylamine or pyridine or alternatively inorganic bases such as alkali metal carbonates. However, when R.sub.3 is hydrogen and when a simultaneous alkylation of the 5-amino group is to be avoided then conveniently a mildly basic condensation agent is used and/or preferably approximately equivalent amounts of alkylating agent and compound of formula Ib are used. A compound of formula Ia, wherein R.sub.2 is alkanoylalkyl as defined above, wherein the carbonyl group is separated by at least two carbon atoms from the nitrogen atom of the tricyclic residue, may be produced in conventional manner by using an appropriate .alpha.,.beta.-unsaturated ketone as an alkylating agent.The reduction according to process variant (b) may be effected in conventional manner for such reductions, e.g. using a complex metal hydride in an inert organic solvent. Suitable hydrides include complex aluminium hydrides such as lithium aluminium hydride.Process (c) may be effected in conventional manner for the splitting off of an amino protecting group from a heterocyclic amine using solvolytic, especially hydrolytic, conditions, for example as for the splitting of a urethane or amide. Suitable protecting groups R.sub.5.sup.I include for example acyl groups, preferably alkoxycarbonyl or aryloxycarbonyl groups, or alkanoyl or aroyl groups, for example those such groups defined above with respect to R.sub.5. The reaction may, depending on the type of group R.sub.5.sup.I used, be preferably effected in an acid medium, for example in the presence of a strong mineral acid, or in an alkaline medium, for example in the presence of a suitable inorganic base.The starting materials may be produced as follows:a') compounds of formula II, wherein R.sub.3 is other than hydrogen may be produced in conventional manner by substituting the amino group in a compound of formula IIa, ##STR8## wherein R.sub.1 and R.sub.5 are as defined above.For example the appropriate alkyl- or phenylalkylhalide may be used in the presence of potassium tert.-butoxide, or when R.sub.3 is methyl, alternatively dimethylsulphate/pyridine may be used.Compounds of formula II, wherein R.sub.3 and R.sub.4 together with the nitrogen atom to which they are bound form a 1-pyrrolyl ring may be produced by reacting a compound of formula IIa with 2,5-dimethoxytetrahydrofuran and splitting off methanol from the resulting reaction product.b') Compounds of formula IIa may be produced from the corresponding 3-benzyl-4-piperidone derivatives of formula V, ##STR9## wherein R.sub.1 and R.sub.5 are as defined above, by (i) introducing hydrogen cyanide using conventional processes for cyanohydrin production, preferably by reaction with acetone cyanohydrin, (ii) splitting off water from the resulting 3-benzyl-4-hydroxy-4-piperidine nitrile, for example using thionyl chloride/pyridine, (iii) cyclizing the resulting 5-benzyl-4-cyano-1,2,3,6-tetrahydropyridine derivative of formula VI, ##STR10## wherein R.sub.1 and R.sub.5 are as defined above, if desired with any corresponding 3-benzyl-4-cyano-1,2,3,6-tetrahydropyridine derivative present as a by-product, for example in the presence of 90% sulphuric acid.Insofar as the production of any starting material is not particularly described these compounds are known, or may be produced and purified in accordance with known processes, or in a manner analogous to processes described herein, e.g. in the Examples, or to known processes.Free base forms of compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid or fumaric acid.In the following Examples all temperatures are in degrees Centigrade and are uncorrected.In the Table the following abbreviations are used:Z = decompositionHcl = hydrochloride saltHbr = hydrobromide saltRf refers to Rf values obtained on silica gel using as eluant benzene/ethanol/(conc. aq.) ammonia 84:15:1.
Description
Claims
1. A compound of formula I, ##STR21## wherein R.sub.1 is hydrogen, halogen of an atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms,
R.sub.2 is hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms, in which the multiple bond is located in a position other than the .alpha.,.beta. position, hydroxyalkyl of 2 to 5 carbon atoms in which the hydroxy group is separated from the nitrogen atom of the tricyclic ring system by at least 2 carbon atoms, alkanoylalkyl of 3 to 5 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or monosubstituted by halogen of atomic number 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, and
either
R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms, or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, and
R.sub.4 is hydrogen,
or
R.sub.3 and R.sub.4 together with the nitrogen atom to which they are bound form a 1-pyrrolyl ring,
in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
2. A compound of claim 1, wherein R.sub.3 is hydrogen, alkyl or substituted or unsubstituted phenylalkyl.
3. A compound of claim 2, wherein R.sub.2 is hydrogen.
4. A compound of claim 1, wherein R.sub.2 is hydrogen, alkyl or unsubstituted or substituted phenylalkyl, and R.sub.3 and R.sub.4 are both hydrogen.
5. A pharmaceutical composition comprising an anti-aggressive or anti-excitation effective amount of a compound according to claim 1 in association with a pharmaceutical carrier or diluent.
6. A method of treating excitation or aggression in animals which comprises administering to an animal in need of such treatment a therapeutically effective amount of a compound of claim 1.
7. The method of claim 6 wherein the compound is 5-amino-1,2,3,4-tetrahydro[g]benzoisoquinoline or a pharmaceutically acceptable acid addition salt thereof.
8. The method of claim 6 wherein the compound is 5-amino-2-(o-chlorophenethyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable addition salt thereof.
9. A compound of claim 1 where R.sub.1, R.sub.2 and R.sub.4 are hydrogen and R.sub.3 is as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.
10. A compound of claim 1 wherein R.sub.1 is as defined in claim 1, R.sub.2 is other than hydrogen, and NR.sub.3 R.sub.4 represents 1-pyrrolyl, or a pharmaceutically acceptable acid addition salt thereof.
11. A compound of claim 1 which is 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
12. A compound of claim 1 where R.sub.1, R.sub.3 and R.sub.4 are as defined in claim 1 and R.sub.2 is phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
13. A compound of claim 1 which is 5-amino-2-(o-chlorophenethyl)-1,2,3,4-tetrahydro[g]benzoisoquinoline, or a pharmaceutically acceptable acid addition salt thereof.
14. A compound of claim 1 where R.sub.1, R.sub.2 and R.sub.4 are as defined in claim 1 and R.sub.3 is hydrogen, alkyl of 1 to 4 carbon atoms or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen of atomic number from 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
15. A compound of claim 1 where R.sub.1 is as defined in claim 1, R.sub.2 is hydrogen, alkyl of 1 to 4 carbon atoms or phenylalkyl of 7 to 10 carbon atoms in which the phenyl ring is unsubstituted or mono-substituted by halogen or atomic number 9 to 35, or alkyl or alkoxy of 1 to 4 carbon atoms, a and R.sub.3 and R.sub.4 are each hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
16. A compound of claim 1 which is 5-amino-2-iso-propyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
17. A compound of claim 1 which is 2-allyl-5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
18. A compound of claim 1 which is 5-amino-2-benzyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
19. A compound of claim 1 which is 5-amino-2-(2-butenyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
20. A compound of claim 1 which is 2-acetonyl-5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
21. A compound of claim 1 which is 5-amino-2-methyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
22. A compound of claim 1 which is 5-amino-2,7,-dimethyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
23. A compound of claim 1 which is 2-methyl-5-(1-pyrrolyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
24. A compound of claim 1 which is 5-(1-pyrrolyl)-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
25. A compound of claim 1 which is 5-amino-7-methyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
26. A compound of claim 1 which is 5-methylamino-1,2,3,4-tetrahydrobenzo[g]isoquinoline or a pharmaceutically acceptable acid addition salt thereof.
27. A compound of claim 14 where R.sub.2 is hydrogen.
Patent Grant
4081543
