CA1164457A - Benzodiazepine compounds and their use as pharmaceuticals - Google Patents
Benzodiazepine compounds and their use as pharmaceuticalsInfo
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- CA1164457A CA1164457A CA000433655A CA433655A CA1164457A CA 1164457 A CA1164457 A CA 1164457A CA 000433655 A CA000433655 A CA 000433655A CA 433655 A CA433655 A CA 433655A CA 1164457 A CA1164457 A CA 1164457A
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides compounds of formula where R1, R2 and R3 independently represent hydrogen, halogen or C1-4haloalkyl, R6 is C1-6alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-6alkyl , and Q is -OH or -NH2. These compounds, which are useful as intermediates for the preparation of compounds of formula (I):
wherein R1, R2, R3 and R6 are defined above; and in which R5 is a group of the formula where R9 is hydrogen, C1-14 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkanoul, benzyl, cyano or optionally substituted phenyl, where R10 is hydrogen, C1-4 alkyl or optionally substituted phenyl, and where n is 0 or 1; are prepared by ring closing a compound of formula where Z is CN, COOH or COOR12, R12 being a C1-4 alkyl group.
The compounds of formula (I) as defined above have neuroleptic, sedative, relaxant, anxiolytic or anti-emetic properties, and low toxicity, and are useful in the treatment of disorders of the central nervous system.
The present invention provides compounds of formula where R1, R2 and R3 independently represent hydrogen, halogen or C1-4haloalkyl, R6 is C1-6alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-6alkyl , and Q is -OH or -NH2. These compounds, which are useful as intermediates for the preparation of compounds of formula (I):
wherein R1, R2, R3 and R6 are defined above; and in which R5 is a group of the formula where R9 is hydrogen, C1-14 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkanoul, benzyl, cyano or optionally substituted phenyl, where R10 is hydrogen, C1-4 alkyl or optionally substituted phenyl, and where n is 0 or 1; are prepared by ring closing a compound of formula where Z is CN, COOH or COOR12, R12 being a C1-4 alkyl group.
The compounds of formula (I) as defined above have neuroleptic, sedative, relaxant, anxiolytic or anti-emetic properties, and low toxicity, and are useful in the treatment of disorders of the central nervous system.
Description
BENZODIAZEPI~E COMPOUNDS A~D THEIR
USE AS PHARMACXUTICALS
This invention relates to novel cornpounds, a process for preparing them,and their use as pharmaceuticals.
~ arious trfcyclic compounds with pharmaceutical properties have already been investigated and these have been mainly of the tvpe that comprfse two benzene nuclei. We have now dfscovered a new grou~ of compounds having the following basic structure The compounds of the invention are of the followfn~
formula (I) or an acid addition salt thereof;
in which Rl, R2, R3 and R4 independently represent hydrogen, Cl_~ alkyl, C2_4 alkenyl, C3_7 cycloalkyl, C3_7 cycloQlkyl ~ .
USE AS PHARMACXUTICALS
This invention relates to novel cornpounds, a process for preparing them,and their use as pharmaceuticals.
~ arious trfcyclic compounds with pharmaceutical properties have already been investigated and these have been mainly of the tvpe that comprfse two benzene nuclei. We have now dfscovered a new grou~ of compounds having the following basic structure The compounds of the invention are of the followfn~
formula (I) or an acid addition salt thereof;
in which Rl, R2, R3 and R4 independently represent hydrogen, Cl_~ alkyl, C2_4 alkenyl, C3_7 cycloalkyl, C3_7 cycloQlkyl ~ .
-2- ~ 1644.57 Cl_4 aL<vl, halogen, Cl_4 halo~lkyl, Cl_4 aL~anovl, nitro, amino, C2 4 acylamino, cy~no, hydroxyl, Cl_4 alkoxy, Cl_4 alkylthio, C~ haloalkoxy or group of the formula -S02N(R8)2, ~02R8 or -S03R8 where R8 is Cl_4 alkvl, Cl_4 halo~lkyl or optionally substituted phenyl; in which R5 is ~ group of the formula where R9 is hydrogen, C]_4 alkvl, C3_7 cvclo~lkYl, C3~7 cyCloalkYl C1_4 alkyl, Cl_4 haloalkyl, C2_4 alkenyl, Cl_~ alkanoyl, benzyl, cyano or option~lly substituted phenyl, where R10 is hydrogen, Cl_~ alkyl or optionally substituted phenyl and where n is O or l; in which R6 is hydrogen, Cl 10 alkyl, C3 7 cycloalkyl, C3 7 cycloallcyl Cl_4 alkyl, Cl_4 haloalkyl, benzyl, Cl 6 alkanoyl, Cl_~ carbaL'coxy or benzoyl and in which R7 is one of the values of R6 or halogen, nitro, cyano, amino or Cl 4 acylamino. The aforesaid compounds of formula (I) are also disclosed and are claimed in Canadian Application No. 362,328, filed October 14, 1980, of which the present application is a divisional.
Compounds of formula (I) h~ve been found to possess useful biological properties and the invention includes a compound of formula (n for use as a pharmaceutical and especially for use in the treatment of disorders o~ the central nervous system.
A particulQr group of compounds of formula (I~ is one in which Rl, R2 and R3 independently represent hydrogen, Cl ,~
1 16d~4r~i7 alkyl, C2 4 alkenyl, h~logen, Cl_4 hsloalkvl, nitro, ~1 4 alkoxy, Cl a haloalkoxy, Cl_~ alkylthio, Cl ,~ haloalkylsulphonvl or phenvlsulDhonyl iR~ is hydrogen; R is hydrogen, Cl_6 alkyl, C3 7 cycloalkyl, C3 7 cycloal!~vl Cl 4 alkyl or benzyl; R7 is hydrogen or Cl_4 alkyl; i~9 is hydro~en, Cl 4 alkyl, ~3 7 cycloalkyl, C3 7 cycloalkyl Cl_4 alkyl or benzy~; and R10 is hvdrogen or Cl_4 aL~yl.
A preferred group of compounds is one of the following formula (II
~ 9 Rl N ~ NR
R ~ N ~R76 ( II ) or an acid addition salt thereof; in which Rl, R2 and R3 independentlv represent hydrogen, Cl 4 alkyl, C2 4 alkenyl, halogen, Cl 4 haloalkyl, nitro, Cl~ alkoxy, C1_4 alkylthio or phenylsulphonyl;R~ is hydrogen, Cl 10 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl Cl_4 alkyl or benzyl; R7 is hydrogen or Cl 10 alkyl;and R is hydrogen, Cl 4 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl Cl_4 alkyl or benzyl.
A preferred group of compounds of formula (Il) is one in which Rl, R2 and R3 independently represent hydrogen, halogen or Cl 4 haloalkvl; R6 is Cl_6 alkyl, C3 7 cycloaL~yl or C3 7 cycloalkvl Cl .4 alkyl; R is hvdrogeniand R9 is hydrogen, Cl_4 alkyl, C3_7 cyclo~kyl Cl_4 alkyl or benzvl, .. , . , . . . ,. . ~
i 16~7 the compowlds in which R9 is hydrogen beinF! useful as intermec~iates in the preparation of preferred compounds.
Within the scope of compounds defined in formula (II) there can be listed compounds of especi~l interest, namely, those hQving one or more OI
the following fe~tures (a) R2 is a halogen substituent, such as fluorine, chlorine or bromine~
and Rl and R3 are hydrogen.
(b) R2 snd R3 both represent halogen, especially fluorine or chlorine, and Rl is hydrogen.
,o . ~c) R3 is hQlogen, especislly nuorine, and Rl and R2 are hydro~en.
(d) R is Cl_4 aL~yl, especially methvl or ethyl .
(e) R is hydrogen.
(f) R9 is methyl.
Specific examples of preferred compounds include 7-8romo-2,10 dihydr~2~nethyl-4~4-methyl-1-,oiperazinyl)pyrazolo ~3,4-b~ ~,5] benzodiazepine 7-Chloro-2-ethyl-2,10~ihydro-4~4-methyl-l~iperazinvl)pyrazolor3,4~1 n,51 hen zodiazepine 7{~hloro-2,1G~ihydro-2-methyl-4~4-methyl-1-piperazinyl~pyrazolot3,4~1 n,51 be nzodiazepine 7~8-Dichloro-2~10~ihydro-2-methyl-4~4-methyl-1-piperazinyl~pyrazolo~3~4-b 5] ~enzodiazepine 7-Fluoro-2-ethyl-2,10~ihydro-4-(4-methyl-1-piperazinyllpvrazolo[3,4-bl n,51 ben zodiazepine 7-Fluoro-2,10-dihydro-2-methyl-4{4-methyl-1-piperazinvl~wrazolo~3,4~1 n,51 be nzodiazepine 8-Fluoro-2,10-dihydro-2-methyl-4~4-methyl-l~iperazinyl~pvrazolo~3,4~1 ~1,51 be nzodiazepine .... . .. .. . . _ , . . . .
In the above general formulae, the term "Cl 1O ~lkvl" me~ns a straig~t or branched chain alkyl group containing 1 to 10 carbon atoms and is especi~lly, for example, methyl, ethyl, isopropyl, propyl, butvl, sec.butvl, isobutyl, tert, but~l, pentyl and hexyl. A preferred alkyl group is "Cl 4 slkyl". The term "Cl_4 haloalkyl" means any su~h Rlkyl group substituted bv one or more, preferably three halogen atoms, snd is espec;slly trifluoromethyl. The terms "Cl_~ alkoxy" and "Cl_~ alkylthio" mean anv Ci_4 alkyl group attached through an oxygen or sulphur atom to a ring atom and "Cl_~ halo lkoxy" means a Cl_4 alkoxy group substituted bv one or more, preferabl~ three h~logen atoms,andis especially trifluorometho~. The term "Cl ~1 carbalkoxy" means fl Cl ~ alkoxy group attached via a carbonvl group to a ring atom. "Cl_4 Alkanoyl" includes the formyl ~roup and ~roups of the formula RllCO where Rll is Cl_4 alkyl. The term "C~ 4 alkenyl" refers to groups such as vinyl, Rllyl and butenyl. The term "amino" indicates a ~roup of formula -NH2 snd also substituted amino groups such as mono-Cl_4 aL"ylamino and di~l_4 alkyl~mino groups. The term "C2_4 acylamino" means an amino group substituted by a C2_4 acyl group, espec ally acrtyl. "C3 7 Cycloalkyl" me~ns a saturated ring having 3 to 7 carbon atoms in the rirg such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptvl, which can, in the group "C3 7 cyclo lkyl Cl_4 alkyl", be attached to the ring via an alkyl chain having 1 to 4 carbon atoms. The term "optionally substituted phenyl" me~ns a phenyl group which is unsubstituted or substituted by one or more groups, for example, halogen, Cl~ haloalkyl, Cl 4 ~lkyl,Cl_4 alkoxv or nitro. Specific examples of such substituents include chlorine, trifluoromethyl, methyl ~nd methoxy.
4 ~ ~ 7 ~6~
As indicated above, the compounds of the invention are useful both in their free base and acid addition sal~ forms. The acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inor~anic acids, for e~ample hvdrochloric, hydrobromic, nitric, sulphuri~ or phosphoric acids, or with organic ~cids, such as organic carboxylic acids, for example, glvcollic, maleic, hvdrox~naleic, fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for exarnple methanesulp~onic, ethanesulphonic,2-hydroxvethane sul~honic, toluene~ulphonic or naphthalene-2~ulphonic acid. Apart from pharmaceutical~y acceptable acid addition salts, other salts are also included within the scope of acid addition salts such as, for example, those with picric or oxalic acid, ~nce they may serve as intermediates in the purification of the compounds or in the preparation of other, for example, pharmaceuticallv acceptable, acid addition selts, or are useful for identification, characterization or purification of the bases.
According to a further aspect of the invention there is provided a process for producing a compound of formula ~n or an acid addition salt thereof, which comprises (a) reacting an amine of formula R5H with a compound of formula (ml R ~ (111) ~7~ i ~ 5~
where Q represents a radical capable of being split off with the hvdro~en atom of the amine R5H, optionally followed ~hen R6 or R9 is hydro~en by reaction with a compound of the formula R6X or R9X respectiYely, X bein~ a leaving group, and optionally followed when n is 0 ~y oxi~ation, or (b) ring-closing a compound of formula (Iv!
R~--2~ 6 , _ (IV) optionally followed when R6 or R9 :Ls hydrogen by reactio~ with a compound of the formula R6X or R9X respectively, X being a leavillg group, and optionally foll~ when n is 0 by c~idation; and where desired, forming an acid ad~ition salt of the compound of formula (1) so produced.
This process is also disclosed, and is claimed, in Canadian Patent Application No. 362,328, filed October 14, 1980, of which this application is a divisional.
The above processes are of a general type previous]y describe~ in the literature (see standard treatises for references to acylation, ~lhylation, oxidation and ring closure) and suitable Q and X radicals and appropriate reaction conditions can be readily chosen.
It may be mentioned, for example, that in reaction (a) the radical Q
can be hydroxyl, thiol, an aLkoxy or alkylthio group containin~ 1 to 4 carhon atoms, for example a methoxy or methylthio grou~, a haloFen atom~
especially a chlorine atom, 3n amino group or a mon~ or dialkyl~ubstituted ~mino group, ea~h alkyl substituent cor.taining 1 to 4 carbon stoms.
Preferably, Q ic hydroxyl, thiol, Cl_4 alkoxy, Cl_4alkylthio, halogen or amino ~nd it is especially preferred that Q is hvdroxyl, thiol or amino (NH2~. When Q is hvdroxyl or thiol, the intermediates of formula (m~ exist predominantlv in their amide asld thioamide forms:
O S
NH - C or NH - i and when Q is amino the intermediates of formula ~m~ mav ~lso exist in the imino form:
NH
NH - ~
When Q is hydroxyl, and the compound of formula ~m) is an amide, reaction (a) can be accomplished in the presence of titanium tetrachloride which hss the ability to react with the amine of formula R5H to form Q metal amine complex. Other metal chlorides such as those of zirconium, hafnium or vanadium may also be employed. The reaction is preferably carried out in the presence o~ an acid binding agent such as a tertiar!r amine, for example, triethylamine. Alternatively, the reaction can be carried out usin~ excess of tl~ amine o~ formula R5H to act as an acid-binding agent. A suitPble organic solvent such as toluene or ~hloro~enzene can be used ~s reaction medium, although it has been fo~md that the g use of ~nisole is particularly desirable, ~t le~st as a co~olvent, in view OI its ability to form a soluble complex ~ith TiC14.
If desired, elevated temperatures, for example up to 200C, can be used to expedite the rea~ tion ~nd a preferred temperature ran~e for carryinF
out the reaction is from lD0C to 150C.
The amidines of formula (~II) (Q is NH2), can be in a salt form for example as the hydrochloride, and they can be similarly reacted with amines of formula R5H, optionally diluted with a solvent such as anisole, dimethylformamide or dimethylsulphoxide, and optionally using a catalvst such as TiC14 at a temperature range of 100 to 150. Alternatively the amidine can be converted into the correspondin~ amide of formula tlII) (G~ is OH) by ~kaline hydrolysis.
Thioam~des of formula (m~ ~ is SH~, iminothioethers, iminoethers or iminohalides, o~ other derivstives containing active Q radic~ls as specified &bove, tend to be more renctive towards the amire RSH and can usually be teacted without the necessity for the presence of TiC14, but otherwise employing the same conditions of temperature and solvent.
In reaction (b) compounds of formuls (IV~ are rin~closed by employing, for example, the same conditions in terms of catalyst and solvent as those described above for reaction (Q) and preferal~ly at a temperature of 150C to 200C. The compound~ of formula ~N) Pre conveniently prepared in situ without isolation.
When the compound prepared by reaction (a~ or (b~ is one in which R6 or R9 is hydrogen, it may be further reacted to provide other ~ompounds of the invention. For example when R6 is .. _ . _ . _ _ . __ ., _ . . . . . . .
hydrogen, the compo~d can be reacted with R6X bv ~onvention~ lation or acylation tvpe methods, X being a leaving group. The compound is dissolved in a suitable inert polar solvent such as ethanol and the rea~ent of formula R6X added, the reaction mixture then bein~ heated under reflux in the presence of ~ base. The group X can be a suitable reactive atom such a chlorine, bromine or iodine, or a reactive group such as tosyl or mesyl.
Similarly, when R LS hydrogen, the ~ompo~d can be reacted with a reaFent of formula R X in an inert solvent and in the presence of a base.
When the compound prepared by reaction (a) or ~ ~ is one in which n a is O it may be oxidised to provide other compounds of the invention, that is, the corresponding compound in which n is 1. Suitable oxidising agents include for e~ample m-chloroperbenzoic acid and the rea~tion is preferably carried out in an inert solvent such as for example dichloromethane at a temperature of from -10C to +10C.
The compounds of formula (I) produced by the ahove processes m~y be isolated E~ se or may be converted to their corresponding acid addition salts using conventional methods.
The present invention, in a urther aspect, as disclosed and claimed herei.n, provides compounds of formula Q
R2'~"`H~N~NR6 where R , R and R3 independenely repre~ent hydrogen, halogen or Cl 4haloalkyl, R6 is Cl ~alkyl, C3_7cycloalkyl or C3_7CYC1al~YlC1-6alkYl -lOa-~nd Q i6 -OH or -NH2- These compounds, which are useful as intermediates for the preparations of compounds of formula (I~:
wherein R , R2, R3 and R6 are as defined above; and in which R is a group of the formula /7~ R9 N/
/ ~n -lOb-where R9 is hydrogen, Cl 4 alkyl, C3 7 cycloalkyl, C3_7 cycloalkyl Cl 4 alkyl, Cl 4 haloalkyl, C2_4 alkenyl, Cl 4 alkanoyl, benzyl, cyano or optionally substituted phenyl, where R10 is hydrogen, Cl 4 alkyl or optionally substituted phenyl, and where n is O or 1, are prepared by ring closing a compound of formula where Z is CN, COOH or COOR12, Rl being a Cl 4 alkyl group.
Theami~sofformula(m)(~isOH)canbepreparedbyaprocess which invoIves the ring-closure of ~ amino~sterof form~a (V) R2~,~ (V) where R12 is a Cl_4 alkyl group, emploving for example sodium methylsulphinyl methanide in a s~table solvent such a dimethyl sulphoxide.
Alternatively amides of formula (m) (~ is OH) can be pre~ared bv ring~losure of an ~mino-acid of formula (YI) R~ R6 IVI) employing for example dicyclohexvlc~bodiimide (DCC) in a suitable solvent such as tetrahydrofuran. These amin~acids can be obtained from the esters of formula (V) by basic hydrolysis using for example sodium hvdroxide in ethanol.
The esters of formula (V) c~n be prepared by condensation of a pyrazole compound of formula R1 202~ R7 ~6 ~2 N~
r~ 7 with an ortho-halonitrobenzene of formula R2 ~'~2 ~3 Z
where Z is halogen, preferably fluorine, chlorine or bromine, in the presence of R base~,for example~sodium hydrideJin ~ solvent such as tetrahydrofuran or dimethylformamide, n~utyl lithium in tetrahydrofuran, potassium carbonate in dimethylsulphoxide or with a tetralkylammonium salt in a two~hsse system, to form a nitro ester of formula ~NO ~7 which can be reduced to the amino ester of formula fV) catalyticallv, employing for instance hydrogen and palladium,or ctlemica11v, emp~oyinF for example, stannous chloride and hydrogen ehloride in aqueous ethanol, or ammonium poly~ulphide.
Similarly, the amidines of formula ~m~ S NH2~ c9n be ~repared by conder6ation of a pyrazole of formul~
5 ~
NC ~F=~ R7 ~ ~I ,NR
with an orth~haloni$robenzene as outlined above, followed hy simultaneous reduction and ring-closure to the amidine of formula tm) employing for e~ample stannous chloride and h~vdrogen chloride in aquesus ethanol or, alternatively, by reduction with hydrogen and palladium or ammonium polysulphide followed by acid~at~lysed rin~ closure.
Pyrszole starting materials used in the processes described above are either known compounds, see for example J. Am. Chem. Soc. tl956) 78 784; Helv. Chim. Acta (1958) 411052; Helv. Chim. Acta (1959~ 42 349 and 763; German Patent 1,106,330 and British Patent 884,851; or can be Drepared by conventional techniques from known compounds. The ortho-halonitrobenzene intermediates are either commercially availa~le can be simply prepared from commercially available su~stances.
Thioamides of formula (m) (Q is SH) c~n be prepared bv treatinF a solution of the corresponding amide in an ~nhydrous basic solvent such as for example pyridine with phosphorus pent~sulphide. Similarly, the amides can be converted to iminothioethers7 iminoethers or iminohalides, or other derivatives containing active Q radicRls, by tre~tment with conventional 9 ~ 5 ~
reagents such as for example in ~he case of an iminoch]oride, phosphorus pentachloride.
Compounds of formula (m~ are novel and, in p~rticular, those in which Q ~ hydroxyl, thiol or amino are included as an aspect of the invention.
In reaction (b)~ the compounds of formula (IV) are novel and thev are included as a further aspect of this invention. They can be prepare~ in situ without isolation by reacting a compound of formula (V~ with an amine of formula R5H such as by heating to a temperature between 30~ ~d 120C, ~or example 100C, in R suitable solvent such as for example anisole and employing TiC14 as catalyst~ or by convention~l methods from compounds of formula (V) or ~VI).
It will be understood that electrophilic substitution on the aromatic nucleus can be carried out on compounds of formulae (I), (m1 or (IV) in ~onventional manner to produce other deriv&tives. For instance, an amide of formula (m) can be acetylated using acetyl chloride and stannic chlori~e or halogenated employing for example N-chlorosuccinimide, to give the corresponding acetyl or chloro derivatives. Products of forrnula (I) in which Rl, R~, R3 or R4 is amino can be acylated or alkylated in conventional manner to form the corresponding acylamino or all~ylamino derivatives.
As an illustration of the preparation of represent~ive compo~ds of the invention the fo~lowing reaction scheme is given, in which various routes for preparing a 4~4 a~ piperazinyl) -2,10-dihydrowrazolo[3,4~ [1,5]benæodiazepine are shown:
.. . _ ~ . . . ... .
R 02~B 1~ B~ L~6 R3 ~F H~Pd H N 25~Q3 R2 ~NH2 B~N ~ N/ DY30 R3~N~ N/
R \ 2 Rl CO~ / ~NR
J ~ \ }~R9 R[~ NY'2 ~ ~:_ }~2C3 \TiC14- R ~ ~ ~/ TiCl -a~isole ~tOX-~20 ~ R ~ rc~lux R / ~ E 7 -- N~NG~ X ~ 7 DM R~ ~N~B6 . SnC12-HCl Rl E tOH R2 ~NO 2 Rl ~3 ~F N 7 ~ ~\ 6 H2N ~R
R3~ ~ ;~ Nf The compounds of the invention have useful central nervous system activitv RS demonstrated by well~cnown test procedures. In behaYiour~ studies in mice, for instance, the compounds of the invention described in the followin~
Examples were observed to produoe h~7pothermia and acti~ty decrease at a dose range of 12.5 to 200 mg/kg p.o. Preferred comPounds have also been tested following chronic administration when Q behavioural supersensitivity is produced to locally injected dopamine in a manner similar to thRt described in Psychopharmacologia (1975) 45151-155. The activity profile observed in this test along with the lack o~ re~ponse in tests such QS the production of catalepsy indicate that these compoun~s possess useful central nervous system activity and do not produce certain undesirable side effects. For some time it has been recognised that conventional central nervous sVstem drugs can have undesirable characteristics and the potentiRl a~sence of these side effects in compounds according to the invention represents a siFni-ficant advance. In addition, compounds of the invention possess unexpected anxiolytic activity as demonstrated by their profile in the test described in Neuropharmacology (1979)18 689~95. The compomlds of formula (I`) and acid addition salts thereof are thus, potent centrally acting compounds with neuroleptic, sedative~ relaxant, anxidytic or anti-emetic properties. l'hese ~o properties, coupled with their low toxicity render them useful in the treatment of mild anxiety states and certain kinds of psychotic conditions such a schizophrenia and acute mania~
_ _ _ .. . _ . _ _, _ . . ~, .. . . . . . . .
4 ~ 7 ~ he compo~ds of this invention Ell'e effective over Q wide dosa~ze range, the actual dose administered being depen~ent on such factors as th particular compour,d being used, the condition bein~ treated and ths tvPe and size of mammal being treated. However, the dosage required will norm 11v fall within the range of 0.5 to 50 mg/kg per dav, for example in the treatment of adult humans, do6ages of from 5 to ~00 mg per clay may be used.
The compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usuall~ he utilised in the form of a pharmaceutical cornposition. Such compositions ~re prepared in a manner well known in the pharmaceutic 1 art ~nd compr;~e at least one active compound. Accordingly the invention includes a pharmaceutical composition comprising as active ingredient Q compound of formula I or an acid addition salt thereof, associated with 8 pharmaceuticsl]v acceptable carrier. In making the compositions of the invention, the active ingredient will usually be mixed with a cQrrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it màv be a solid, semi~olid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gurn acacia, c~lcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl-and propyl-hydroxvbenzoate, talc, magnesium stearate or mineral oil. The compositions of the invention may, if desirPd, be formulated so &s to provide quick, sustained or delayed release of the ~ctive in~redient after administration to the patient.
_ . .. . , ..... . . _ . .... _ . . . .
-~18--Depending on the route of administration, the foregoin~
compositlons may be formulated as tablets, capsules or suspensions for oral use and injection solutions for parenteral use or as suppositories. Preferablv the compositions are formulated in a do6a~e ~mit form, each dosa2e containing from l to 200 mg, more usuall 5 to 100 m~, of the active ingredi ent.
The following Examples illustrate the invention:
Ethyl 3~4-fluoro-2-nitroanilino~-1-methylpyrazole ~arboxylate A solution of ethyl 3-amino-1-methvlpvrazole-4~arhoxv1ate tHelv. Chim. Acta (1959) 42 349~(17g~ in dry tetrahv~lrofuran (250ml~ w~s stirred under nitrogen at -10C. n-Butyl lithium (75ml of 1.84 molar solution in hexane~ was added at -lO to -15C. The mixture was stirred at -15C for 10 minutes and a solution of 2,5~ifluoronitrobenzene (16g! in dry tetrahydrofuran (50ml) was added at -15 to -10C. The solution was warmed to r oom temperature and stirred for 1 hour. The ink-~lue solution ~as poured into 500 ml of a 1:1 mixture of hydrochloric acid (2M~ and ic~brine, ex~racted with chloroforrn (3 x 250ml), washed with water (2 x 250mll, ~ried with magnesium sulphate and evaporated to drvness. The brick-red residue WQS
crystallised from ethanol (800ml) to give the title compound havin~ a m.p. of 162C.
The following compounds were similarly prepared usin~ the above process. In each case the recrystallisation solvent is ~iven in parenthesis.
Ethyl l-methyl-3~4,5~ifluoro-2-nitroanilino) pyr~zole-4~arboxy1ate, m.p.
141C (isopropanol) Ethyl l-ethyl-3~4-fluoro-2-nitroanilino) pyrazole-4~arbo2~1ate, m.D. 136C
(ethanol).
Ethyl l-methyl-3~2-nitro-4-trifluoromethylQnilino) pyrazole-4~arboxvlate, m.p. 158C (isopropanol).
Ethyl 3~5-fluoro-2-nitroanilino~1-methylpyrazole-4~arboxylate, m.o. 165C
(ethanol).
.. . . . . . . ... .
Ethyl 3~4-fluoro-~-nitroanilino)-l~l~ropyl~pvrazo.e-4~arboxvlate, m.p.
109C (ethanol~.
Ethyl 3~4-fluoro-2-nitroanilino)-1~1-methylethyl)pvrazol~4~arboxvlate, m.p. 106.5~C (ethanol).
Ethyl 3~-fluoro-2-nitroanilino)-1l1-hexyl~pyrazole-4~arboxylate, m.p. 73 1 (ethanol~.
Ethyl 3~2-nitrosn~ino)-1-methylpyrRzole-4-carboxylate, m.p. 146 C
(isopropanol~ .
EXAMPLE 2~
Compounds of formula (I) h~ve been found to possess useful biological properties and the invention includes a compound of formula (n for use as a pharmaceutical and especially for use in the treatment of disorders o~ the central nervous system.
A particulQr group of compounds of formula (I~ is one in which Rl, R2 and R3 independently represent hydrogen, Cl ,~
1 16d~4r~i7 alkyl, C2 4 alkenyl, h~logen, Cl_4 hsloalkvl, nitro, ~1 4 alkoxy, Cl a haloalkoxy, Cl_~ alkylthio, Cl ,~ haloalkylsulphonvl or phenvlsulDhonyl iR~ is hydrogen; R is hydrogen, Cl_6 alkyl, C3 7 cycloalkyl, C3 7 cycloal!~vl Cl 4 alkyl or benzyl; R7 is hydrogen or Cl_4 alkyl; i~9 is hydro~en, Cl 4 alkyl, ~3 7 cycloalkyl, C3 7 cycloalkyl Cl_4 alkyl or benzy~; and R10 is hvdrogen or Cl_4 aL~yl.
A preferred group of compounds is one of the following formula (II
~ 9 Rl N ~ NR
R ~ N ~R76 ( II ) or an acid addition salt thereof; in which Rl, R2 and R3 independentlv represent hydrogen, Cl 4 alkyl, C2 4 alkenyl, halogen, Cl 4 haloalkyl, nitro, Cl~ alkoxy, C1_4 alkylthio or phenylsulphonyl;R~ is hydrogen, Cl 10 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl Cl_4 alkyl or benzyl; R7 is hydrogen or Cl 10 alkyl;and R is hydrogen, Cl 4 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl Cl_4 alkyl or benzyl.
A preferred group of compounds of formula (Il) is one in which Rl, R2 and R3 independently represent hydrogen, halogen or Cl 4 haloalkvl; R6 is Cl_6 alkyl, C3 7 cycloaL~yl or C3 7 cycloalkvl Cl .4 alkyl; R is hvdrogeniand R9 is hydrogen, Cl_4 alkyl, C3_7 cyclo~kyl Cl_4 alkyl or benzvl, .. , . , . . . ,. . ~
i 16~7 the compowlds in which R9 is hydrogen beinF! useful as intermec~iates in the preparation of preferred compounds.
Within the scope of compounds defined in formula (II) there can be listed compounds of especi~l interest, namely, those hQving one or more OI
the following fe~tures (a) R2 is a halogen substituent, such as fluorine, chlorine or bromine~
and Rl and R3 are hydrogen.
(b) R2 snd R3 both represent halogen, especially fluorine or chlorine, and Rl is hydrogen.
,o . ~c) R3 is hQlogen, especislly nuorine, and Rl and R2 are hydro~en.
(d) R is Cl_4 aL~yl, especially methvl or ethyl .
(e) R is hydrogen.
(f) R9 is methyl.
Specific examples of preferred compounds include 7-8romo-2,10 dihydr~2~nethyl-4~4-methyl-1-,oiperazinyl)pyrazolo ~3,4-b~ ~,5] benzodiazepine 7-Chloro-2-ethyl-2,10~ihydro-4~4-methyl-l~iperazinvl)pyrazolor3,4~1 n,51 hen zodiazepine 7{~hloro-2,1G~ihydro-2-methyl-4~4-methyl-1-piperazinyl~pyrazolot3,4~1 n,51 be nzodiazepine 7~8-Dichloro-2~10~ihydro-2-methyl-4~4-methyl-1-piperazinyl~pyrazolo~3~4-b 5] ~enzodiazepine 7-Fluoro-2-ethyl-2,10~ihydro-4-(4-methyl-1-piperazinyllpvrazolo[3,4-bl n,51 ben zodiazepine 7-Fluoro-2,10-dihydro-2-methyl-4{4-methyl-1-piperazinvl~wrazolo~3,4~1 n,51 be nzodiazepine 8-Fluoro-2,10-dihydro-2-methyl-4~4-methyl-l~iperazinyl~pvrazolo~3,4~1 ~1,51 be nzodiazepine .... . .. .. . . _ , . . . .
In the above general formulae, the term "Cl 1O ~lkvl" me~ns a straig~t or branched chain alkyl group containing 1 to 10 carbon atoms and is especi~lly, for example, methyl, ethyl, isopropyl, propyl, butvl, sec.butvl, isobutyl, tert, but~l, pentyl and hexyl. A preferred alkyl group is "Cl 4 slkyl". The term "Cl_4 haloalkyl" means any su~h Rlkyl group substituted bv one or more, preferably three halogen atoms, snd is espec;slly trifluoromethyl. The terms "Cl_~ alkoxy" and "Cl_~ alkylthio" mean anv Ci_4 alkyl group attached through an oxygen or sulphur atom to a ring atom and "Cl_~ halo lkoxy" means a Cl_4 alkoxy group substituted bv one or more, preferabl~ three h~logen atoms,andis especially trifluorometho~. The term "Cl ~1 carbalkoxy" means fl Cl ~ alkoxy group attached via a carbonvl group to a ring atom. "Cl_4 Alkanoyl" includes the formyl ~roup and ~roups of the formula RllCO where Rll is Cl_4 alkyl. The term "C~ 4 alkenyl" refers to groups such as vinyl, Rllyl and butenyl. The term "amino" indicates a ~roup of formula -NH2 snd also substituted amino groups such as mono-Cl_4 aL"ylamino and di~l_4 alkyl~mino groups. The term "C2_4 acylamino" means an amino group substituted by a C2_4 acyl group, espec ally acrtyl. "C3 7 Cycloalkyl" me~ns a saturated ring having 3 to 7 carbon atoms in the rirg such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptvl, which can, in the group "C3 7 cyclo lkyl Cl_4 alkyl", be attached to the ring via an alkyl chain having 1 to 4 carbon atoms. The term "optionally substituted phenyl" me~ns a phenyl group which is unsubstituted or substituted by one or more groups, for example, halogen, Cl~ haloalkyl, Cl 4 ~lkyl,Cl_4 alkoxv or nitro. Specific examples of such substituents include chlorine, trifluoromethyl, methyl ~nd methoxy.
4 ~ ~ 7 ~6~
As indicated above, the compounds of the invention are useful both in their free base and acid addition sal~ forms. The acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those with inor~anic acids, for e~ample hvdrochloric, hydrobromic, nitric, sulphuri~ or phosphoric acids, or with organic ~cids, such as organic carboxylic acids, for example, glvcollic, maleic, hvdrox~naleic, fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for exarnple methanesulp~onic, ethanesulphonic,2-hydroxvethane sul~honic, toluene~ulphonic or naphthalene-2~ulphonic acid. Apart from pharmaceutical~y acceptable acid addition salts, other salts are also included within the scope of acid addition salts such as, for example, those with picric or oxalic acid, ~nce they may serve as intermediates in the purification of the compounds or in the preparation of other, for example, pharmaceuticallv acceptable, acid addition selts, or are useful for identification, characterization or purification of the bases.
According to a further aspect of the invention there is provided a process for producing a compound of formula ~n or an acid addition salt thereof, which comprises (a) reacting an amine of formula R5H with a compound of formula (ml R ~ (111) ~7~ i ~ 5~
where Q represents a radical capable of being split off with the hvdro~en atom of the amine R5H, optionally followed ~hen R6 or R9 is hydro~en by reaction with a compound of the formula R6X or R9X respectiYely, X bein~ a leaving group, and optionally followed when n is 0 ~y oxi~ation, or (b) ring-closing a compound of formula (Iv!
R~--2~ 6 , _ (IV) optionally followed when R6 or R9 :Ls hydrogen by reactio~ with a compound of the formula R6X or R9X respectively, X being a leavillg group, and optionally foll~ when n is 0 by c~idation; and where desired, forming an acid ad~ition salt of the compound of formula (1) so produced.
This process is also disclosed, and is claimed, in Canadian Patent Application No. 362,328, filed October 14, 1980, of which this application is a divisional.
The above processes are of a general type previous]y describe~ in the literature (see standard treatises for references to acylation, ~lhylation, oxidation and ring closure) and suitable Q and X radicals and appropriate reaction conditions can be readily chosen.
It may be mentioned, for example, that in reaction (a) the radical Q
can be hydroxyl, thiol, an aLkoxy or alkylthio group containin~ 1 to 4 carhon atoms, for example a methoxy or methylthio grou~, a haloFen atom~
especially a chlorine atom, 3n amino group or a mon~ or dialkyl~ubstituted ~mino group, ea~h alkyl substituent cor.taining 1 to 4 carbon stoms.
Preferably, Q ic hydroxyl, thiol, Cl_4 alkoxy, Cl_4alkylthio, halogen or amino ~nd it is especially preferred that Q is hvdroxyl, thiol or amino (NH2~. When Q is hvdroxyl or thiol, the intermediates of formula (m~ exist predominantlv in their amide asld thioamide forms:
O S
NH - C or NH - i and when Q is amino the intermediates of formula ~m~ mav ~lso exist in the imino form:
NH
NH - ~
When Q is hydroxyl, and the compound of formula ~m) is an amide, reaction (a) can be accomplished in the presence of titanium tetrachloride which hss the ability to react with the amine of formula R5H to form Q metal amine complex. Other metal chlorides such as those of zirconium, hafnium or vanadium may also be employed. The reaction is preferably carried out in the presence o~ an acid binding agent such as a tertiar!r amine, for example, triethylamine. Alternatively, the reaction can be carried out usin~ excess of tl~ amine o~ formula R5H to act as an acid-binding agent. A suitPble organic solvent such as toluene or ~hloro~enzene can be used ~s reaction medium, although it has been fo~md that the g use of ~nisole is particularly desirable, ~t le~st as a co~olvent, in view OI its ability to form a soluble complex ~ith TiC14.
If desired, elevated temperatures, for example up to 200C, can be used to expedite the rea~ tion ~nd a preferred temperature ran~e for carryinF
out the reaction is from lD0C to 150C.
The amidines of formula (~II) (Q is NH2), can be in a salt form for example as the hydrochloride, and they can be similarly reacted with amines of formula R5H, optionally diluted with a solvent such as anisole, dimethylformamide or dimethylsulphoxide, and optionally using a catalvst such as TiC14 at a temperature range of 100 to 150. Alternatively the amidine can be converted into the correspondin~ amide of formula tlII) (G~ is OH) by ~kaline hydrolysis.
Thioam~des of formula (m~ ~ is SH~, iminothioethers, iminoethers or iminohalides, o~ other derivstives containing active Q radic~ls as specified &bove, tend to be more renctive towards the amire RSH and can usually be teacted without the necessity for the presence of TiC14, but otherwise employing the same conditions of temperature and solvent.
In reaction (b) compounds of formuls (IV~ are rin~closed by employing, for example, the same conditions in terms of catalyst and solvent as those described above for reaction (Q) and preferal~ly at a temperature of 150C to 200C. The compound~ of formula ~N) Pre conveniently prepared in situ without isolation.
When the compound prepared by reaction (a~ or (b~ is one in which R6 or R9 is hydrogen, it may be further reacted to provide other ~ompounds of the invention. For example when R6 is .. _ . _ . _ _ . __ ., _ . . . . . . .
hydrogen, the compo~d can be reacted with R6X bv ~onvention~ lation or acylation tvpe methods, X being a leaving group. The compound is dissolved in a suitable inert polar solvent such as ethanol and the rea~ent of formula R6X added, the reaction mixture then bein~ heated under reflux in the presence of ~ base. The group X can be a suitable reactive atom such a chlorine, bromine or iodine, or a reactive group such as tosyl or mesyl.
Similarly, when R LS hydrogen, the ~ompo~d can be reacted with a reaFent of formula R X in an inert solvent and in the presence of a base.
When the compound prepared by reaction (a) or ~ ~ is one in which n a is O it may be oxidised to provide other compounds of the invention, that is, the corresponding compound in which n is 1. Suitable oxidising agents include for e~ample m-chloroperbenzoic acid and the rea~tion is preferably carried out in an inert solvent such as for example dichloromethane at a temperature of from -10C to +10C.
The compounds of formula (I) produced by the ahove processes m~y be isolated E~ se or may be converted to their corresponding acid addition salts using conventional methods.
The present invention, in a urther aspect, as disclosed and claimed herei.n, provides compounds of formula Q
R2'~"`H~N~NR6 where R , R and R3 independenely repre~ent hydrogen, halogen or Cl 4haloalkyl, R6 is Cl ~alkyl, C3_7cycloalkyl or C3_7CYC1al~YlC1-6alkYl -lOa-~nd Q i6 -OH or -NH2- These compounds, which are useful as intermediates for the preparations of compounds of formula (I~:
wherein R , R2, R3 and R6 are as defined above; and in which R is a group of the formula /7~ R9 N/
/ ~n -lOb-where R9 is hydrogen, Cl 4 alkyl, C3 7 cycloalkyl, C3_7 cycloalkyl Cl 4 alkyl, Cl 4 haloalkyl, C2_4 alkenyl, Cl 4 alkanoyl, benzyl, cyano or optionally substituted phenyl, where R10 is hydrogen, Cl 4 alkyl or optionally substituted phenyl, and where n is O or 1, are prepared by ring closing a compound of formula where Z is CN, COOH or COOR12, Rl being a Cl 4 alkyl group.
Theami~sofformula(m)(~isOH)canbepreparedbyaprocess which invoIves the ring-closure of ~ amino~sterof form~a (V) R2~,~ (V) where R12 is a Cl_4 alkyl group, emploving for example sodium methylsulphinyl methanide in a s~table solvent such a dimethyl sulphoxide.
Alternatively amides of formula (m) (~ is OH) can be pre~ared bv ring~losure of an ~mino-acid of formula (YI) R~ R6 IVI) employing for example dicyclohexvlc~bodiimide (DCC) in a suitable solvent such as tetrahydrofuran. These amin~acids can be obtained from the esters of formula (V) by basic hydrolysis using for example sodium hvdroxide in ethanol.
The esters of formula (V) c~n be prepared by condensation of a pyrazole compound of formula R1 202~ R7 ~6 ~2 N~
r~ 7 with an ortho-halonitrobenzene of formula R2 ~'~2 ~3 Z
where Z is halogen, preferably fluorine, chlorine or bromine, in the presence of R base~,for example~sodium hydrideJin ~ solvent such as tetrahydrofuran or dimethylformamide, n~utyl lithium in tetrahydrofuran, potassium carbonate in dimethylsulphoxide or with a tetralkylammonium salt in a two~hsse system, to form a nitro ester of formula ~NO ~7 which can be reduced to the amino ester of formula fV) catalyticallv, employing for instance hydrogen and palladium,or ctlemica11v, emp~oyinF for example, stannous chloride and hydrogen ehloride in aqueous ethanol, or ammonium poly~ulphide.
Similarly, the amidines of formula ~m~ S NH2~ c9n be ~repared by conder6ation of a pyrazole of formul~
5 ~
NC ~F=~ R7 ~ ~I ,NR
with an orth~haloni$robenzene as outlined above, followed hy simultaneous reduction and ring-closure to the amidine of formula tm) employing for e~ample stannous chloride and h~vdrogen chloride in aquesus ethanol or, alternatively, by reduction with hydrogen and palladium or ammonium polysulphide followed by acid~at~lysed rin~ closure.
Pyrszole starting materials used in the processes described above are either known compounds, see for example J. Am. Chem. Soc. tl956) 78 784; Helv. Chim. Acta (1958) 411052; Helv. Chim. Acta (1959~ 42 349 and 763; German Patent 1,106,330 and British Patent 884,851; or can be Drepared by conventional techniques from known compounds. The ortho-halonitrobenzene intermediates are either commercially availa~le can be simply prepared from commercially available su~stances.
Thioamides of formula (m) (Q is SH) c~n be prepared bv treatinF a solution of the corresponding amide in an ~nhydrous basic solvent such as for example pyridine with phosphorus pent~sulphide. Similarly, the amides can be converted to iminothioethers7 iminoethers or iminohalides, or other derivatives containing active Q radicRls, by tre~tment with conventional 9 ~ 5 ~
reagents such as for example in ~he case of an iminoch]oride, phosphorus pentachloride.
Compounds of formula (m~ are novel and, in p~rticular, those in which Q ~ hydroxyl, thiol or amino are included as an aspect of the invention.
In reaction (b)~ the compounds of formula (IV) are novel and thev are included as a further aspect of this invention. They can be prepare~ in situ without isolation by reacting a compound of formula (V~ with an amine of formula R5H such as by heating to a temperature between 30~ ~d 120C, ~or example 100C, in R suitable solvent such as for example anisole and employing TiC14 as catalyst~ or by convention~l methods from compounds of formula (V) or ~VI).
It will be understood that electrophilic substitution on the aromatic nucleus can be carried out on compounds of formulae (I), (m1 or (IV) in ~onventional manner to produce other deriv&tives. For instance, an amide of formula (m) can be acetylated using acetyl chloride and stannic chlori~e or halogenated employing for example N-chlorosuccinimide, to give the corresponding acetyl or chloro derivatives. Products of forrnula (I) in which Rl, R~, R3 or R4 is amino can be acylated or alkylated in conventional manner to form the corresponding acylamino or all~ylamino derivatives.
As an illustration of the preparation of represent~ive compo~ds of the invention the fo~lowing reaction scheme is given, in which various routes for preparing a 4~4 a~ piperazinyl) -2,10-dihydrowrazolo[3,4~ [1,5]benæodiazepine are shown:
.. . _ ~ . . . ... .
R 02~B 1~ B~ L~6 R3 ~F H~Pd H N 25~Q3 R2 ~NH2 B~N ~ N/ DY30 R3~N~ N/
R \ 2 Rl CO~ / ~NR
J ~ \ }~R9 R[~ NY'2 ~ ~:_ }~2C3 \TiC14- R ~ ~ ~/ TiCl -a~isole ~tOX-~20 ~ R ~ rc~lux R / ~ E 7 -- N~NG~ X ~ 7 DM R~ ~N~B6 . SnC12-HCl Rl E tOH R2 ~NO 2 Rl ~3 ~F N 7 ~ ~\ 6 H2N ~R
R3~ ~ ;~ Nf The compounds of the invention have useful central nervous system activitv RS demonstrated by well~cnown test procedures. In behaYiour~ studies in mice, for instance, the compounds of the invention described in the followin~
Examples were observed to produoe h~7pothermia and acti~ty decrease at a dose range of 12.5 to 200 mg/kg p.o. Preferred comPounds have also been tested following chronic administration when Q behavioural supersensitivity is produced to locally injected dopamine in a manner similar to thRt described in Psychopharmacologia (1975) 45151-155. The activity profile observed in this test along with the lack o~ re~ponse in tests such QS the production of catalepsy indicate that these compoun~s possess useful central nervous system activity and do not produce certain undesirable side effects. For some time it has been recognised that conventional central nervous sVstem drugs can have undesirable characteristics and the potentiRl a~sence of these side effects in compounds according to the invention represents a siFni-ficant advance. In addition, compounds of the invention possess unexpected anxiolytic activity as demonstrated by their profile in the test described in Neuropharmacology (1979)18 689~95. The compomlds of formula (I`) and acid addition salts thereof are thus, potent centrally acting compounds with neuroleptic, sedative~ relaxant, anxidytic or anti-emetic properties. l'hese ~o properties, coupled with their low toxicity render them useful in the treatment of mild anxiety states and certain kinds of psychotic conditions such a schizophrenia and acute mania~
_ _ _ .. . _ . _ _, _ . . ~, .. . . . . . . .
4 ~ 7 ~ he compo~ds of this invention Ell'e effective over Q wide dosa~ze range, the actual dose administered being depen~ent on such factors as th particular compour,d being used, the condition bein~ treated and ths tvPe and size of mammal being treated. However, the dosage required will norm 11v fall within the range of 0.5 to 50 mg/kg per dav, for example in the treatment of adult humans, do6ages of from 5 to ~00 mg per clay may be used.
The compounds of the invention will normally be administered orally or by injection and, for this purpose, the compounds will usuall~ he utilised in the form of a pharmaceutical cornposition. Such compositions ~re prepared in a manner well known in the pharmaceutic 1 art ~nd compr;~e at least one active compound. Accordingly the invention includes a pharmaceutical composition comprising as active ingredient Q compound of formula I or an acid addition salt thereof, associated with 8 pharmaceuticsl]v acceptable carrier. In making the compositions of the invention, the active ingredient will usually be mixed with a cQrrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it màv be a solid, semi~olid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gurn acacia, c~lcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl-and propyl-hydroxvbenzoate, talc, magnesium stearate or mineral oil. The compositions of the invention may, if desirPd, be formulated so &s to provide quick, sustained or delayed release of the ~ctive in~redient after administration to the patient.
_ . .. . , ..... . . _ . .... _ . . . .
-~18--Depending on the route of administration, the foregoin~
compositlons may be formulated as tablets, capsules or suspensions for oral use and injection solutions for parenteral use or as suppositories. Preferablv the compositions are formulated in a do6a~e ~mit form, each dosa2e containing from l to 200 mg, more usuall 5 to 100 m~, of the active ingredi ent.
The following Examples illustrate the invention:
Ethyl 3~4-fluoro-2-nitroanilino~-1-methylpyrazole ~arboxylate A solution of ethyl 3-amino-1-methvlpvrazole-4~arhoxv1ate tHelv. Chim. Acta (1959) 42 349~(17g~ in dry tetrahv~lrofuran (250ml~ w~s stirred under nitrogen at -10C. n-Butyl lithium (75ml of 1.84 molar solution in hexane~ was added at -lO to -15C. The mixture was stirred at -15C for 10 minutes and a solution of 2,5~ifluoronitrobenzene (16g! in dry tetrahydrofuran (50ml) was added at -15 to -10C. The solution was warmed to r oom temperature and stirred for 1 hour. The ink-~lue solution ~as poured into 500 ml of a 1:1 mixture of hydrochloric acid (2M~ and ic~brine, ex~racted with chloroforrn (3 x 250ml), washed with water (2 x 250mll, ~ried with magnesium sulphate and evaporated to drvness. The brick-red residue WQS
crystallised from ethanol (800ml) to give the title compound havin~ a m.p. of 162C.
The following compounds were similarly prepared usin~ the above process. In each case the recrystallisation solvent is ~iven in parenthesis.
Ethyl l-methyl-3~4,5~ifluoro-2-nitroanilino) pyr~zole-4~arboxy1ate, m.p.
141C (isopropanol) Ethyl l-ethyl-3~4-fluoro-2-nitroanilino) pyrazole-4~arbo2~1ate, m.D. 136C
(ethanol).
Ethyl l-methyl-3~2-nitro-4-trifluoromethylQnilino) pyrazole-4~arboxvlate, m.p. 158C (isopropanol).
Ethyl 3~5-fluoro-2-nitroanilino~1-methylpyrazole-4~arboxylate, m.o. 165C
(ethanol).
.. . . . . . . ... .
Ethyl 3~4-fluoro-~-nitroanilino)-l~l~ropyl~pvrazo.e-4~arboxvlate, m.p.
109C (ethanol~.
Ethyl 3~4-fluoro-2-nitroanilino)-1~1-methylethyl)pvrazol~4~arboxvlate, m.p. 106.5~C (ethanol).
Ethyl 3~-fluoro-2-nitroanilino)-1l1-hexyl~pyrazole-4~arboxylate, m.p. 73 1 (ethanol~.
Ethyl 3~2-nitrosn~ino)-1-methylpyrRzole-4-carboxylate, m.p. 146 C
(isopropanol~ .
EXAMPLE 2~
3~4-Chloro-2-nitroanilino)-1-m eth~lDvr~zole-4~arbonitrile .
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763) (3.66g) was stirred in ~ry tetrshydrofuran (40ml~. Sodium h~7dride (509f, oil dispersion, 2.28g) was added snd the mixture was stirred for 10 minutes.
2,5-Dichloronitrobenzene t5.76g~ was added and the solution stirred under nitrogen for ~0 hours. Water was added dropwise to destrov any excess sodium hydride, then the solution was poured`on to a mixture of ice and dilute hydrochloric acid. After standing for 1 hour the brick-red precipitate was f~tered, washed with water and dried. Crystallisntion from ethanol-ethvl scetate afforded the product m.p. 205C.
The following compounds were simil~rly prepsred. In each case the recrystallisation solvent is given in parenthesis.
3~4-Iodo-2-nitroanilino~ methylpyrszol~4-carbonitrile, m.o. 212C
(ethanol-ethyl acetate) 5 ~
3~5~hloro-2-nitrcanilino!-1-methvlpyrazol~4~arhonitrile, m.p. 187C
(ethanol-ethyl acetate~
3~4,5-Dichloro-2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m.D. 225C.
(ethanol~thyl acetate) 3~4-33rom~2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m~D. 208C
(ethanol-ethyl acetate) 3~4-Trinuoromethyl-2-nitroanilino)-1-methylpvrazol~4-carbonitrile, m.P.
183C-i84C (ethanol~
3{4~hloro-2-nitroanilino)-l~thylpyrazol~4~arbonitrile, m.p. 1~2C
(ethanol-ethyl~cetate) 3~4-Chloro-2-nitroanilino~ 3-methyl-1-propyl)pyrazol~4~arbonitrile, m.p.
151C (ethanol) 3-(4~hloro-2-nitroanilino)-l~yclopentylpyrazole-~arbonitrile, m.p. 145 C
(ethanol) 3-(4-Fluoro-2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m.p. 174C
(ethanol) 3~3~hloro-2-nitroanilino)-1-methylpyrazol~4~arbonitrile, m.p. 190C
(ethanol) l-Methyl-3~2,4~initro~nilino)pyrazole-4~arbonitrile, m.p. 224C
(ethanol-ethyl acetate) Ethyl 1,5~imethyl-3-(4-lluoro-2-nitroan lino~Dvrazole~art~o~vlate Ethyl 3-amino-1,5-dimethylpyr~zol~4~arboxy1ate ~5.5g), 2~5-difluoronitrobenzene (6.6g) and anhydrous potassium ~arbonate (g.
were stirred in dimethylsulphox~de (60 ml) under dry ~ 3 ~;4~5~
nitrogen at ,0C for 20 hours. The mixture was poured on to 300 ml of ic~cold dilute hydrochloric acid, extracted with chloroform (3x~, washed with water ~2x), dried with magnesium sulphate and the solvent evaporated under reduced pressure. The yellow~rown residue was crystallised from ethanol to give the title compound havin~ a m.p. o~ 174C.
EXA~qPLE 4 l-Methvl-3~2~itroanilino)Dvrazole~arbonitrile 3-Amino-l-methylpyrazole-4~Qrbonitrile (Helv. Chim. Acta ~1959) a2, 763) t7.5g) and 2-fluoronitrobenzene (8.4g) were stirred in toluene tl20ml~ with I'Adogen 464 ~3.0g) and potassium carhonate (16.5~ at 60C. 50% Sodium hydroxide solution (0.1 ml~ was added and the mixture was heated un~ler refl~lx for a hours. The mixture was poured on to dilute hydrochloric acid, extrscted, the aqueous layer washed with toluene and the combined extracts washed twice with water. After evaporation the residue was crystallised from ethanol (750 ml) to give the title compound, m.p. 172C.
_XAMPLE 5 Ethvl 3~2-amino~-trifluoromethvlanilino)-1-methvl~vrazole~_arboxvlate Ethyl l-methyl-3~2-nitr~4-trifluoromethylanilino~pyrazole-4-carboxvlate (9.2g) was hydrogenated at 60 poS~i~ in a mixture o~ ethyl acetate (200 ml) and ethanol (50 ml) over 10% palladium on charcoal ~l.Og~. The catalyst was removed by filtration, the solvent * Trademark for trimethyl C ,Cl quaternary amm~nium chloride, it has a nu~ber of uses inclua~g use as a chemical intermediate.
, . . . _ .. _ . . . . . .
--23~
evaporated and the residue crystallised from carbon tetrachloride to ~ive the title compound m.p. 162C.
The following compounds were s;milarlq preDared and used in Examples 10 and 13 without purification.
Ethyl 3~2-amino-4-fluoroanilino)-1-methylpyrazole-4-carhoxylate.
Ethyl 3 (2-amino~-fluoroanilino~1,5~im ethylpyrazole~-carboxvlate.
Ethyl 3~2-amino-4-fluoroanilino)-1-ethylpyrazole-4-carboxylate.
Ethyl 3~2-amino-5-fluoroanilino~l-methylpyrazole~-carl~oxvlate.
Ethyl 3~2-amino-4,5~ifluoroanilino)-1-methylpyrazole-4~arbo~1ate.
Ethyl 3~2-amino~-fluoroanilino~l-(l~ropyl~pyrazole~-carboxvlate.
Ethyl 3~2-amino-4-fluoroanilino?-1~1-methylethyl~pyrazole-4-carbox~late.
Ethyl 3~(2-amino~-fluoroanilino~l~l-hexyl~pyrazole 4-carboxylate.
Ethyl 3~2-aminoanilino)-1-methylpyrazole 4-carboxylate.
EXAMPLE 6.
3-(2-Amino~-nitroanilino)-l- ethvlDvrazole~arbonitrile l-Methyl-3~2,4~initroanilino)pyrazole-4~arbonitrile (2.88g~ was stirred in a mixture of 0.88 ammonia solution (60ml~, water (9Oml~ and ethanol t~Oml~
under ren ~c whilst a slow stream of hydrogen sulphide gas was bubbled through for 2 hours. The mixture was cooled, filtered and the residue crystallised from ethyl acetate- n-hexane to give the title compound m.p.
:~04C
.. . . _, _ _ _ . . . . . .. . .
1 1~4~7 -2~-- EXAMPLE 7.
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763) (3.66g) was stirred in ~ry tetrshydrofuran (40ml~. Sodium h~7dride (509f, oil dispersion, 2.28g) was added snd the mixture was stirred for 10 minutes.
2,5-Dichloronitrobenzene t5.76g~ was added and the solution stirred under nitrogen for ~0 hours. Water was added dropwise to destrov any excess sodium hydride, then the solution was poured`on to a mixture of ice and dilute hydrochloric acid. After standing for 1 hour the brick-red precipitate was f~tered, washed with water and dried. Crystallisntion from ethanol-ethvl scetate afforded the product m.p. 205C.
The following compounds were simil~rly prepsred. In each case the recrystallisation solvent is given in parenthesis.
3~4-Iodo-2-nitroanilino~ methylpyrszol~4-carbonitrile, m.o. 212C
(ethanol-ethyl acetate) 5 ~
3~5~hloro-2-nitrcanilino!-1-methvlpyrazol~4~arhonitrile, m.p. 187C
(ethanol-ethyl acetate~
3~4,5-Dichloro-2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m.D. 225C.
(ethanol~thyl acetate) 3~4-33rom~2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m~D. 208C
(ethanol-ethyl acetate) 3~4-Trinuoromethyl-2-nitroanilino)-1-methylpvrazol~4-carbonitrile, m.P.
183C-i84C (ethanol~
3{4~hloro-2-nitroanilino)-l~thylpyrazol~4~arbonitrile, m.p. 1~2C
(ethanol-ethyl~cetate) 3~4-Chloro-2-nitroanilino~ 3-methyl-1-propyl)pyrazol~4~arbonitrile, m.p.
151C (ethanol) 3-(4~hloro-2-nitroanilino)-l~yclopentylpyrazole-~arbonitrile, m.p. 145 C
(ethanol) 3-(4-Fluoro-2-nitroanilino)-1-methylpyrazole-4~arbonitrile, m.p. 174C
(ethanol) 3~3~hloro-2-nitroanilino)-1-methylpyrazol~4~arbonitrile, m.p. 190C
(ethanol) l-Methyl-3~2,4~initro~nilino)pyrazole-4~arbonitrile, m.p. 224C
(ethanol-ethyl acetate) Ethyl 1,5~imethyl-3-(4-lluoro-2-nitroan lino~Dvrazole~art~o~vlate Ethyl 3-amino-1,5-dimethylpyr~zol~4~arboxy1ate ~5.5g), 2~5-difluoronitrobenzene (6.6g) and anhydrous potassium ~arbonate (g.
were stirred in dimethylsulphox~de (60 ml) under dry ~ 3 ~;4~5~
nitrogen at ,0C for 20 hours. The mixture was poured on to 300 ml of ic~cold dilute hydrochloric acid, extracted with chloroform (3x~, washed with water ~2x), dried with magnesium sulphate and the solvent evaporated under reduced pressure. The yellow~rown residue was crystallised from ethanol to give the title compound havin~ a m.p. o~ 174C.
EXA~qPLE 4 l-Methvl-3~2~itroanilino)Dvrazole~arbonitrile 3-Amino-l-methylpyrazole-4~Qrbonitrile (Helv. Chim. Acta ~1959) a2, 763) t7.5g) and 2-fluoronitrobenzene (8.4g) were stirred in toluene tl20ml~ with I'Adogen 464 ~3.0g) and potassium carhonate (16.5~ at 60C. 50% Sodium hydroxide solution (0.1 ml~ was added and the mixture was heated un~ler refl~lx for a hours. The mixture was poured on to dilute hydrochloric acid, extrscted, the aqueous layer washed with toluene and the combined extracts washed twice with water. After evaporation the residue was crystallised from ethanol (750 ml) to give the title compound, m.p. 172C.
_XAMPLE 5 Ethvl 3~2-amino~-trifluoromethvlanilino)-1-methvl~vrazole~_arboxvlate Ethyl l-methyl-3~2-nitr~4-trifluoromethylanilino~pyrazole-4-carboxvlate (9.2g) was hydrogenated at 60 poS~i~ in a mixture o~ ethyl acetate (200 ml) and ethanol (50 ml) over 10% palladium on charcoal ~l.Og~. The catalyst was removed by filtration, the solvent * Trademark for trimethyl C ,Cl quaternary amm~nium chloride, it has a nu~ber of uses inclua~g use as a chemical intermediate.
, . . . _ .. _ . . . . . .
--23~
evaporated and the residue crystallised from carbon tetrachloride to ~ive the title compound m.p. 162C.
The following compounds were s;milarlq preDared and used in Examples 10 and 13 without purification.
Ethyl 3~2-amino-4-fluoroanilino)-1-methylpyrazole-4-carhoxylate.
Ethyl 3 (2-amino~-fluoroanilino~1,5~im ethylpyrazole~-carboxvlate.
Ethyl 3~2-amino-4-fluoroanilino)-1-ethylpyrazole-4-carboxylate.
Ethyl 3~2-amino-5-fluoroanilino~l-methylpyrazole~-carl~oxvlate.
Ethyl 3~2-amino-4,5~ifluoroanilino)-1-methylpyrazole-4~arbo~1ate.
Ethyl 3~2-amino~-fluoroanilino~l-(l~ropyl~pyrazole~-carboxvlate.
Ethyl 3~2-amino-4-fluoroanilino?-1~1-methylethyl~pyrazole-4-carbox~late.
Ethyl 3~(2-amino~-fluoroanilino~l~l-hexyl~pyrazole 4-carboxylate.
Ethyl 3~2-aminoanilino)-1-methylpyrazole 4-carboxylate.
EXAMPLE 6.
3-(2-Amino~-nitroanilino)-l- ethvlDvrazole~arbonitrile l-Methyl-3~2,4~initroanilino)pyrazole-4~arbonitrile (2.88g~ was stirred in a mixture of 0.88 ammonia solution (60ml~, water (9Oml~ and ethanol t~Oml~
under ren ~c whilst a slow stream of hydrogen sulphide gas was bubbled through for 2 hours. The mixture was cooled, filtered and the residue crystallised from ethyl acetate- n-hexane to give the title compound m.p.
:~04C
.. . . _, _ _ _ . . . . . .. . .
1 1~4~7 -2~-- EXAMPLE 7.
4-Methvl-1~3-~2-ami~o~-trifluoromethvlAnilino~ methvlDvrazole 4~arbonvl~DiDerazine -Ethyl 3~2-amino-4-trifluoromethylanilino~-1-methylpyrazole-4~arboxylate (4.75g) was stirred in a mixture of ~-methylpiperazine (25ml~ and aniso]e ~65ml3. A solution of titanium tetrachloride (4.2ml) in anisole (20ml) was added ~nd the mixture was stirred under nitrogen at 65C for 30 minutes.
mixture of isopro~anol (25ml) and 0.88 ammonia solution (25ml) was added and the stirred mixture cooled to 25~C. The precipitate was removed by filtration, washing with ethyl acetate. The combined filtrates were washed with water (3X), dried over magnesium sulphate, the solvent evaporated and the residue crystallised from acetonitrile to give the title compound m.p.
170C.
Other examples of this type were prepared in situ and cyclised as in ExamDle 13.
4-Amino-7~hloro-2.10-dihvdro-2-methvl~vrazolo r3~4-bl n 51 henzodiazeDine To 1-methyl-3~4-chloro-2-nitroanilino~pyrazole-4~arbonitrile (16g~ stirred in ethanol (500 ml) was added a solution of anhydrous stannous chloride t33.1g~ in concentrated hydrochloric acid (176ml). The mîxture w~s heated under reflux for 2 hours, cooled, f~tered and crystallised from methylated spirits (1 litre~
to give _ . _ . _ .. .. . . . . _ ... . . . . .
the title compo~d as its hydrochloride salt m.p.~ 260C. 2.0~ of the hydrochloride salt was phrtitioned between dilute ammonia solution ancl chloroform. The organic phase was washed with water, dried with magnesi~lm sulphate, evaporated and the residue cryst~llised ~rsm chlorofor~n-n-hexane to give the title compo~md as the free base m.p. 240C.
The following compounds were similarly prepared and used as the hydrochlorides without purification in Example iS.
4-Amin~2,10~ihydr~7-iodo-2~nethylpyrazolo[3,4~ ~1,51benzodia2epine 4-Amino-8~hloro-2,10-dihydro-2-methylpyrazolo [3,4~] ~1,5]benzodiazepine 4-Amino-7,8~ichloro-2,1Wihydro-2-methylpyrazolo[3,4~1 ~1,51 benzodiazepine 4-Amino-7-brom~2,10-dihydro-2-methylpyrazolo[3,4-bl [1,51benzodiazepine 4-Amino-2~lo~ihydro-7-trifluoromethyl-2-methylpyrazlolor3~4~l ~1,51 henzodiaze pine 4-Amino-7~hloro-2-ethyl-2,10~ihydropyrazolo[3,4-bl n,51 t~enzodiazeDine 4-Amino-7-chloro-2,10-dihydro-2-S2-m ethyl-l-propyl~pyrazolo [3,4~] [195] benzodiazepine 4-Amino-7~hloro-2-cyclopentyl-2,10-dihydropyrazolor3,4-bl i],51 benzodiazepine 4-Amin~7-fluoro-2,10-dihydr~2~nethylpyrazolor3,4-bl n,51 benzodiazepine 4-Amino-6~hlo~o-2,10~ihydr~2-methylpyrazolo~3;4~1 ~l,Sl benzodiazepine ,, _ .. . _ _ .. . .. . .. .. .. . . .
mixture of isopro~anol (25ml) and 0.88 ammonia solution (25ml) was added and the stirred mixture cooled to 25~C. The precipitate was removed by filtration, washing with ethyl acetate. The combined filtrates were washed with water (3X), dried over magnesium sulphate, the solvent evaporated and the residue crystallised from acetonitrile to give the title compound m.p.
170C.
Other examples of this type were prepared in situ and cyclised as in ExamDle 13.
4-Amino-7~hloro-2.10-dihvdro-2-methvl~vrazolo r3~4-bl n 51 henzodiazeDine To 1-methyl-3~4-chloro-2-nitroanilino~pyrazole-4~arbonitrile (16g~ stirred in ethanol (500 ml) was added a solution of anhydrous stannous chloride t33.1g~ in concentrated hydrochloric acid (176ml). The mîxture w~s heated under reflux for 2 hours, cooled, f~tered and crystallised from methylated spirits (1 litre~
to give _ . _ . _ .. .. . . . . _ ... . . . . .
the title compo~d as its hydrochloride salt m.p.~ 260C. 2.0~ of the hydrochloride salt was phrtitioned between dilute ammonia solution ancl chloroform. The organic phase was washed with water, dried with magnesi~lm sulphate, evaporated and the residue cryst~llised ~rsm chlorofor~n-n-hexane to give the title compo~md as the free base m.p. 240C.
The following compounds were similarly prepared and used as the hydrochlorides without purification in Example iS.
4-Amin~2,10~ihydr~7-iodo-2~nethylpyrazolo[3,4~ ~1,51benzodia2epine 4-Amino-8~hloro-2,10-dihydro-2-methylpyrazolo [3,4~] ~1,5]benzodiazepine 4-Amino-7,8~ichloro-2,1Wihydro-2-methylpyrazolo[3,4~1 ~1,51 benzodiazepine 4-Amino-7-brom~2,10-dihydro-2-methylpyrazolo[3,4-bl [1,51benzodiazepine 4-Amino-2~lo~ihydro-7-trifluoromethyl-2-methylpyrazlolor3~4~l ~1,51 henzodiaze pine 4-Amino-7~hloro-2-ethyl-2,10~ihydropyrazolo[3,4-bl n,51 t~enzodiazeDine 4-Amino-7-chloro-2,10-dihydro-2-S2-m ethyl-l-propyl~pyrazolo [3,4~] [195] benzodiazepine 4-Amino-7~hloro-2-cyclopentyl-2,10-dihydropyrazolor3,4-bl i],51 benzodiazepine 4-Amin~7-fluoro-2,10-dihydr~2~nethylpyrazolor3,4-bl n,51 benzodiazepine 4-Amino-6~hlo~o-2,10~ihydr~2-methylpyrazolo~3;4~1 ~l,Sl benzodiazepine ,, _ .. . _ _ .. . .. . .. .. .. . . .
5 7 4-Amino-2,10~ vdro-2-methvl-7-nitro~vrazolo~3,4~1 [1,51 benzodiaze~ine hvdrochloride 3~2-Amino-4~itroanilino)-1-methylpyrazole-4~ar~onitrile (250 mg~ was heated unde~ reflux in a mixture of isopropanol (10 ml~ and concentrated hydrochloric acid (1 ml) for 20 hours. The solution was evaporated under reduced pressure and the residue crystallised from methylated spirits to ~ive the title compo~d m.p.>260.
7-Fluoro-2-methyl-2,~,5,10-tetrahvdro~vrazolo [3.4~1 n,5] benzodiazeDin~-one A solution of sodium methyl sulphinyl methanide was generated bv stirring sodium hydride (50% oil disper~non, 1.5~ in dry dimethylsulphoxi~e ~15 ml) at 65C until gas evolution ceased. A solution of ethyl 3~2-smino~-nuoroanilino)-1- ~
methylpyrazol~4-carboxylate (2.7g~ dissolved in dry dimethyl sulphoxide (5 ml) was added dropwise and the mixture stirred at 65C for 2~ minutes. The mixture was poured on to excess ice-water, filtered and dried to give the title compound which was crystallised from chloroform-hexane m.p. 264C.
EXAMPLl~ D
7-chlor~2~4~5~lo-tetrah~dro-2-methv~ vrazolo~3~4~ln.51benzodiaze~in~one 4-Amin~7~hloro-2,10~ihydro-2-m ethylpyrazold394~~ 1 benzodiazepine .. _ _ ~ , _ . . , . . . . , . . _ . . .
-27~
hydrochloride (11.3 g? and pota~sium carbonate (16.8 ~ were heated under reflux in a mixture of ethanol f200 ml~ and water (20 ml) for 48 hours. Water (30û ml) was added and the solution eooled. Tlle precipitate was crystallised from acetic acid to give the title compo~d m.p.~260C
7 Ch oro-2,4.5~10-tetrahvdro-2-methvlpvrazolo~324~1 n,~ benZodiazeDine~-th one ~hloro-2,4,5,10-tetrahydro-2-methylpyrazoloi~,4,bl n,51 henzodiazepine-4-one (7.2 g) was added to a stirred solution of phosphoru5 pentasulphide f6.5 g~ in ~0 anhydrous pyridine (145 ml). The mixture was heated under reflu~ for 1.5 hours, poured on to ice, and the precipitate crystallised from chloroform - -_methanol to yield the title compound m.p.~260C
l~XAMPLE 13 2-Ethvl-7-fluoro-2,10~ihvdro~4-methvl-l~iDerazinvl)pvrazolor3,4-bl rl,Sl benz odiazee~
-Ethyl 3~2-amin~4-fluoroanilino~l-ethylpyrazole-4~arboxylate (2.~4g~ was dissolved in a mixtur~ of N-methyl piperazine /12.5ml.~ and anisole (~Oml~.
Titanium tetrachlor;de t3ml~ in anisole (12ml) was added, dropwise, and the stirred solution was heated at reflux under an atmosphere of dry nitrogen for 24 hours. 'rhe mixture was cooled to 60C and ~ mixture of isopropsnol (lOmV and 0.~8 ammonia solution (lOmV cautiously adcled. This mixture WRS
allowed to cool to room temperature over 1 hour, then filtered through a pad -~9~ 5 ~ .
o~'Celite,"whilst washing with ethyl ~cetate. The filtrate was washed ~ith water (3x), drie~ over m~nesium sulphate and the solvent removed. The re~idue was f~tered through a short column of Florisil, elutin~ with ethvl ~cetate. After removal of solvent the title product was crvstal]ised from acetonitrile m.p. 181G.
The followinF compo~ds were similarlv prepared:
_ 7-Fluoro-2,10~ihydr~2,3~imethvl 4~4 ;nethyl-l-piperazinyl!pyrazolo [3,4-b~ [195~ benzodiazepine, m.p. 234C (acetonitrile) 7{~hloro-2,10~ihvdro-2-methyl-4~4-methv!-l~iperazinyl~pyrazolo [3,4~ [l,S] benzodiazepine, m.p. 107-109C (acetonitrile) 8-Fluoro-2,10~ihydro-2-m ethvl-4~4-~nethyl-l~iperazinvl~pvrazolo 13,4~ [l,Sl benzodiazepine, m.p. 192C (acetonitrile) 7,8-Difluoro-2,10-dihydro-~ methyl-4~4-methyl-l-piperazinyl~p~yrazolor3~4 5] benzodiazepine, m.p. 214C (acetonitrile).
7-Fluoro-2,10-dihydro-4-(4-methyl-1-piperazinyl~-2~1~ropvl)pvrazolor~,4~1 ~],51 b~nz~diazepine, m.p. 146C (a~etonitr~e~.
7-Fluoro-2,10-dihydro-2-(1-methylethyl!~4-methyl-1-piperazinyl)pvrazolo~,4-b~ 11,5] benzodiazepine, m.p. 74-76C(cyclohexane-n-hexanel 7-Fluor~2~1-he2~yl)-2,1û~ihydro 4~4 rnethyl-l~iperazinyl)pyrazolo~3,4~1 ~l,Slb enzodiazepine, m.p. 99C (cyciohexane~exane).
2,10-Dihydro-2 rnethyl~4 rnethyl-l~iperazinyl)pyrazolor3,4~1 ll,Slbenzodiaze pine, m.p. 212C (scetonitrile) ?-Fluoro-2~10~ v~dro 2-methvl~-(4-methvl~ ' D~---l-13 4~] n.5~ benzodiazeDine and citrate salt.
7-Fluor~2,4,5,10-tetrahydro-2~nethylpyrazolo [~4-bl [1,51 * Trademark for diatomaceous earth.
** Trademark for a highly selective adsorbent of magnesium silicate in the fonm of hard white granules, I :L64457 benzodiazepin-4~ne (0.9Sg) was stirred in a mixture of N-methvlpiperazine (lOml~ and anisole (15ml!~ A solution of ti~anium tetrachloride (0.~5 ml~ in anisole (lOml) was added and the mixture stirred under nitro~en at 130C for 2 hours, poured on to ice dilute ammonia solution and extra~ted into methylene chloride. The extract was washed with water ~3x~, dried and evaporated.
The residue was chromatographed on'Plorisil"elutin~ with ethyl acetate and crystallised from acetonitr~e, m.p. 192C~
The citrate salt wa~; prepared by adding a solution of citric aeid in eth~nol to a solution of the title compound in a 1:1 mixture of ethano~ and ethyl acetate m.p. 138C (softens) 2,10-Dihydro-7-iodo-?-methvl~4-methvl-l-Diperazinvl~p~7razolor~.4~1 1l~5l t-en zodisze~ine To a mixture of N-methylpiperazine ~10 ml~, dimethylsulphoxide ~25 ml~ and toluene (25 ml~ through which nitrogen had been bubbled for ~0 minutes was added 4-amino-2,10-dihydro-7-iodo-2-methylpyrszolo ~3,4-b] [1,5~ benzodiazepine hydrochloride (3.84 g). The stirred mixture ~vas hested under nitrogen at 120C for 20 hours. The mixture was cooled to 60C
and water (25 ml) added. The residue was filtered, drie~ and crystPllised from chloroform-n-hexane m.p. 113C.
The following compounds were similarly prepared:
8{~hloro-2,10-dihydro-2-methyl-4 (4~methyl-1-piperazinyl)pyrazolor~,4~~ s1 be nzodiazepine, m.p. 221C (chlsroform~-hexane).
7,8-Dichloro-2,10~ihydr~2~nethyl-4~4-methyl-l~iperazinvl~pvrazo]o .. . . _ , .. . ... .. .. .. . . . .
[3,4~] ~1,5] benzodiazepine, m.P. 158C (acetonitrile~
7-8romo-2,10~ihydro-2-methyl-4~4-rnethvl-1-,Diperazinvl~pvrazolo~3,4~1 ~l,hl~e nzodiazepine, m.p. 162C (acetonitrile) 2,10-Dihydro-7-trifluoromethyl-2-methyl-4-(4-methyl-1-piperazinyl)pyrQzolo~3,~
-b] n,5~ benzodiazepine, m.p. 129-130 C (ethyl acetat~hexane~
7~hloro-2-ethyl-2,10~ihydro~4-methyl~l-piperazinvl~pyrazolo~3,4~1 [l~5ll~en zodiazepine, m.p. 165C (acetonitrile) 7~hloro-2,10-dihydro-4 (4-methyl-l~iperazinyl~2~2-methyl-1-propyl~pyrazolo~
3,4~] [1,5] ben~odiazepine, m.p. 161C (aeetonitrile) 7~oro~2-cy~lopenty~ o~ihydro-4~4-methv~ perazinyl~p~razolor3~4~l r 1,5] benzodiazepine, m.p. 151C (acetonitrile~
7-Fluoro-2,10-dihydro-2-m ethyl-4~1~ip e~azinyl~pyrazolo[3,4-bl rL 51 benzodiazep ine, m.p. 183-185C (acetonitrile)
7-Fluoro-2-methyl-2,~,5,10-tetrahvdro~vrazolo [3.4~1 n,5] benzodiazeDin~-one A solution of sodium methyl sulphinyl methanide was generated bv stirring sodium hydride (50% oil disper~non, 1.5~ in dry dimethylsulphoxi~e ~15 ml) at 65C until gas evolution ceased. A solution of ethyl 3~2-smino~-nuoroanilino)-1- ~
methylpyrazol~4-carboxylate (2.7g~ dissolved in dry dimethyl sulphoxide (5 ml) was added dropwise and the mixture stirred at 65C for 2~ minutes. The mixture was poured on to excess ice-water, filtered and dried to give the title compound which was crystallised from chloroform-hexane m.p. 264C.
EXAMPLl~ D
7-chlor~2~4~5~lo-tetrah~dro-2-methv~ vrazolo~3~4~ln.51benzodiaze~in~one 4-Amin~7~hloro-2,10~ihydro-2-m ethylpyrazold394~~ 1 benzodiazepine .. _ _ ~ , _ . . , . . . . , . . _ . . .
-27~
hydrochloride (11.3 g? and pota~sium carbonate (16.8 ~ were heated under reflux in a mixture of ethanol f200 ml~ and water (20 ml) for 48 hours. Water (30û ml) was added and the solution eooled. Tlle precipitate was crystallised from acetic acid to give the title compo~d m.p.~260C
7 Ch oro-2,4.5~10-tetrahvdro-2-methvlpvrazolo~324~1 n,~ benZodiazeDine~-th one ~hloro-2,4,5,10-tetrahydro-2-methylpyrazoloi~,4,bl n,51 henzodiazepine-4-one (7.2 g) was added to a stirred solution of phosphoru5 pentasulphide f6.5 g~ in ~0 anhydrous pyridine (145 ml). The mixture was heated under reflu~ for 1.5 hours, poured on to ice, and the precipitate crystallised from chloroform - -_methanol to yield the title compound m.p.~260C
l~XAMPLE 13 2-Ethvl-7-fluoro-2,10~ihvdro~4-methvl-l~iDerazinvl)pvrazolor3,4-bl rl,Sl benz odiazee~
-Ethyl 3~2-amin~4-fluoroanilino~l-ethylpyrazole-4~arboxylate (2.~4g~ was dissolved in a mixtur~ of N-methyl piperazine /12.5ml.~ and anisole (~Oml~.
Titanium tetrachlor;de t3ml~ in anisole (12ml) was added, dropwise, and the stirred solution was heated at reflux under an atmosphere of dry nitrogen for 24 hours. 'rhe mixture was cooled to 60C and ~ mixture of isopropsnol (lOmV and 0.~8 ammonia solution (lOmV cautiously adcled. This mixture WRS
allowed to cool to room temperature over 1 hour, then filtered through a pad -~9~ 5 ~ .
o~'Celite,"whilst washing with ethyl ~cetate. The filtrate was washed ~ith water (3x), drie~ over m~nesium sulphate and the solvent removed. The re~idue was f~tered through a short column of Florisil, elutin~ with ethvl ~cetate. After removal of solvent the title product was crvstal]ised from acetonitrile m.p. 181G.
The followinF compo~ds were similarlv prepared:
_ 7-Fluoro-2,10~ihydr~2,3~imethvl 4~4 ;nethyl-l-piperazinyl!pyrazolo [3,4-b~ [195~ benzodiazepine, m.p. 234C (acetonitrile) 7{~hloro-2,10~ihvdro-2-methyl-4~4-methv!-l~iperazinyl~pyrazolo [3,4~ [l,S] benzodiazepine, m.p. 107-109C (acetonitrile) 8-Fluoro-2,10~ihydro-2-m ethvl-4~4-~nethyl-l~iperazinvl~pvrazolo 13,4~ [l,Sl benzodiazepine, m.p. 192C (acetonitrile) 7,8-Difluoro-2,10-dihydro-~ methyl-4~4-methyl-l-piperazinyl~p~yrazolor3~4 5] benzodiazepine, m.p. 214C (acetonitrile).
7-Fluoro-2,10-dihydro-4-(4-methyl-1-piperazinyl~-2~1~ropvl)pvrazolor~,4~1 ~],51 b~nz~diazepine, m.p. 146C (a~etonitr~e~.
7-Fluoro-2,10-dihydro-2-(1-methylethyl!~4-methyl-1-piperazinyl)pvrazolo~,4-b~ 11,5] benzodiazepine, m.p. 74-76C(cyclohexane-n-hexanel 7-Fluor~2~1-he2~yl)-2,1û~ihydro 4~4 rnethyl-l~iperazinyl)pyrazolo~3,4~1 ~l,Slb enzodiazepine, m.p. 99C (cyciohexane~exane).
2,10-Dihydro-2 rnethyl~4 rnethyl-l~iperazinyl)pyrazolor3,4~1 ll,Slbenzodiaze pine, m.p. 212C (scetonitrile) ?-Fluoro-2~10~ v~dro 2-methvl~-(4-methvl~ ' D~---l-13 4~] n.5~ benzodiazeDine and citrate salt.
7-Fluor~2,4,5,10-tetrahydro-2~nethylpyrazolo [~4-bl [1,51 * Trademark for diatomaceous earth.
** Trademark for a highly selective adsorbent of magnesium silicate in the fonm of hard white granules, I :L64457 benzodiazepin-4~ne (0.9Sg) was stirred in a mixture of N-methvlpiperazine (lOml~ and anisole (15ml!~ A solution of ti~anium tetrachloride (0.~5 ml~ in anisole (lOml) was added and the mixture stirred under nitro~en at 130C for 2 hours, poured on to ice dilute ammonia solution and extra~ted into methylene chloride. The extract was washed with water ~3x~, dried and evaporated.
The residue was chromatographed on'Plorisil"elutin~ with ethyl acetate and crystallised from acetonitr~e, m.p. 192C~
The citrate salt wa~; prepared by adding a solution of citric aeid in eth~nol to a solution of the title compound in a 1:1 mixture of ethano~ and ethyl acetate m.p. 138C (softens) 2,10-Dihydro-7-iodo-?-methvl~4-methvl-l-Diperazinvl~p~7razolor~.4~1 1l~5l t-en zodisze~ine To a mixture of N-methylpiperazine ~10 ml~, dimethylsulphoxide ~25 ml~ and toluene (25 ml~ through which nitrogen had been bubbled for ~0 minutes was added 4-amino-2,10-dihydro-7-iodo-2-methylpyrszolo ~3,4-b] [1,5~ benzodiazepine hydrochloride (3.84 g). The stirred mixture ~vas hested under nitrogen at 120C for 20 hours. The mixture was cooled to 60C
and water (25 ml) added. The residue was filtered, drie~ and crystPllised from chloroform-n-hexane m.p. 113C.
The following compounds were similarly prepared:
8{~hloro-2,10-dihydro-2-methyl-4 (4~methyl-1-piperazinyl)pyrazolor~,4~~ s1 be nzodiazepine, m.p. 221C (chlsroform~-hexane).
7,8-Dichloro-2,10~ihydr~2~nethyl-4~4-methyl-l~iperazinvl~pvrazo]o .. . . _ , .. . ... .. .. .. . . . .
[3,4~] ~1,5] benzodiazepine, m.P. 158C (acetonitrile~
7-8romo-2,10~ihydro-2-methyl-4~4-rnethvl-1-,Diperazinvl~pvrazolo~3,4~1 ~l,hl~e nzodiazepine, m.p. 162C (acetonitrile) 2,10-Dihydro-7-trifluoromethyl-2-methyl-4-(4-methyl-1-piperazinyl)pyrQzolo~3,~
-b] n,5~ benzodiazepine, m.p. 129-130 C (ethyl acetat~hexane~
7~hloro-2-ethyl-2,10~ihydro~4-methyl~l-piperazinvl~pyrazolo~3,4~1 [l~5ll~en zodiazepine, m.p. 165C (acetonitrile) 7~hloro-2,10-dihydro-4 (4-methyl-l~iperazinyl~2~2-methyl-1-propyl~pyrazolo~
3,4~] [1,5] ben~odiazepine, m.p. 161C (aeetonitrile) 7~oro~2-cy~lopenty~ o~ihydro-4~4-methv~ perazinyl~p~razolor3~4~l r 1,5] benzodiazepine, m.p. 151C (acetonitrile~
7-Fluoro-2,10-dihydro-2-m ethyl-4~1~ip e~azinyl~pyrazolo[3,4-bl rL 51 benzodiazep ine, m.p. 183-185C (acetonitrile)
6-chloro-2~lo-dihydro-2-methyl~-(4-methyl-l~iperazinyl)~3~4-b1 ~l~5 benzodiazepine, rn.p~ 214C (chloroform-n-hexane~
-
-
7~hloro-2,10~ihvdro-2-methyl~4-methvl-l~iDerazinvllpvrazolor3,4,~1 n.51 b enzodiazepine 7-Chloro-2,4,5,10-tetrahydro-2-methyl-4~4-methyl-l~iperazinyl)pvra~olor8,4 ] n,5~ benzodiazepin-4-thione(0.265g! was heated under reflux in N-methylpiperazine (~ ml) for 20 hollrs. The cooled mi~ture was dissolved in lM hydrochloric acid, washed with ethyl acetate (2X~, basified with 0.88 ammoniQ and extracted into dichlorometllane. The extract was washed with water, dried with magnesiusn sulphate snd evaporated to le~ve a residue whlch was crystallised from chloroform-n-hexane m.p. 173-176C
.... . . .. _ ., . _ _ .. . . _ . . . . . . . .
4~4-CvcloDroDvlmethvl~ iDerazinvl~-7-fluoro-~-methvl-2,10-dihvdroDvrszolo [3.4~1 ~1. 51 benzodiaz eDine A solution of 7-fluoro~2,10~ihydro-2-methyl~4-(l-piperazinyl)pyr~zolo[3,4-bl [1,5jbenzodiazepine tl.Og), bromomethylcyclopropane (0.5g~ and triethylamine (0.0375~) in ~cetonitrile (30 ml) was stirred at ambient temperature for 20 hours. The solution w~
poured into water and the product extracted with chloroform (3X). The organic extract was washed with saturated brine and water, dried over magnesium s~phate, the solvent removed and the residue crvst llised from ethyl acetate to give the title compound m.p. 188-189C
4~4-8enzyl-l~iperazinyl)-7-fluoro-2,10-dihydro-2 methyl~vrazolor~ n,.~ e nzodiazepine was similarly prepared, m.p. 241-245C (ethyl acetat~diethyl ether) 4~7-Fluoro-~,lO~ihydro2-methyl~vrazolo[3,4~1 n,51 benzodiazeDin~-yl~-l-methvl Diperazin~l-oxide monohvdrate 7-Fluoro-2,10-dihydro-2-m ethyl~4-m ethyl~
piper~zinyl~yrazolo~3,4-b] n,51 benzodi~zepine ~2.0g~ was stirred in dichlorometh~e (50 ml) at 0-5C whilst m~hloroperbenzoic acid (l.~g~ was added in portions. The solution was stirred for 30 minutes then filtered through a column of basic alumina~,eluting with 9:1 chloroform: methanol to give,afte3 remov~l of the solYent and crystallisation from acetonitrile~iethyl ether,the title compound m.p. 228 .
The following formulations were prepared emplovin~
7-fluoro-2,10~ihydro-2-methyl-4~4-methyl-1-piper~zin~l~wrazolo ~3,4~] ~1~5] benzodiazepine as the active ingredient. Formulations containiny other active ingredients of the invention can be prepared in a similar manner Tablets each containg iO mg of active ingredient were made up as follows Active ingredient 10 rng Starch 45 mg M icr;:~crystal1ine cellulo~e 35 mg Polyvinylpyrrolidone 4 mg (as 1096 solution in water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Tslc 1 mR' Total 100 mg The active ingredient, starch and cellulose were passed through a No. 44 mesh B.S.
sieve and mixed thoroughly. The solution of polvvinylpyrrolidone was mixed with t11e resultant powders which were then passed through a No. 12 mesh B.S. sieve. The granules so produced were dried at 50~0C and passed through a No. 16 mesh B.S.
sieveO The sodium c~rboxyme~hyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh B.5. sieve, were then added to the granules - 3 ~-which, after mixing, were comp~essed on a tablet machine to yield tablets eacl weighting 100 mg.
CQPSU1eS eaeh containing 20 mg of medichment were made as ~ollows Active ingredient 20 mg Starch 89 mg Microcrystalline cellulose 89 mg Magnesium stearate 2 mg Total 200 m~
The active ingredient, cellulose, starch and magnesium stearate were passed tho~lgh a No. 44 mesh B.S~ sieve and filled into hard gelatin capsules in 700 mg quantities.
Suppositories each containing 25 mg of active ingredient were macle as follows Medicament 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient was passed throu~h ~ No. R0 mesh B.S. sieve and suspended in the satura~ed fatty acid glycerides previously melted usinF the minimum heat necessary. The mixture was then poured into a suppositorv mould of nominal 2 g capacity and allowed to cool.
. . ~
A T~ P LE 2 2 Suspensions each containing 5 mg of medicament per 5 ml dose were made as follows Medicament 5 mg Sodium carboxymethyl celllllose 50 mg Syr-up 1.25 ml Benzoic acid solution 0.10 ml Flavour q-5-Colour q.s.
Purified wate~ to S ml The medicament was passed through a No. 44 mesh B.S. sieve and mixed with the sodium carboxymethylcellulose and svrup to ~orm a smooth paste.
The benzoic acid solution, flavour and colour were diluted with some of the water and added, with stirring. Sufficient water was then added to produce the required volume.
.., _ .. ~ . . . .. . . .
.
.... . . .. _ ., . _ _ .. . . _ . . . . . . . .
4~4-CvcloDroDvlmethvl~ iDerazinvl~-7-fluoro-~-methvl-2,10-dihvdroDvrszolo [3.4~1 ~1. 51 benzodiaz eDine A solution of 7-fluoro~2,10~ihydro-2-methyl~4-(l-piperazinyl)pyr~zolo[3,4-bl [1,5jbenzodiazepine tl.Og), bromomethylcyclopropane (0.5g~ and triethylamine (0.0375~) in ~cetonitrile (30 ml) was stirred at ambient temperature for 20 hours. The solution w~
poured into water and the product extracted with chloroform (3X). The organic extract was washed with saturated brine and water, dried over magnesium s~phate, the solvent removed and the residue crvst llised from ethyl acetate to give the title compound m.p. 188-189C
4~4-8enzyl-l~iperazinyl)-7-fluoro-2,10-dihydro-2 methyl~vrazolor~ n,.~ e nzodiazepine was similarly prepared, m.p. 241-245C (ethyl acetat~diethyl ether) 4~7-Fluoro-~,lO~ihydro2-methyl~vrazolo[3,4~1 n,51 benzodiazeDin~-yl~-l-methvl Diperazin~l-oxide monohvdrate 7-Fluoro-2,10-dihydro-2-m ethyl~4-m ethyl~
piper~zinyl~yrazolo~3,4-b] n,51 benzodi~zepine ~2.0g~ was stirred in dichlorometh~e (50 ml) at 0-5C whilst m~hloroperbenzoic acid (l.~g~ was added in portions. The solution was stirred for 30 minutes then filtered through a column of basic alumina~,eluting with 9:1 chloroform: methanol to give,afte3 remov~l of the solYent and crystallisation from acetonitrile~iethyl ether,the title compound m.p. 228 .
The following formulations were prepared emplovin~
7-fluoro-2,10~ihydro-2-methyl-4~4-methyl-1-piper~zin~l~wrazolo ~3,4~] ~1~5] benzodiazepine as the active ingredient. Formulations containiny other active ingredients of the invention can be prepared in a similar manner Tablets each containg iO mg of active ingredient were made up as follows Active ingredient 10 rng Starch 45 mg M icr;:~crystal1ine cellulo~e 35 mg Polyvinylpyrrolidone 4 mg (as 1096 solution in water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Tslc 1 mR' Total 100 mg The active ingredient, starch and cellulose were passed through a No. 44 mesh B.S.
sieve and mixed thoroughly. The solution of polvvinylpyrrolidone was mixed with t11e resultant powders which were then passed through a No. 12 mesh B.S. sieve. The granules so produced were dried at 50~0C and passed through a No. 16 mesh B.S.
sieveO The sodium c~rboxyme~hyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh B.5. sieve, were then added to the granules - 3 ~-which, after mixing, were comp~essed on a tablet machine to yield tablets eacl weighting 100 mg.
CQPSU1eS eaeh containing 20 mg of medichment were made as ~ollows Active ingredient 20 mg Starch 89 mg Microcrystalline cellulose 89 mg Magnesium stearate 2 mg Total 200 m~
The active ingredient, cellulose, starch and magnesium stearate were passed tho~lgh a No. 44 mesh B.S~ sieve and filled into hard gelatin capsules in 700 mg quantities.
Suppositories each containing 25 mg of active ingredient were macle as follows Medicament 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient was passed throu~h ~ No. R0 mesh B.S. sieve and suspended in the satura~ed fatty acid glycerides previously melted usinF the minimum heat necessary. The mixture was then poured into a suppositorv mould of nominal 2 g capacity and allowed to cool.
. . ~
A T~ P LE 2 2 Suspensions each containing 5 mg of medicament per 5 ml dose were made as follows Medicament 5 mg Sodium carboxymethyl celllllose 50 mg Syr-up 1.25 ml Benzoic acid solution 0.10 ml Flavour q-5-Colour q.s.
Purified wate~ to S ml The medicament was passed through a No. 44 mesh B.S. sieve and mixed with the sodium carboxymethylcellulose and svrup to ~orm a smooth paste.
The benzoic acid solution, flavour and colour were diluted with some of the water and added, with stirring. Sufficient water was then added to produce the required volume.
.., _ .. ~ . . . .. . . .
.
Claims (2)
1. A process for preparing a compound of formula where R1, R2 and R3 independently represent hydrogen, halogen or C1-4haloalkyl, R6 is C1-6alkyl, C3-7cycloalkyl or C3-7cycloalkylC1-4alkyl, and Q i8 -OH or -NH2,which comprises ring closing a compound of formula where Z is CN, COOH or CO2R12, R12 being a C1-4alkyl group.
2. A compound of formula where R1, R2 and R3 independently represent hydrogen, halogen or C1-4 haloalkyl, R6 is C1-6 alkyl, C3-7 cycloalkyl or C3-7 cycloalkyl C1-4 alkyl, and Q is -OH or -NH2,when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000433655A CA1164457A (en) | 1979-10-16 | 1983-07-29 | Benzodiazepine compounds and their use as pharmaceuticals |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7935846 | 1979-10-16 | ||
| GB7935846 | 1979-10-16 | ||
| CA000362328A CA1159056A (en) | 1979-10-16 | 1980-10-14 | Benzodiazepine compounds and their use as pharmaceuticals |
| CA000433655A CA1164457A (en) | 1979-10-16 | 1983-07-29 | Benzodiazepine compounds and their use as pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1164457A true CA1164457A (en) | 1984-03-27 |
Family
ID=27166848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000433655A Expired CA1164457A (en) | 1979-10-16 | 1983-07-29 | Benzodiazepine compounds and their use as pharmaceuticals |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1164457A (en) |
-
1983
- 1983-07-29 CA CA000433655A patent/CA1164457A/en not_active Expired
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