CA1087174A

CA1087174A - Tetracyclic compounds and production thereof

Info

Publication number: CA1087174A
Application number: CA291,693A
Authority: CA
Inventors: Atsuyuki Kojima; Yoshito Kameno; Junki Katsube
Original assignee: Sumitomo Chemical Co Ltd
Current assignee: Sumitomo Chemical Co Ltd
Priority date: 1976-12-08
Filing date: 1977-11-24
Publication date: 1980-10-07
Also published as: DE2754760A1; ES464875A1; FR2373531A1; GB1551590A; FR2373531B1; ES473437A1; AU511203B2; AU3133077A; AT359508B; BE861656A; SE7713824L; HU177752B; NL7713626A; ATA875977A

Abstract

Abstract of the Disclosure:

The specification discloses novel tetracyclic compounds of the formula:

Description

~ 37174 The present invention relates to novel tetracyclic cGmpounds, and to their proauction and use.

The t~tracyclic compounds of this invention can be represent~d by the formula:

CH2~N [I]
\ 2 . \

wherein Rl is hydrogen or Cl-C3 alkyl, R2is Cl-C3 alkyl, yl is hydrogen or halogen and X1 is a divalent radical selected from the group consisting of -O-, -S-, -N(R3)- and -CO-, R3 being hydrogen or Cl-C3 alkyl, and the pharmaceutically acceptahle salts thereof.
In the above , the term "Cl-C3 alk~yl"
ncludes methyl, ethyl and isopropyl, ancl the term "halogen" covers fluorine, chlorine and bromine.
The tetracyclic compounds [I] may form acid addi-~ion salts (e.g. hydrochloride, hydrobromide, sulfate, acetate, oxalate, citrate, f~arate, maleate, lactate, tartrate) and quaternary ammonium salts (e.g. methochloride, methiodide).
The tetracyclic compounds [I~ and the pharmaceutically acceptable salts thereof exhibit various ph2rmacological activities and are thus useful as medicines. In general, they affect the functioning or the central n~rvous syste~. That is, they antagonize the central nerVous system depressaIIt effect induced by tetrabenazine and by reserpine, and also potentiate the central action of norepinephrine. Therefore, the co~lpounds and their salts are useful as antidepressants.

, .

. ~

1~37174 - ~mong the tetracyclic com~ounds lI] of the inven-tion, those having the following formula are preferable:

( _ ~ ~ R4 wherein R4 is hydrogen or methyl, and Xl and yl are each as defined above, and the pharmaceutically acceptable salts thereof.
The compounds of the fo].lowi.n~ formula are particularly preferable:

2 \ ~I"] ~ :~

~1 . .
wherein x2 is a divalent radical selected from the group consisting of -O-, -NH-, -N(CH3)- and -CO-, and R and Y
are each as defined above, and the pharmaceutically accept-able salts thereof.
~ he compounds of the follow.ing formula ar2 the most preferable:

' ~ [I"']
~-~ CH3 \y~
wherein y2 is hydrogell or chlorine, and R4 and x2 are each as defined a~)ove, and the pharmaceutically acceptable salts 10~37174 thereof.
The tetracyclic compounds [I] and the pharma-ceutically acce~table salts thereof can be administered parenterally or orally with dosages adjusted to individual requirem~nts (10 - 300 mg/hurnan body ~i.e. a body ~eight of 60 kg]/day) in the form of conventional pharmaceutical prepara-tions. For instancc, they may be administered in the form of a conventional solid pharmaceutical preparation,such as tablets or capsules,or in the form of a conventional liquid pharmaceutical preparation,such as suspensions, emulsions or solutions.
The tetracyclic compounds [I] can be prepared by various methods according to the invention, as follows:
(a) The tetracyclic compound of the formula:

CH2 N \ 2 [Ial R
yl wherein X3 is a divaient radical selected from the group co~sisting of -O-, -S- and -N(R3)-, and Rl, R2, R3 ~n~ yl are each as defined above,can be prepared by reduction of the corresponding amide of the formula:

~C-N I I I ]
~\ \R2 , ~yl wherein R , R , R , X and Y are each as defined above.

~_ . . ...... .... , .. _ - , . .

The reduction may be carried out by the use of any reducing agent conventionally employed for the reduction of ~ -an amide to an amine. One of the most preferred reducing agents is a metal hydride such as lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride or sodium dihydrodiethyl aluminate. The reducing agent can be used in an equimolar amount to the amide [II], or in an excess. r When sodium borohydride is used as the reducing agent, the presence of a salt such as aluminum chloride is 10 desirable. ~hen desired, an inert solvent such as an ether (e.g. diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether), an aliphatic hydrocarbon (e.g. n- -hexane n-heptane, cyclohexane) or an aromatic hydrocarbon (e.g. benzene, toluene), may be employed in the reduction.
The temperature employed during the.reduction can be any temperature from the ice-cooling temperature to the refluxing temperature of the reduction system.
(b) The tetracyclic compound of the formula:

H ~ `C~I2 N lIb]

`yl wherein Rl, R2 and yl are each as defined above can be prepared by hydrcgenolysis or by hydrogenolysis and reduc-tion of the corresponding compound of the formula:

7j Rl \ R? [III]

101!37174 wherein ~ is Cl-C3 alkyl or cl-c3 al~oxy and z is an oxygen or two hydrouens, and Rl, R2 and yl are each as defined above.
The hydrogenolysis and reduction may be carri~d out by using a metal hydride,such as lithium aluminum hydride, lithium aluminum diethoxyhydride or lithium aluminum trietho~yllydride, preferably in the presence of an inert solvent,such as an ether ~e.g. diethyl ether, tetra-hydrofuran, dio~ane, ethylene glycol dime.hyl ether), an aliphatic hydrocarbon (e.g. n-hexane, n-heptane, cyclo-hexane) or an aromatic hydrocarbon (e.g. benzene, toluene).
The temuerature employed for the hydro~-enolysis and reduction ~` can be any temperature from the ice-cooliny tem~era~ure to the : .
refluxing temperature of the reaction system.

(c) The tetracyclic compounds of the formula:
.. ; ~

o=C ~ CH2-N~ ~Ic]
>=\ \ R2 ,,. ~1 .

wherein Rl, R2 and yl are each as defined above can be prepared by oxidation of the corresponding alcohol of the formula: -'' f~\
Rl ~--~
HO~ C112-N \ R2 [IV] ~

yl ::
wherein 1~l, R2 and yl are each as defined above.

; The oxidation may be accomplish~d by the use of an ' ~ o ~
. .
. . .

~ ~ .
.

. .
- - . .... .

oxidiziny agcllt conventionally e~ployed for the oxi-dation of an alcohol to a ketone. Preferred o~:idizing agents are mangancse dioxide, chromic acid, chromates and so on. The oxida'ion reaction is ordinarily carried out in an inert solvent,such as an aliphatic hydrocarbon (e.g. n-hexane, n-pentane), a chlcrinated aliphatic hydrocarbon (e.g. dichloromethane, chloroform, carbon tetrachloride), an aromatic hydrocarbon (e.g. benzene, toluene), a carboxylic acid (e.g. acetic acid) or a ketone (e.g. acetone, ~ethyl ethyl ketone). The temperature for the reaction can be varied from ice-cooling to the refluxing temperature of the reaction system.
(d) The tetracyclic compound of the formula:

CH / [Id]

.
\yl wherein X4 is a divalent radical selected from the group consisting of -n-, -s-, -N(Cl-C3 alkyl)- and -CO-, and Rl,`
R2 and yl are each as defined above can be p~epared by the reaction of the corresponding compound of the formula:

~4 ~ C [V]

wherein W i~ a conventional"leaving group"selecte~d from the group consisting of halogen (e.g. chlorine, bromine) or _' ' -- _~

..

sulfonyloxy (e.g. methanesulfonylo~y, p-toluenesulfonyloxy), and X4 and yl are each as de~ined ~bove, with ar. amine of the formula:

Rl H-N EVI]
\R2 wherein Rl and R2 are each as defined above in an inert organic solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethanol, methanol, benzene, toluene or pyrldine in the presence or absence of an acid binding agent. Examples of the acid binding agent are pyridine, pico].ine, triethyl-ami.ne, di.methylaniline, etc. The temperature employed for the reaction may be any temperature from the ice-cooling tem-perature to the refluxing- temperature of the reaction system.
(e) The tetracyclic compound of the formula:

~R6 R -N ~ ~ CH2-N [Ie]

\yl wherein R6 and R7 are each Cl-C3 alkyl, and R2 and yl are each as defined above can be prepared by the condensation of the corres~onding compounc of the formula:

~--) / R
H ~ ~ CH2-~ VII]

\yl wherein R2, R6 alld yl are each as defined above with an alkylating agent of the formula:
.

., 10~37174 ; W-R7 tVIII]
wherein R7 and W are each as defined above, in the presence of an acid binding agent such as sodium hydride or sodium amide in an inert solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl : ether, benzene or toluene. The temperature er.~loyed for the condensation may be any temperature from the ice-cooling tem-pexature to the refluxing terllperature of the reaction syste~.

The thus prepared tetracyclic compounds [I] can be converted into their salts by any conventional procedure, and reconversion from the salts to the original free bases can be also carried out in a conventional manner.
Various starting materials in the above methods are novel and can be produced according to the following scheme:

. .

., .

." . .
:. :

_ g _ .. : . : , ' 1~37174 ; X~5 ~ <~ ~ C02R8 \yl / yl IIX] / ~Xl --CH 20H ~ CON

yl~ \ yl [XIII] / IXI] I

f ~

-CH2-W HN~--CON HO-CH ,~>-C112-N

\yl yl \yl :~ [V] [XII] [IV]

wherein X5 is a divalent radical selected Erom the group : consisting of -O-, -S-, -N(Cl-C3 alkyl)-, -NCoR5- and -CO-, x6 is a divalent radical selected from the group consisting of - -o-, -S-, -N(R )- and -CHOH-, R is Cl-C3 alkyl, and ~ , R , R , :~ :

~: .
X4, yl and W are each as d~fined abov~.
That is, the tricyclic compounds [IX~ are reacted with alkoxycarbonyl carbenes, prepared from alkyl diazo-acetates, to afford the alkyl cyclopropanecarboxylates lX].
The carboxylates [X] are saponified to the corresponding carboxylic acids, which are then converted into their active derivatives such as acid anhydrides or acid halides and reacted with amines to afford the tetracyclic amides [XI].
Further, the amides [XI] wherein X5 is -~CoR5- may be 10 reacted with metal hydride complexes such as lithium aluminum hydride at lower temperatures to afford the amides [XIIl, or the amides [XI] wherein X5 is -CO- are reduced to the amines c [IV]. Alternatively, the carboxylates lX] may be reduced to I the corresponding alcohols [XIII], followed by active ester-ification to afford the compounds lV]. The compound [XIII] - -wherein x6 is -CHOH- may be oxidized to the corresponding ketones, followed by active esterification to afford the compounds [V] wherein X4 is -CO-.
Some of the tricyclic compounds [IX] and their methods 20 of preparation are known, and the other compounds may be derived . ~
therefrom according to per se conventional procedures or -~
synthesized in the similar manner thereto.
~or instance, dibenz[b,f]oxepin [IX: X5 = O; yl 3 H] and its 2-chloro derivative [IX X5 a o; yl = Cl] [V~
Seidlova et al.: Coll. Czech. Chem. Collm., 34, 2258 (1969)], dibenzolb,f]thiepin [IX: X5 = S; yl = H] EJ.o.
Jilek et al.: M~natsch. Chem., 96, 182 (1965)], dibenzo-[b,f]tropone [IX: X5 = CO; yl = H] [W. Treibs et al.:
Chem. Ber., 84, 671 (1951)] and its 2-ch1oro derivative [IX:
30 X = CO; yl = Cl] [C.A. Stone et al.: J. Med. Chem., 8, 829 (1965)], SH-dibenz[b,f]azepine [IX: X5 = NH; Y = H] [L.J
Kricka et al.: J.C.S. Perkin I, 2292 (1972)] and its 2- i fluoro derivati~e [IX: X5 = NH; yl = F] and 2-chloro deri-vative [IX: X5 = NH; yl = Cl] [R.S. Varma et al.: J. Med.
Chem., 12, 913 (1969)], etc. are known. 2-Fluorodibenz[b,f]-oxepin [IX: X5 = O; yl = F], 2-bromodibenz[b,f]oxepin [IX:
X5 = O; yl = Br], 2-fluorodibenz[b,f]thiepin [IX: X5 = S;
yl = F], 2-chlorodibenz[b,f]thiepin [IX: X5 = S; yl = Cl]
and 2-bromodibenzlb,f]thiepin [IX: X5 = S; yl = Br] may be produced in the same manner as described in the said V.
Seidlov~ et al. literature or the said J.O. Jilek et al.
literature. 2-Fluorodibenzo[b,f]tropone [IX: X5 = CO; yl =
F~ and 2-bromodibenzo[b,f]tropone [IX: X5 = CO; yl = Br]
may be produced by the same method as described in the said -~
C.A. Stone et al. literature. 2-Bromo-5H-dibenz[b,f]azepine may be produced in the same procedure 2S disclosed in the said R.S. Varma et al. literature.
Further, methylation of 5H-dibenz[b,f]azepine by a per se conventional proceudre affords 5-methyl-5H-dibenz-[b,f]azepine [IX: XS = N(CH3); yl = H] (M.P. 130 -131C).
Likewise, acylation of 5H-dibenz[b,f]azepine with an acetylat-ing agent or a carbethoxylating agent can afford respec-tively S-acetyl-5H-dibenz[b,f]azepine [IX: X = N(COCH3);
Y = H] (M.P. 121 - 122C) and 5-carbethoxy-SH-dibenz[b,f]-azepine [IX: X = N(COOC2H5); yl = H] (M.P. 142 - 144C).
Examples of the compounds which are producible by alkylation or acylation of 2-fluoro-5H-dibenz[b,f]azepine, 2-chloro-SH-dibenz[b,f]azepine or 2-bromo-SH-dikenz[b,f]azepine are as follows: 2-fluoro-5-(Cl-C3)alkyl-5H-dibenz[b,f]azepine [IX:
X5 = N(Cl-C3 alkyl); yl = F], 2-fluoro-5-(C2-C4)alkanoyl-5H-.
. . .

10i37~74 dibenz[b,f]azepine ~IX: X5 = NCO(Cl-C3 alkyl); Y = F], 2-fluoro-5-(~2-C4)carbalkoxy-5H-dibenz[b,f]azepine [IX: X5 =
NCOO(Cl-C alkyl); yl = F], 2-chloro-5-(Cl-C3)alkyl-5H-dibenz[b,f]azepine [IX: X5 = N(Cl-C3)alkyl; yl = Cl], 2-chloro-5-(C2-C4)alkanoyl-51l-dibenz[b,flazepine [IX: X5 =
NCO(Cl-C3 alkyl); yl = Cl], 2-chloro-5-(C2-C4)carba]koxy-5~1-dibenz[b,f]azepine [IX: X5 = NCOO(Cl-C3 alkyl); yl = Cl], 2-bromo-5-(cl-c3)al!~yl-5~l-dibenz[b~f]a~epine [IX: X5 =
N(Cl-C3)alkyl; yl = Br], 2-bromo-5-(C2-C4)al~anoyl-5El-dibenz[b,f]azepine [IX: X5 = NCO(Cl-C3 alkyl); yl = Br], 2-bromo-5-(C2-C~)carbalkoxy-5~-dibenz[b,f]azepine [IX: X5 =
NCOO(Cl-C3 alkyl); yl = sr], etc.
The following Examples are given for the purpose of illustration only, and it is not intended to limit the scope of thP invention thereto.
Example 1 . .
A solution of l-(N,N-dimethyl-carbamoyl)-3-chloro-1,la,6,10b-tetrahydrodebenzo [b,f]-cyclopropa[d]oxepin (2.10 g) in tetrahydrofuran (20 ml) was added to a solution 20 of llthium aluminum hydride (1.25 g) in ether (20 ml) under ice-cooling, and the resulting mixture was stirred for

3 hours at room ~emperature. Water was added to the cooled reaction mixture in order to decompose excess lithium ; aluminum hydride. The reaction mixture was dried over sodium sul~ate and filtered. The filtrate ~YaS evaporated and chromatographed to afford l-tN,~-dimethylaminomcthyl)-3-; chloro-l,la,6,10b-tetrahydrodibenzo[b,fjcyclopropa[d]oxepin as an oily substance. M.P. 243 - 244C (hydrochloride).
Exdmple 2 A solution of l-(N-methyl-carbamoyl)-6-ethoxycarbonyl-~ 37174 l~la~6~lob-tetrahydrodibenzo-~b~f]cyclopropa[d]azepine (0.67 g) in tetrahydrofuran (40 ml) was added to a solu-tion of lithium aluminum hydride (0.45 g) in ether (10 ml) under ice-cooling, and the resulting mixture was stirred for 6 hours at room temperature and then refluxed for 6 hours. ~ater was added to the cooled reaction mi~ture in order to decompose excess lithium aluminum hydride. The reaction mixture was dried over sodium sulfate and filtered.
The filtrate was evaporated and chromatographed to afford 1-(N-methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo[b,f]-cyclopropa[d]azepine as crystalline materials. ~I.P. 104 - -~ -107C.
Example 3 - . _ A mixture of l-(N,N-dimethylaminomethyl)-6-hydroxy-l,la,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-cycloheptdne (0.25 g) in chloroform (20 ml) and mnqanese dioxide (2.7 g) was stirred at 5~C for 1.5 hours and then at room temperature for 4 hours. ~fter filtration of inorganic materials, the filtrate was evaporated and chro;natosraphed to afford 1-(N,N-dimethylaminomethyl)-l,la,6,10b-tetra-hydrodibenzo[a,e]cyclopropa[c]cycloheptan-6-one as crystalline materials. M.P. 78 - 79C.
Example 4 A solution of 1-chloromethyl-6-methyl-l,la,6,10b-tetrahydrodibenzo~b,f]cyclopropa[d]azepine (0.35 g) in ethanol (5 ml) was added at room temperature to a solution --of diisopropylamine (0.30 g) in ethanol (5 ml)~ and stirring was carried out under reflux for 7 hours. The reaction mixture was evaporated and poured in~o 10 ~ a~u~ous solutiGn of sodium hydroxide. The chloroform ~xtract was dried and .

,:

` ! 1t)~37174 chromatographed to afford l-(N,N-diisopropylaminomethyl)-6-methyl-l,la,6,10b-tetrahydrodibenzo[b,f~cyclopropa[d]-azepine as an oily material. M.P. 233 - 235C
(hydrochloride).
Example 5 Sodium amide (60 mg) was added at room temperature to a solution of l-(N,N-dimethylaminomethyl)-l,la,6,10b-tetrahydrodibenzo[b,f]cyclopropa[d~azepine (0.25 9) in tetrahydrofuran (10 ml), and the resulting mixture was heated under reflux for 1 hour. After cooling, a solu-tion of methyl iodide (0.25 9) in tetrahydrofuran (1 ml) was added to the mixture under ice-cooling, and then the mixture was heated under reflux for 1 hour. After cooling, water was added thereto, and inorganic materials were eliminated by filtration. The filtrate was evaporated and ' chromatographed to afford l-(N,N-dimethylaminomethyl)-; 6-methyl-l,la,6,10b-tetrahydrodibenzo[b,f]cyclopropa[d]-azepine as crystalline materials. M.P. 93 - 94C;
279 - 280C (hydrochloride).
The following compounds were produced by one or more of the procedures above:
;- l-(N,N-Dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-benzo[b,f]cyclopropa[d]oxepin, M.P. 243 - 244C (hydro-chloride), (by the methods of Example 1 and Example 4);
l-(N-Methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo-[b,f]cyclopropa[d]oxepin, M.P. 234 - 235C (hydrochloride), (by the methods of Example 1 and Example 4);
;~ l-(N,N-Diisopropylaminomethyl)-l,la,6,10b-tetrahydro-dibenzo[b,f]cyclopropa[d]oxepin, M.P. 172 - 174C (hydro-chloride), (by the methods of Example 1 and Example 4);
l-(N,N-Dimethylaminomethyl)-3-chloro-l,la,6,10b-tetra-hydrodibenzo[b,f]cyclopropa[d]oxepin, M.P. 243 - 244C

1~87174 (hydrochloride), (by the methods of Example 1 and Example 4);
l-(N-Methylaminomethyl)-3-chloro-l,la,6,10b-tetrahydro-dibenzo[b,f]cyclopropa[dloxepin, M.P. 245 - 247C (hydro-chloride), (by the methods of Example 1 and Example 4);
l-(N,N-Diisopropylaminomethyl)-3-chloro-l,la,6,10b- :
tetrahydrodibenzo]b,flcyclopropa[dloxepin, I.R. tneat):
2950, 1600, 1485, 1260, 1230, 1180, 1110, 835, 770 cm~
(by the methods of Example 1 and Example 4);
1-(N,N-Dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-benzo[b,flcyclopropa[d]thiepin, M.P. 112 - 114C, (by the methods of Example 1 and Example 4);
l-(N-Methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo-[b,f]cyclopropaldlthiepin~ M.P. 238 - 239C (hydro-chloride), (by the methods of Example 1 and Example 4); -l-(N,N-Diisopropylaminomethyl)-l,la,6,10b-tetrahydro- :
dibenzolb,f]cyclopropa[d]thiepin, I.R. (neat): 3050, 2950, 1590, 1565, 1470, 1205, 755 cm 1, (by the methods of Example 1 and Example 4);
1-(N,N-Dimethylaminomethyl)-6-methyl-l,la,6,10b-tetra-` hydrodibenzo]b,f]cyclopropaEd]azepine, M.P. 93 - 94~C, (by the methods of Example 1, Example 4 and Example S);
l-(N,N-Dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-~: benzo[b,flcyclopropald]azepine, M.P. 128 - 129C, (by the methods of Example 1 and Example 2);
l-(N-Methylaminomethyl)-6-methyl-l,la,6,10b-tetra-hydrodibenzo[b,f]cyclopropa[d]azepine, M.P. 202 - 207C
.~ (hydrochloride), (by the methods of Example 1 and -~ Example 4);
1-(N-Methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo-[b,f]cyclopropa[d]azepine, M.P. 104 - 107C, (by the .

~ 10~,7174 . .

methods of Example 1 and Example 2);
l-(N,N-Diisopropylaminomethyl)-6-methyl-l,la,6,10b-tetrahydrodibenzo[b,f]cyclopropa[d]azepine, M.P. 233 - -~
235C (hydrochloride), (by the methods of Example 1, Example 4 and Example 5);
l-(N,N-dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-~ benzo[a,e]cyclopropa[c]cycloheptan-6-one, M.P. 78 - 79C, (by the methods of Example 3 and Example 4).

. .

;

- 16a -

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing tetracyclic compounds of the formula:

[I]

wherein R1 is hydrogen or C1-C3 alkyl, R2 is C1-C3 alkyl, Y1 is hydrogen or halogen, X1 is a divalent radical selected from the group consisting of -O-, -S-, -N(R3)- and -CO- and R3 is hydrogen or C1-C3 alkyl, and the pharmaceutically acceptable salts thereof, which comprises:
(a) reducing the corresponding amide of the formula:

wherein X3 is a divalent radical selected from the group consisting of -O-, -S- and -N(R3)-, and R1, R2, R3 and Y1 are each as defined above to give a compound of the formula:

wherein R1, R2, X3, R3 and Y1 are each as defined above;

(b) subjecting the corresponding compound of the formula:

wherein R5 is C1-C3 alkyl or C1-C3 alkoxy and Z is an oxygen or two hydrogens, and R1, R2 and Y1 are each as defined above to hydrogenolysis or to hydrogenolysis and reduction to give a compound of the formula:

wherein R1, R2 and Y1 are each as defined above;
(c) oxidizing the corresponding alcohol of the formula:

wherein R1, R2 and Y1 are each as defined above to give a compound of the formula:

wherein R1, R2 and Y1 are each as defined above;
(d) condensing the corresponding compound of the formula:

wherein X4 is a divalent radical selected from the group consisting of -O-, -S-, -N(C1-C3 alkyl)- and -CO-, W is a conventional leaving group and Y1 is as defined above with an amine of the formula:

wherein R1 and R2 are each as defined above to give a com-pound of the formula:

wherein R1, R2, X4 and Y1 are each as defined above; or (e) condensing the corresponding compound of the formula:

wherein R6 is C1-C3 alkyl, and R2 and Y1 are each as defined above with an alkylating agent of the formula:

wherein R7 is C1-C3 alkyl and W is as defined above to give a compound of the formula:

wherein R2, R6, R7 and Y1 are each as defined above; and, when the pharmaceutically acceptable salts are required, reacting the resulting compounds with a pharmaceutically acceptable acid.

2. A process according to claim 1, other than part (e) thereof, which comprises carrying out the said reactions on a starting material in which R1 is hydrogen or methyl and R2 is methyl.

3. A process according to claim 1 wherein said reactions are carried out on appropriate ones of said starting materials that produce compounds of formula [I] in which X1 is a divalent radical selected from the group consisting of -O-, -NH-, -N(CH3)- and -CO-.

4. A process according to claim 1 wherein said reactions are carried out on said starting materials in which Y1 represents hydrogen or chlorine.

5. A process according to claim 1 wherein said reactions are carried out on said starting materials in which R1 is methyl.

6. A compound of the formula:

[I]

wherein R1 is hydrogen or C1-C3 alkyl, R2 is C1-C3 alkyl, Y1 is hydrogen or halogen, X1 is a divalent radical selected from the group consisting of -O-, -S-, -N(R3)- and -CO- and R3 is hydrogen or C1-C3 alkyl, and the pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 1 or an obvious chemical equivalent.

7. The compound of formula [I] as defined in claim 6, wherein R1 is hydrogen or methyl and R2 is methyl, and the pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 2 or an obvious chemical equivalent.

8. The compound of formula [I] as defined in claim 6, wherein X1 is a divalent radical selected from the group consisting of -O-, -NH-, -N(CH3)- and -CO-, and the phar-maceutically acceptable salts thereof, whenever prepared by a process according to claim 3 or an obvious chemical equivalent.

9. The compound of formula [I] as defined in claim 6, wherein Y1 is hydrogen or chlorine, and the pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 4 or an obvious chemical equivalent thereof.

10. The compound of formula [I] as defined in claim 6, wherein R1 is methyl, and the pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 5 or an obvious chemical equivalent thereof.