GB2142332A - Spirosuccinimide derivatives - Google Patents
Spirosuccinimide derivatives Download PDFInfo
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- GB2142332A GB2142332A GB08416172A GB8416172A GB2142332A GB 2142332 A GB2142332 A GB 2142332A GB 08416172 A GB08416172 A GB 08416172A GB 8416172 A GB8416172 A GB 8416172A GB 2142332 A GB2142332 A GB 2142332A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Abstract
Compounds having the formula (I) wherein A, R2, R3, R4, R5, X1, X2, m and n have the meaning given in claim 1, production thereof and drugs containing said compounds.
Description
SPECIFICATION
Spirosuccinimide derivatives
This invention relates to spirosuccinimides.
The present invention provides a compound of formula I
wherein A is
R, is (C, 6)alkyl, (C, 6)alkyl substituted by 1 to 6 halogens of atomic number from 9 to 35, (C36)alkenyl or-alkinyl, wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C3-7)cycloalkyl(C1-2)alkyl, (C3-7)cycloalkyl(C1-2)alkyl substituted by hydroxy, (C, 4)alkoxy or (C2-5)alkanoyl, benzyl, tetrahydrobenzocycloheptenyl or a group of formula -(CH2),-X wherein r is 1, 2 or 3 or alternatively also 0 when A is
and
X is hydroxy, mercapto, amino, (C1 4)alkoxy, phenoxy, benzoxy, (C, 4)alkylthio, phenylthio, benzylthio, (C1Jalkylamino,phenylamino, benzylamino, cyano,formyl, carbamoyl,carbamoyl mono- or independently di-substituted by phenyl or (C1 4)alkyl,
sulfamoyl, sulfamoyl mono- or independently di-substituted by phenyl or (C1 4)alkyl, guanyl,
(C25)alkanoyl, (C25)alkanoyl independently substituted by 1 to 3 halogen atoms of atomic number from 9 to 35 or 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N-(C, 4)alkyl dihydronicotinoyl, alkoxycarbonyl with 2 to 5 carbon atoms, benzoxycarbonyl, (C1-4)alkoxyoxalyi, (C1 4)alkanoyloxy or benzoyloxy,
R2 is hydrogen, (C, 6)alkyl, (C1-6alkyl substituted by 1 to 6 halogen atoms of atomic number of 9 to 35, hydroxy(C1 4)alkyl, (C, 4)alkoxy(C, 4)alkyl, (C, 4)mercaptoalkyl, (C1-4)alkylthio(C1- 4)al- kyl, amino(C, 4)alkyl, mono- or independently di(C, 4)aikylamino(C, -4)alkyl, (36)alkenyl or alkinyl wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C37cycloalkyl (C, 2)alkyl, phenyl or benzyl,
R3 is hydrogen, (C1-4)alkyl, benzyl or benzyl substituted by halogen of atomic number of from 9 to 35 or methoxy,
R4 and R5 independently are hydrogen or (C1-4)alkyl,
X, and X2 are independently oxygen or sulphur,
m and n independently are 1,2, 3 or 4 with the proviso that m + n is not more than 6 with the proviso that X, and X2 are not both oxygen when m and n are each 2,
A is
wherein R, is unsubstituted (C, 6)alkyl, chloropropyl, hydroxypropyl, allyl,benzyl, ethoxycarbonyl, benzoylalkyl and R2 is hydrogen, unsubstituted (Cl 6)alkyl, allyi, phenyl or benzyl,
or an acid addition salt thereof.
As described hereinafter reference to a particular formula and definitions relating thereto implies reference also to any provisos in the definitions.
Any alkyl, alkoxy or alkylthio group preferably has 1 or 2 carbon atoms and especially 1 carbon atom. Halogen is preferably fluorine or chlorine. Where a group is substituted it may be poly substituted, preferably up to 3 substituents, unless stated otherwise.
R, is for example hydrogen, methyl, ethyl substituted by halogen, cyclopropylmethyl or cyano.
R2 is preferably ethyl m and n are preferably 2 and 2 respectively or 3 and 1 respectively.
Preferred compounds are compounds of formula I wherein A is as defined above and R, is (C, 4)alkyl, (C, 4)alkyl substituted by 1 to 6 halogen atoms of atomic number from 9 to 35, cyclopropylmethyl, (C37)cycloalkyI, cyano, cyanomethyl or formyl, R2 is hydrogen, (C, 4)alkyl, (C, 4)alkyl substituted by 1 to 6 halogen atoms of atomic number from 9 to 35, or (C3 7)cycloalkyl, R3, R4 and F5 are each hydrogen, X, and X2 are independently oxygen or sulphur, m and n are each 2,with the provisos that (i) when A is
is other than cyano or formyl, and (ii) X, and X2 are not both oxygen when A is
wherein R, is unsubstituted alkyl or chloropropyl and R2 is hydrogen or unsubstituted alkyl, or an acid addition salt thereof.
The present invention also provides a process for the production of a compound of formula I or an acid addition salt thereof, which comprises
(a) for the production of a compound of formula la
wherein R, 5, X1, X2, m and n are as defined above, or an acid addition salt thereof, oxidizing an appropriate compound of of formula Il
wherein R, 5, X1, X2, m and n are as defined above, or an acid addition salt thereof,
(b) for the production of a compound of formula lb
wherein R' is hydrogen or R, as defined above, and F25, X1, X2, m and n are as defined above with the provisos thereto and the further proviso that both X, and X2 are not oxygen,
or an acid addition salt thereof,
replacing at least one oxo group by a thio group in an appropriate compound of formula Ill
wherein R', R5, m and n are as defined above or an acid addition salt thereof,
(c) - for the production of a compound of formula
wherein F25, m an n are as defined above, and R;; is hydrogen, (C1-6)alkyl,(C1-6)alkyl substituted
by 1-6 halogens of atomic number of from 9 to 35, (C36)alkenyl or alkinyl, wherein the
multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C3-7)cycloalkyl(C1-2)alkyl, (C3-7)cycloalkyl(C1-2)alkyl substituted by hydroxy, (C, 4)alkoxy or (C25)alkanoyl, benzyl, tetrahydrobenzocycloheptenyl,
with the proviso that m and n are not both 2 when R; ; is hydrogen, unsubstituted (C1-6)alkyl,hydroxypropyl,chloropropyl, allyl or benzyl and R2 is hydrogen, (C, 6)alkyl, allyl, phenyl or benzyl,
or an acid addition salt thereof,
cyclising the product obtainable by condensing a compound of formula IV
wherein R1a, F35, m and n are as defined above with respect to formula Ic, and R' and R" are independently leaving groups, with an appropriate compound of formula V
R2-NH2 V
wherein R2 is as defined above with respect to formula Ic, (d) for the production of a compound of formula Id
wherein F25, m and n are as defined above and Rb is as defined above for R, with the proviso that m and n are not both 2 when Rb is unsubstituted (C, 6)alkyl, hydroxypropyl, chloropropyl, allyl, benzyl ethoxycarbonyl or benzoylalkyl and R2 is hydrogen, unsubstituted(C16)aIkyl, allyl, phenyl or benzyl,
or an acid addition salt thereof,
introducing a group of formula Rb into a compound of formula VI
wherein F25, m and n are as defined above with respect to formula Id, and recovering the compound of formula I or an acid addition salt thereof.
Process (a) may be effected in conventional manner for the production of N-oxides using e.g.
oxidising agents. Examples of oxidising agents include hydrogen peroxide or organic peracids such as chloroperbenzoic acid.
Process (b) is conveniently carried out using a conventional sulphur-containing agents used for analogous reactions, e.g. P4S,o or a 2,4-dithiooxocyclo di-À5-phosphathiane e.g. the compound of formula
also called Lawesson Reagent.
The reaction may be effected in an inert solvent, e.g. at temperatures from about 50 and 1 50 C. Mixtures of compounds of formula lb may be obtained e.g. compounds of formula Ib wherein
(i) X1 and X2 are both sulphur
(ii) X, is sulphur and X2 is oxygen
(iii) X, is oxygen and X1 is sulphur.
The compounds may be separated in conventional manner, e.g. by chromatography.
Process (c) may be effected in conventional manner for analogous cyclisations. The reaction is conveniently effected by warming to a high temperature, e.g. from about 1 50 to about 250 C, if desired in an inert solvent.
The reaction may be effected if desired in a closed vessel e.g. an autoclave. R' and R" may be for example hydroxy, (C, 4)alkoxy or amino.
Process (d) may be effected in conventional manner for the preparation of tertiary amines, e.g.
by reaction with a compound of formula Rb-Y wherein Y is a leaving group, e.g. halogen or an organic sulphonic acid radical.
The compounds of formula I and their acid addition salts may be isolated and purified in conventional manner. The compounds of formula I may be converted into their acid addition salts in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric acid, maleic acid and methane-sulphonic acid.
Starting materials of formula IV may for example be produced by reacting a compound of formula VII
wherein Rt R3, R4, R,, m and n are as defined above with respect to formula IV, and Rx and Ry are independently cyano or lower alkoxycarbonyl, hydrolysed in acid conditions, decarboxylated and if desired treated with an alkanol, or amine or otherwise converted into another compound of formula IV.
Compounds of formula VII wherein R3 is other than hydrogen may be obtained by appropriately alkylating a compound of formula VIII
wher.ein F1, R4, R5, Rx, Fy, m and n are as defined above, e.g. with an alkyl halide.
A compound of formula VIII may for example be produced by treating a compound of formula
IX
with for example HCN in conventional manner.
A compound of formula IX may for example be produced by reacting a compound of formula
X
and an appropriate compound of formula Xl
in conventional manner.
The invention also provides groups of compounds comprising:
(a) compounds of formula Ill as defined above or an acid addition salt thereof
(b) compounds of formula Ib as defined above or an acid addition salt thereof
(c) compounds of formula la wherein R, is as defined above and when it contains the group X1, this is hydroxy, alkoxy, phenoxy, formyl, optionally substituted alkanoyl, benzoyl, cinnamoyl, alkoxycarbonyl, benzoxycarbonyl, alkanoyloxy or benzoyloxy as defined above, and R2 is hydrogen, alkyl, optionally substituted by halogen, alkoxyalkyl, hydroxyalkyl, alkenyl or alkinyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl as defined above, or an acid addition salt thereof.
Insofar as the preparation of the starting materials is not particularly described these are known or may be prepared in conventional manner.
Furthermore we have found that the compounds of formula A
wherein X, and X2 are each hydrogen, m and n are each 2,
A is HN
wherein R, is unsubstituted (C, 6)alkyl, hydroxypropyl, chloropropyl, allyl, benyl, ethoxycarbonyl or benzoylalkyl, R2 is hydrogen, unsubstituted (C, 6), alkyl, allyl, phenyl or benzyl and acid addition salt thereof are particularly indicated for use as pharmaceuticals. These compounds are in general known. Any compound which is not specifically known may be made in analogous manner to that described above.
Compounds of formula A wherein R1 is hydroxypropyl, chloropropyl or ethoxycarbonyl have not been previously disclosed as having pharmacological activity. The compound of formula
A wherein A is
R2 is ethyl, F2, R3 and R4 are each hydrogen,
X, and X2 are each oxygen and m and n each 2 has been shown to be clinically useful as described in earlier filed copending patent applications. The remaining compounds have been in general disclosed as having pharmacological activity, e.g. cholinergic or analgesic activity, e.g.
in German Patent 1,211,646 and E. Jucker et al, Arch. Pharm. (1 961), 294, 210-220, and
Helv.Chem.Acta (1966), 49, 1135-45.
We have now found that these compounds are useful for the treatment of senile dementia,
Alzheimer's disease, Huntington's Chorea, tardive diskinsia, hyperkinesia and mania as indicated in activity in tests mentioned below.
The compounds of formula I and A and their acid addition salts, hereinafter referred to as compounds of the invention, exhibit pharmacologically activity and are therefore indicated for use as pharmaceuticals, e.g. for therapy.
In particular the compounds show activity in the following tests:
(i) in the observation test in the mouse the compounds at doses from 1 to 300 mg/kg p.o.
provoke a prolongation of the wake phase and an increased reactivity to external stimuli,
(ii) in the sleep/wake cycle test in chronically implanted rats the compounds at doses from about 1 to about 500 mg/kg p.o. increase the REM sleep phase, and
(iii) in the carbon-14 deoxyglucose rat test [according to the principles of L.Sokoloff, Journal of Cerebral Blood Flow and Metabolism 1981, 1, 7-36, H.E. Savaki et al., Brain Research
1982, 233, 347 and J.McCulloch et al.,Journal of Cerebral Blood Flow and Metabolism 1981,
1, 133-1361, the compounds at doses from about 1 to 300 mg/kg increase the carbon-14 deoxyglucose uptake in particular areas of the brain, particularly the limbic system.
The compounds of the invention are therefore indicated for use for the treatment -of senile dementia, Alzheimer's disease, Huntington's chorea, tardive diskinesia, hyperkinesia, and mania.
An indicated total daily dosage is in the range from about 1 to about 100 mg of the compound, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing for example from about 0.2 to about 50 mg of the compound or in sustained release form.
The example 2 title compound is the preferred compound. The sensile dementia and
Alzheimer's disease indications are the preferred indications.
Appropriate unit doses for oral administration contain for example about 0.5 to about 15 mg of the compounds, e.g. from 1- to 10 mg. Appropriate doses for parenteral administration contain for example about 0.2 to about 30 mg of the compounds, e.g. from 0.3 to 10 mg.
The compounds of the invention may be administered in free base form or as a pharmaceutically acceptable acid addition salt. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free forms.
The present invention also provides a pharmaceutical composition comprising a composition of the invention in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
The pharmaceutical compositions may be formulated in conventional manner and contain a compound of the invention alone or in admixture with a pharmaceutical carrier or diluent. Oral pharmaceutical compositions may be in the form of, for example, tablets, dispersible powders, granulates, capsules, sirups, suspensions, solutions or elixiers. Liquid forms may contain for example from about 0.1 to about 5 mg/ml, e.g. 0.5 to 2 mg/ml of a compound. Parenteral pharmaceutical forms may be for example solutions or suspensions, e.g. sterile injectable aqueous solutions. Rectal pharmaceutical compositions may be in the form of, for example, suppositories.
Oral pharmaceutical compositions may contain excipients such as sweetening agents, aromas, dyes, and conserving agents to provide an elegant and palatable preparation. Tablets may contain conventional pharmaceutical excipients e.g. inert diluents, e.g. calcium carbonate and lactose, dispersing agents like starch or alginic acid, binding agents such as starch, polyvinylpyrrolidone, gelatin, lubricating agents such as magnesium stearate, stearic acid and talc.
The tablets may be coated in conventional manner to delay disintegration and resorption in the gastrointestinal tract and thereby to prolong activity.
Suspensions, sirups and elixirs may contain the conventional excipients, e.g. suspending agents like methyl cellulose, tragacanth and sodium alginate, wetting agents such as lecithin,
polyoxyethylene stearate, and polyoxyethylene sorbitan monooleate and conserving agents such
as ethyl parahydroxy benzoate. Capsules may contain the compound mixed for example with an
solid diluent such as lactose, starch and a lubricating agent such as magnesium stearate.
The pharmaceutical compositions may contain up to 90% by weight of the compound as
active agent.
Preferred compositions are solid dosage forms, e.g. tablets or capsules.
Representative formulations are as follows: Capsules Constituent Weight
Compound of the invention,e.g 2-ethyl-8-cyclopropylmethyl-2,8diazaspiro(4,5)decan-1,3-dione 1 mg -Lactose 133.5 mg
Corn starch 92 mg
Silica (e.g.Aerosil 200 - Registered Trademark) 1.2 mg
Magnesium stearate 2.3 mg
230 mg
The constituents are mixed and filled into capsules.
Ampoules Constituent Weight
Compound of the invention, e.g.
2,8-dimethyl -2,8- diazaspiro(4,5)decan-l,3-dione 10 mg
Sodium chloride 8 mg
Water for injectable solutions qu.s.bis 1 ml
The ampoules were filled with 1 ml solution, closed and sterilized at 121 =C for 15 minutes.
Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula B
wherein A is
R, is (C, 6)alkyl, (C1 6)alkyl substituted by 1 to 6 halogens of atomic number from 9 to 35, (C36)alkenyl or-alkinyl, wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C37)cycloalkyl(Cl 2)alkyl, (C37)cycloalkyl(C12)aíkyl substituted by hydroxy, (C1 4)alkoxy or (C25)alkanoyl, benzyl, tetrahydrobenzocycloheptenyl or a group of formula -(CH2),-X wherein r is 1, 2 or 3 or alternatively also 0 when A is
and
X is hydroxy, mercapto, amino, (C, 4)alkoxy, phenoxy, benzoxy, (C, 4)alkylthio, phenylthio, benzylthio, (C1-4)alkylamino, phenylamino, benzylamino, cyano, formyl, carbamoyl, carbamoyl mono- or independently di-substituted by phenyl or (C,4)alkyl,
sulfamoyl, sulfamoyl mono- or independently di-substituted by phenyl or (C14)alkyl, guanyl,
(C25)alkanoyl, (C25)alkanoyl independently substituted by 1 to 3 halogen atoms of atomic number from 9 to 35 or 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N (C, 4)alkyl dihydronicotinoyl, alkoxycarbonyl with 2 to 5 carbon atoms, benzoxycarbonyl, (C1 4)alkoxyoxalyl, (C, 4)alkanoyloxy or benzoyloxy,
R2 is hydrogen, (C, 6)alkyl, (C, 6)alkyl substituted by 1 to 6 halogen atoms of atomic number of 9 to 35, hydroxy(Ct 4)alkyl, (C1-4)alkoxy(C1-4)alkyl, (C1 4)mercaptoalkyl, (C1 4)alkylthio(C14)al- kyl, amino(C,4)alkyl, mono- or independently di-(C, 4)alkylamino(C,4)alkyl, (C36)alkenyl or alkinyl wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C37)cycloalkyl(C12)alkyl, phenyl or benzyl,
R3 is hydrogen, (C, 4)alkyl, benzyl or benzyl substituted by halogen of atomic number of from 9 to 35 or methoxy,
R4 and R5 independently are hydrogen or (C, 4)alkyl, X1 and X2 are independently oxygen or sulphur,
m and n independently are 1,2, 3 or 4 with the proviso that m + n is not more than 6 wherein A is other than
when R2 is ethyl, R3, R4 and R5 are each hydrogen, X1 and X2 are each hydrogen, and m and n each 2 or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier or-diluent, preferably a pharmaceutical composition comprising a compound of formula B as defined with the proviso that X, and X2 are not each oxygen, when m and n are each 2,
A is
wherein R, is unsubstituted alkyl, allyl, benzyl or benzoylalkyl, F1 is hydrogen, unsubstituted alkyl, allyl, phenyl or benzyl or a pharmaceutically acceptable acid addition salt thereof.
In the following Examples all temperatures are uncorrected and are in degrees Centigrade.
EXAMPLE 1: 2-ethyl-8-cyclopropylmethyl-2, 8-diazaspiro-(4, 5)decan- 1, 3-dione-8-oxide (process a)
A solution of 15.6'9 2-ethyl-8-cyclopropylmethyl-2,8-diazaspiro(4,5)decan-1,3-dione (produced e.g. according to Example 27) in 100 ml chloroform at O to 58 is treated over 30 minutes with 37.8 9 m-chloroperbenzoic acid in 300 ml chloroform. The yellow solution is stirred for 20 hours at room temperature, treated with 600 ml chloroform and shaken with 200 ml 5N potassium carbonate solution. The aqueous phase is separated and extracted twice with chloroform. The combined aqueous phases are washed with aqueous saturated sodium chloride solution, dried over sodium sulphate and concentrated to a brown oil.Chromatography on a tenfold amount of silicagel using methylene chloride/10% methanol/1% ammonia yields a yellow oil, which is converted into the crystalline hydrochloride of the title compound. Mpt.
(C2HsOH/ether) 179-180 .
In analogous manner to example 1 the following compounds are made.
EXAMPLE 2:
2-ethyl-8-methyl-2, 8-diazaspiro(4, 5)decan- 1, 3-dione-8-oxide
Mpt. of hydrochloride: 238-239".
EXAMPLE 3:
2-(2-methoxyethyl)-8-methyl-2, 8-diazaspiro(4, 5)decan- 1, 3-dione-8-oxide
Mpt. of hydrochloride: 204-206".
EXAMPLE 4:
2-etyl-8-methyl-2, 8-diazaspiro(4, 5)decan- 1, 3-dithione, 2-ethyl-8-methyl-2, 8-diazaspiro-(4, 5)de
can- 1-thion-3-one and 2-ethyl-8-methyl-2, 8-diazaspiro(4, 5)decan- 1-on-3-thione (process b)
8.7 9 2-ethyl-8-methyl-2,8.diazaspiro-(4,5)decan-1,3-dione and 12.1 9 Lawesson Reagent
(see above) in 100 ml toluene are boiled in 100 ml toluene for 20 hours. The solvent is then
evaporated off and the residue taken up in methylene chloride. The organic phase is washed
with 2N sodium carbonate solution and ice water, dried over sodium sulphate, filtered and
concentrated. The yellow residue is chromatographed on a 100 fold amount of silicagel using as
eluant methylene chloride containing 2% methanol and 0.2% ammonia.The title compounds
are eluted in the following order in a rate of 2:1:1 and characterised as the hydrochloride salt: 2-ethyl-8-methyl-2,8-diazaspiro-(4,5)decan-1 , 3-dithione hydrochloride: M pt. 257-260".
2-ethyl-8-methyl-2, 8-diazaspiro-(4, 5)decan-1 -thion-3-one hydrochloride: Mpt. 307-31 08.
2-ethyl-8-methyl-2, 8-diazaspiro-(4, 5)decan-1 -on-3-thione hydrochloride: Mpt. 214-215 .
EXAMPLE 5: 2-ethyl-2, 7-diazaspiro(4, 5)decan- 1, 3-dione (process c)
10 9 [3-ethoxycarbonyl-3-piperidyl]-acetic acid ethyl ester and 200 ml anhydrous ethylamine,
are treated at 180 for 12 hours in a steel autoclave. The excess amine is removed by a water
pump vacuum at 40"C. The residue is chromatographed in a 25 fold amount of silicagel using
as eluant methylene chloride containing 5% methanol/ 1 % ammonia. The title compound is
crystallised as the hydrogen maleate. Mpt. 177-180".
The starting material is produced as follows:
(a) 1 -ethoxycarbonyl-3-piperidylidene-malonic acid diethyl ester
100 g N-ethoxycarbonyl-piperidin-3-one and then 98.6 g malonic acid diethyl ester are added
to a well stirred suspension of 3.5 litres tetrahydrofuran and 1 35 ml titanium tetrachloride at 0'.
1 85 ml pyridine are added over 30 minutes. The reaction mixture is stirred vigorously for 20
hours at room temperature.
The solvent is removed by a rotatory evaporator. The residue is treated with ice-water,
dissolved in ether, and washed first with acid (2N HCI) and then sodium bicarbonate solution
(10%). The ether solution is dried with sodium sulphate and treated with active charcoal. The
ether is removed to give an orange brown syrup which is purified by quick chromatography
through silicagel using ether as eluant. The resultant yellow oil of the heading compound is
used -in the next step as such.
(b) 1-ethoxycarbonyl-3-cyano-3-piperidyl-malonic acid diethyl ester
50 g of the product obtained from step (a) is dissolved in 350 ml ethanol and treated with
9.6 g acetic acid. A solution of 1 5.7 g sodium cyanide in 95 ml water is added dropwise at room temperature. The mixture is stirred for 90 minutes, treated with 2N HCI solution, and
concentrated on a rotary evaporator. The residue is extracted with ether. The organic phase is
washed neutral and dried. The ether is removed to give a yellow oil of the heading compound
which is used in the next stage as such.
(c) (3-ethoxycarbonyl-3-piperidyl),-acetic acid ethyl ester
50 9 of the product obtained in step (b) in 1 60 ml ethanol/water (1:2) at 60 are treated
over 45 minutes with 230 ml concentrated hydrochloric acid. The mixture is boiled for 20 hours
under reflux and then concentrated (after hydrolysis and decarboxylation) in a vacuum at 60 (bath temperature). The residue is used for the next stage as such or esterified with 65 ml
ethanolic hydrochloric acid for 5 hours under reflux. After the reaction the solvent is removed at 60 (bath temperature). To work up, the residue is taken up in methylene chloride that contains
5% methanol, extracted twice with 2N sodium carbonate, washed neutral, dried over sodium
sulphate, filtered and evaporated on a rotary evaporator. An orange oil of the ester heading
compound is obtained.
In analogous manner to Example 5 the following compounds wherein A is
(designated H hereinafter) or
and X, and X2 are both oxygen are obtained:
Ex R1 or H R2 R3 9 R5 m n Salt mpt. form 6 > CH2- -CH2-CH3 H H H 2 2 hml 163-165' 7 CH3- -CH2-CH3 H H H 3 1 ch 273-276' 8 CH3- H H H H 2 2 hml 171-173 9 CH3- O H H H 2 2 hml 162-163 /CH3 10 CH3- -(CHE)3-N: H H H 2 2 dch 284 CH3 11 O -CH2-CH3 H H H 2 2 hml 206-207' 12 > CH2- -CH3 H H H 2 2 hml 187-189 13 CHXC-CH2- -CH2-CH3 H H H 2 2 b 102-104'
Ei. R1 or H R2 R3 R4 R5 rn n Salt Mpt. form 114 X -CH2-CH3 H H H 2 2 ch 268' 15 CH3- -CH2-CH2-OCH3 H H H 2 2 rns 201-201 16 CH3- -CH2-CH2-OH H H H 2 2 hb 281-282' 17 9 CH2- -CH2-CH3 H H H 2 2 ch 191-193' OH 18 H -CH2-CF3 H H H 2 2 ch 217-220' 19 CH3 -CH2-CF3 H H H 2 2 ch 269-272' 20 -CH2-CH3 -CH2-CF3 H H H 2 2 ch 178-181 21 > CH2- -CH2-CF3 H H H 2 2 ch 202-205 22 CF3-CH2- -CH2-CH3 H H H 2 2 ch 191-195 23 Cl-CH2-CH2- -CH2-CH3 H H H 2 2 ch 140-142' 24 CH3- CH3- H H H 3 2 hb 199-202 25 H CH3- H H H 3 2 nds 293-295 26 O 2- -CH2-CF3 H H H 2 2 b 123-126'
*-b = base ms = methanesulfonate
ch = hydrochloride hml = hydrogen maleate
dch = dihydrochloride nds = naphthaleneEbis][base] hb = hydrobromide disulfonateEl,8] EXAMPLE 27: 2-ethyl-8-cyclopropylmethyl-2, 8-diazaspiro-(4, 5)decan- 1, 3-dione (process d)
A suspension of 23.3 g 2-ethyl-2,8-diazaspiro(4,5)decan-1 ,3-dione, 20.6 g cyclopropylmethylbromide, 27.6 g potassium carbonate and 18.3 g potassium iodide in 500 ml dimethylformamide are stirred for 2 hours at 80 . The mixture is concentrated and the residue partitioned between water and methylene chloride. The aqueous phase is separated off and extracted twice with methylene chloride. The combined organic phases are washed with a little water, dried over sodium sulphate and concentrated to a yellow oil.Chromatography on a 20fold amount of silicagel with methylene chloride containing 2% methanol as eluant gives the title compound as a yellow oil which is converted into the hydrogen maleate. Mpt. 163-5".
In analogous manner to Example 27, the compounds of examples 6-17, 19-24 and 26 as well as the following compounds of formula i wherein A is
and Xl and X2 are both oxygen are produced:
Ex. Rl R2 R3 R4 R5 m n Salt Mpt.
form 28 CH2CHR N-CO-CH2' -CH2-CH3 H H H 2 2 hml 155-1570 29 OHC- -CH2-CH3 H H H 2 2 n 142-1440 30 NC- -CH2-CH3 H H H 2 2 n 125-126
Ex. R1 R2 R3 R4 Rs m n Salt Mpt. form 31 NC-CH2- -CH3 H H H 2 2 ch 212-214 32 C2H50-CO-CH2- -CH2-CH3 H H H 2 2 b 79-80 33 4 N-CH2-CO- -CH2-CH3 H H H 2 2 n 194-196 0 34 OHC- -CH3 H H H 2 2 n 137-138 35 5 CH=CH-CO- -CH2-CH3 H H H 2 2 n 88-92 36 H2N-CO- -CH2-CH3 H H H 2 2 n 208-209 37 C2Hs-O-CO- -CH2-CH3 H H H 2 2 n 84-85 38 O NH-CO- -CH3 H H H 2 2 n 210-211' CH3 39 / N-S02- -CH2-CH3 H H H 2 2 n 156-157' /NSO2 CH3 CO 40 S -CH2-CH3 H H H 2 2 n 122-123 N CO 41 W -CH2-CH3 H H H 2 2 b 130-137' N I CH3.
Ex. R1 R2 R3 R4 4 m n Salt Mpt. form NH 42 % C- -CH2-CH3 H H H 2 2 ch 216-217 H2Nw 43 Ho-CH2-CH2- -CH2-CH3 H H H 2 2 ch 215-218' 44 C1-CH2-CO- -CH2-CH3 H H H 2 2 n 163-166' 45 (CH3)3C-O-CO- -CH2-CH3 H H H 2 2 n 101-104 46 CH3-CO -CH2-CH3 H H H 2 2 n 154-157' 47 (CH3)3C-CO- -CH2-CH3 H H H 2 2 n 109-112' 48 CH30-CO- -CH2-CH3 H H H 2 2 n 117-120 49 CH3-S-CH2- -CH2-CH3 H H H 2 2 ch 168-171' N 50 t t -CN2-CH3 H H H 2 2 n 210-211' N
* b = base
n = neutral
ch = hydrochloride
hml = hydrogen maleate
Claims (69)
1. A process for the production of a compound of formula I
wherein A is
R, is (C, 6)alkyl, (C, 6)alkyl substituted 1 to 6 halogens of atomic number from 9 to 35, (C36)alkenyl or-alkinyl, wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C3-7)cycloalkyl(C, 2)alkyl, (C3-7)cycloalkyl(C1-2)alkyl substituted by hydroxy, (C, 4)alkoxy or (C2-5)alkanoyl, benzyl, tetrahydrobenzocycloheptenyl or a group of formula -(CH,)r-X wherein r is 1, 2 or 3 or alternatively also 0 when A is
and
X is hydroxy, mercapto, amino, (Ct 4)alkoxy, phenoxy, benzoxy, (C, 4)alkylthio, phenylthio, benzylthio, (C1-4)alkylamino,phenylamino,benzylamino, cyano, formyl, carbamoyl, carbamoyl mono- or independently di-substituted by phenyl or (C, 4)alkyl,
sulfamoyl, sulfamoyl mono- or independently di-substituted by phenyl or (C1 4)alkyi, guanyl,
(C2-5)alkanoyl, (C25)alkanoyl independently substituted by 1 to 3 halogen atoms of atomic number from 9 to 35 or 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N (C,4)alkyI dihydronicotinoyl, alkoxycarbonyl with 2 to 5 carbon atoms, benzoxycarbonyl, (C1-4)alkoxyoxalyl, (C1 4)alkanoyloxy or benzoyloxy,
R2 is hydrogen, (C1 6)alkyl, (C1-6)alkyl substituted by 1 to 6 halogen atoms of atomic number of 9 to 35, hydrnxy(C14)alkyl, (C1 (C1-4)alkoxy(C1-4)alkyl, (C1 4)mercaptoalkyl, (C14)alkylthio(C1 4)al- kyl, amino(C1 4)alkyl, mono- or independently di-(C1-4)alkylamino(C1-4)alkyl, (C36)alkenyl or alkinyl wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C3-7)cycloalkyl(C1-2)alkyl, phenyl or benzyl,
R3 is hydrogen, (C14)alkyl, benzyl or benzyl substituted by halogen of atomic number of from 9 to 35 or methoxy,
R4 and Fs independently are hydrogen or (C1 4)alkyl, X1 and X2 are independently oxygen or sulphur,
m and n independently are 1,2, 3 or 4 with the proviso that m + n is not more than 6 with the proviso that X1 and X2 are not both oxygen when m and n are each 2,
A is
wherein R1 is unsubstituted (C1 6)alkyl, chloropropyl, hydroxypropyl, allyl, benzyl, ethoxycarbonyl, benzoylalkyl and R2 is hydrogen, unsubstituted (C1 6)alkyl, allyl, phenyl,. or benzyl, or an acid addition salt thereof, which comprises (a) for the production of a compound of formula la
wherein R1-5, X1, X2, m and n are as defined above, or an acid addition salt thereof, oxidizing an appropriate compound of formula II
wherein R1 s, X1, X2, m and n are as defined above, or an acid addition salt thereof,
(b) for the production of a compound of formula Ib
wherein R' is hydrogen or R, as defined above, and F25, X1, X2, m and n are as defined above with the provisos thereto and the further proviso that both X1 and X2 are not oxygen,
or an acid addition salt thereof,
replacing at least one oxo group by a thio group in an appropriate compound of formula Ill
wherein R', R5, m and n are as defined above or an acid addition salt thereof,
(c) for the production of a compound of formula Ic
wherein R25, m and n are as defined above, and R1 is hydrogen, (C1-6)alkyl,(C1-6)alkyl substituted by 1 to 6 halogens of atomic number of from 9 to 35, (C36)alkenyl or-alkinyl, wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C37)cycloalkyl (C, 2)alkyl, (C37)cycloalkyl(C1 2)alkyl substituted by hydroxy, (C, 4)alkaxy or (C25)alkanoyl, ben- zyl, or tetrahydrobenzocycloheptenyl,
with the proviso that m and n are not both 2 when R1 is hydrogen, unsubstituted (C1-6)alkyl,hydroxypropyl,chloropropyl, allyl or benzyl and R2 is hydrogen, (C,6)alkyl, allyl, phenyl or benzyl,
or an acid addition salt thereof,
cyclising the product obtainable by condensing a compound of formula IV
wherein F?, R35, m and n are as defined above with respect to formula Ic, and R' and R" are independently leaving groups, with an appropriate compound of formula V
R2-NH2 V
wherein R2 is as defined above with respect to formula Ic,
(d) for the production of a compound of formula Id
wherein R25, m and n are as defined above and Rb is as defined above for R1 with the proviso that m and n are not both 2 when Rb is unsubstituted (C, 6)alkyl, hydroxypropyl, chloropropyl, allyl, benzyl,ethoxycarbonyl or benzoylalkyl and R2 is hydrogen, unsubstituted (C1 6)alkyl, allyl, phenyl or benzyl,
or an acid addition salt thereof,
introducing a group of formula R1 into a compound of formula VI
wherein R25, m and n are as defined above with respect to formula Id, and recovering the compound of formula I or an acid addition salt thereof.
2. A. process for the production of a compound of formula I or an acid addition salt thereof substantially as hereinbefore described.
3. A compound of formula I or an acid addition salt thereof whenever produced by the process of claim 1 or 2.
4. A compound of formula I or an acid addition salt thereof as defined in claim 1.
5. A compound of claim 4 wherein A is as defined in claim 1, R1 is (C1 4)alkyl, (C, 4)alkyl substituted by 1 to 6 halogen atoms of atomic number from 9 to 35, cyclopropylmethyl, (C37)cycloalkyl, cyano, cyanomethyl or formyl, R2 is hydrogen, (C, 4)alkyl, (C, 4)alkyl substituted by 1 to 6 halogen atoms of atomic number from 9 to 35, or (C37)cycíoalkyl, R3, R4 and R5 are each hydrogen, X, and X2 are independently oxygen or sulphur, m and n are each 2,
with the provisos that (i) when A is
R, is other than cyano or formyl, and (ii) X, and X2 are not both oxygen when A is
wherein R, is unsubstituted alkyl orchloropropyl and R2 is hydrogen or unsubstituted alkyl, or an acid addition salt thereof.
6. A compound of claim 4 which is 2-ethyl-8-cyclopropylmethyl-2,8-diazaspiro(4,5)-decan1,3-dione-8-oxide or an acid addition salt thereof.
7. A compound of claim 4 which is 2-ethyl-8-methyl-2,8-diazaspiro(4,5)decan-1 ,3-dione-8- oxide or an acid addition salt thereof.
8. A compound of claim 4 which is 2-(2-methoxyethyl)-8-methyl-2,8-diazaspiro(4,5)decan- 1,3-dione-8-oxide or an acid addition salt thereof.
9. A compound of claim 4 which is 2-ethyl-8-methyl-2,8-diazaspiro-(4,5)decan-1,3-dithione or an acid addition salt thereof.
10. A compound of claim 4 which is 2-ethyl-8-methyl-2,8-diazaspiro-(4,5)decan-1-thion-3- one or an acid addition salt thereof.
11. A compound of claim 4 which is 2-ethyl-8-methyl-2,8-diazaspiro-(4,5)decan-1-one-3- thione or an acid addition salt thereof.
12. A compound of claim 4 which is 2-ethyl-2,7-diazaspiro-(4,5)decan-1 ,3-dione or an acid addition salt thereof.
1 3. A compound of claim 4 which is 2-ethyl-8-cyclopropylmethyl-2,8-diazaspiro-(4,5)decan- 1,3-dione or an acid addition salt thereof.
14. A compound of formula I wherein A is R1N
X, and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 each are hydrogen, m and n each two or an acid addition salt thereof.
15. A compound of formula I wherein A is R,l
X1 and X2 are both oxygen, R, is
CH3-, F2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m is 3, n is 1 or an acid addition salt thereof.
1 6. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
CH3, R2 is
R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
1 7. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
CH3-, R2 is
R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
18. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
CH3,
R2 is
R3, R4 and R5 are each hydrogen, m and n two or an acid addition salt thereof.
1 9. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
20. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
R2 is -CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
21. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is CHsC-CH2-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
22. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
23. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
CH3-, R2 is -CH2-CH2-OCH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
24. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
CH3-, R2 is -CH2-CH2-OH, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
25. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thp.renf
26. A compound of formula I wherein A is HN
X, and X2 are both oxygen, F2 is -CH2-CF3, r3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
27. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
CH3, R2 is -C H2-CF3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
28. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is -CH2-CH3, R2 is -CH2-CF3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
29. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
R2 is -CH2-CF3, R3, R4 and R5 are each hydrogen, m an n each two or an acid addition salt thereof.
30. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
CF3-CH2-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
31. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is Cl-CH2-CH2-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, n and n each two or an acid addition salt thereof.
32. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is CH3-, F2 is CH3-, F3, F4 and F5 are each hydrogen, m is 3, n is 2 or an acid addition salt thereof.
33. A compound of formula I wherein A is HN
and X2 are both oxygen, R2 is
CH3, R3, R4 and R5 are each hydrogen, m is 3, n is 2 or an acid addition salt thereof.
34. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
R2 is -CH2-CF3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
35. A compound of formula I wherein A is
X1 and X2 are both oxygen, are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
36. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
OHC-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
37. A compound of formula I wherein A is
X, and X2 are both oxygen, R1 is
NC-, R2 is -CH2-CH3, F3, F4 and F5 are each hydrogen, m and n each two or an acid addition Rnit thereof.
38. A compound of formula I wherein A is
X, and X2 are both oxygen, R1 is
NC-CH2-, R2 is -CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
39. A compound of formula I wherein A is
X, and X2 are both oxygen, R1 is
C2H5O-CO-CH2-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
40. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
41. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
OCH-, R2 is -CH3, R3, R4 and R5 are each hydrogen, m an n each two or an acid addition salt thereof.
42. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
43. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
H2N-CO-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
44. A compound of formula I wherein A is
X, and X2 are both oxygen, R1 is
C2H5-O-CO-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
45. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is
R2 is CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
46. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
R2 is -CH2-CH3, F3 R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
47. A compound of formula I wherein A is
X, and X2 are both oxygen, R1 is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
48. A compound of formula I wherein A is
X1 and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 R5 are each hydrogen, m and n each two or an acid addition salt thereof.
49. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
50. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
OH-CH2-CH2, R2 is -CH2-CH3, R3, R4 and R5 are both oxygen, m and n each two or an acid addition salt thereof.
51. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is Cl-CH2-CO-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
52. A compound of formula I wherein A is
X1 and X2 are both oxygen, R1 is (CH3)3C-O-CO-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
53. A compound of formula I wherein A is R1N
X, and X2 are both oxygen, R, is
CH3-CO, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
54. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is (CH3)3C-CO-, R2 is -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
55. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is CH3O-CO, R2 is -CH2-CH3, R3, R4 and F5 are each hydrogen, m and n each two or an acid addition salt thereof.
56. A compound of formula I wherein A is
X, and X2 are both oxygen, R, is
CH3-S-CH2-, R2 -CH2-CH3, R3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
57. A compound of formula I wherein A is
X, and X2 are both oxygen, Rf is
R2 is -CH2-CH3, F3, R4 and R5 are each hydrogen, m and n each two or an acid addition salt thereof.
58. A compound of any one of claims 3 to 57 or a pharmaceutically acceptable acid addition salt thereof for use as a pharmaceutical.
59. A compound of any one of claims 3 to 57 or a pharmaceutically acceptable acid addition salt thereof for use in the treatment of senile dementia, Alzheimer's disease, Huntington's chorea, tardive diskinesia or hyperkinesia, or mania.
60. A pharmaceutical composition comprising a compound of any one of claims 3 to 57 or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or diluent.
61. A pharmaceutical composition comprising a compound of formula B
wherein A is
R, is (C, 6)alkyl, (C, 6)alkyl substituted by 1 to 6 halogens of atomic number from 9 to 35, (C36)alkenyl or alkinyl, wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycoalkyl, (C37)cycloalkyl(C, 2)alkyl, (C37)cycloalkyl(C1 2)alkyl substituted by hydroxy, (C, 4)alkoxy or (C25)alkanoyl, benzyl, tetrahydrobenzocloheptenyl or a group of formula -(CH2),-X wherein r is 1, 2 or 3 or alternatively also 0 when A is
and
X is hydroxy, mercapto, amino, (C, 4)alkoxy, phenoxy, benzoxy, (C14)alkylthio, phenylthio, benzylthio, (C1-4)alkylamino.phenylamino,benzylamino, cyano, formyl, carbamoyl, carbamoyl mono- or independently di-substituted by phenyl or (C14)alkyl,
sulfamoyl, sulfamoyl mono- or independently di-substituted by phenyl or (Ct 4)alkyl, guanyl,
(C25)alkanoyl, (C25)aIkanoyI independently substituted by 1 to 3 halogen atoms of atomic number from 9 to 35 or 2-oxo-pyrrolidinyl, benzoyl, cinnamoyl, nicotinoyl, dihydronicotinoyl, N (C1 4)alkyl dihydronicotinoyl, alkoxycarbonyl with 2 to 5 carbon atoms, benzoxycarbonyl, (C1 4)alkoxyoxalyl, (C1 4)alkanoyloxy or benzoyloxy,
R2 is hydrogen, (C1 6)alkyl, (C1 6)alkyl substituted by 1 to 6 halogen atoms of atomic number of 9 to 35, hydroxy(C, 4)alkyl, (C, 4)alkoxy(C, 4)alkyl, (C, 4)mercaptoalkyl, (C, 4)alkylthio(C, 4)alkyl, amino(C, 4)alkyl, mono- or independently di-(C, 4)alkylamino(C, 4)alkyl, (C36)alkenyl or alkinyl wherein the multiple bond is not adjacent to the nitrogen atom, (C37)cycloalkyl, (C3 7)cycloalkyl(C, 2)alkyl, phenyl or benzyl,
R3 is hydrogen, (C, 4)alkyl, benzyl or benzyl substituted by halogen of atomic number of from 9 to 35 or methoxy,
R4 and R5 independently are hydrogen or (C, 4)alkyl, X, and X2 are independently oxygen or sulphur,
m and n independently are 1,2, 3 or 4 with the proviso that m + n is not more than 6 wherein A is other than
when R2 is ethyl, R3, R4 and R5 are each hydrogen,
X, and X2 are each oxygen, and m and n each 2 or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier or diluent.
62. A pharmaceutical composition comprising a compound of formula B as defined in claim 56 with the proviso that X, and X2 are not each oxygen, m and n are each 2,
A is
wherein R, is unsubstituted (C, 6)alkyl, hydroxypropyl,chloropropyl,allyl, allyl,phenyl or benzyl or a pharmaceutically acceptable acid addition salt thereof.
63. A pharmaceutical composition according to claim 59 wherein the compound is a compound of formula B wherein A, R,. R2, R3, R4, R5, X1, X2, m and n are defined as in claim 61 with the proviso that X1 and X2 are not each oxygen, when m and n are each two,
A is
wherein R, is unsubstituted alkyl, allyl, benzyl or benzoylallyl, and R2 is hydrogen, unsubstituted alkyl, allyl, phenyl or benzyl or a pharmaceutically acceptable acid addition salt thereof.
64. A pharmaceutical composition according to claim 59 wherein the compound is a compound of formula B wherein R, is hydroxypropyl, chloropropyl or ethoxy-carbonyl.
65. A compound of formula B as defined in claim 61, 62, 63 or 64 for use in the treatment of senile demantia, Alzheimer's disease, Huntington's chorea, tardive diskinesia or hyperkinesia, or mania.
66. A compound of formula IV as defined in claim 1 or a compound obtainable by reacting a compound of formula IV as defined in claim 1 and a compound of formula V as defined in claim 1.
67. Compounds of formula Ill as defined in claim 1 or an acid addition salt thereof.
68. Compounds of formula lb as defined in claim 1 or an acid addition salt thereof.
69. Compounds of formula IA wherein R, is as defined in claim 1 and when it contains the group X1 this is hydroxy, alkoxy, phenoxy, formyl, optionally substituted alkanoyl, benzoyl, cinnamoyl, alkoxycarbonyl, benzoxycarbonyl, alkanoyloxy or benzoyloxy as defined in claim 1, and R2 is hydrogen, alkyl optionally substituted by halogen, alkoxyalkyl, hydroxyalkyl,alkenyl or alkinyl,cycloalkyl,cycloalkylalkyl,phenyl or benzyl as defined in claim 1 ,or an acid addition salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH350483 | 1983-06-27 | ||
| CH350383 | 1983-06-27 | ||
| CH350583 | 1983-06-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8416172D0 GB8416172D0 (en) | 1984-08-01 |
| GB2142332A true GB2142332A (en) | 1985-01-16 |
Family
ID=27174377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08416172A Withdrawn GB2142332A (en) | 1983-06-27 | 1984-06-25 | Spirosuccinimide derivatives |
Country Status (16)
| Country | Link |
|---|---|
| AU (1) | AU2983384A (en) |
| DE (1) | DE3422411A1 (en) |
| DK (1) | DK310184A (en) |
| ES (1) | ES533735A0 (en) |
| FI (1) | FI842547A (en) |
| FR (1) | FR2549061A1 (en) |
| GB (1) | GB2142332A (en) |
| GR (1) | GR82274B (en) |
| HU (1) | HUT36793A (en) |
| IL (1) | IL72218A0 (en) |
| IT (1) | IT1199148B (en) |
| LU (1) | LU85434A1 (en) |
| NL (1) | NL8401907A (en) |
| PT (1) | PT78787B (en) |
| SE (1) | SE8403376L (en) |
| WO (1) | WO1985000171A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0273659A1 (en) * | 1986-12-27 | 1988-07-06 | Takeda Chemical Industries, Ltd. | Azaspiro compounds, their production and use |
| WO2004005293A2 (en) * | 2002-07-05 | 2004-01-15 | Targacept, Inc. | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
| WO2005023809A1 (en) * | 2003-09-10 | 2005-03-17 | Virochem Pharma Inc. | Spiro compounds and methods for the modulation of chemokine receptor activity |
| US7612056B2 (en) | 2004-04-06 | 2009-11-03 | Jenssen Pharmaceutica N.V. | Substituted diaza-spiro-[4.5]-decane derivatives and their use as neurokinin antagonists |
| US8604200B2 (en) | 2005-03-08 | 2013-12-10 | Janssen Pharmaceutica N.V. | Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists |
| US9005578B2 (en) | 2008-03-21 | 2015-04-14 | Fluoropharma, Inc. | Compounds and compositions for the detection and treatment of Alzheimer's disease and related disorders |
| US10058625B2 (en) | 2004-02-24 | 2018-08-28 | The General Hospital Corporation | Catalytic radiofluorination |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3431195A1 (en) * | 1984-08-24 | 1986-03-06 | Troponwerke GmbH & Co KG, 5000 Köln | NEW BENZODIAZEPINES, PROCESS FOR THEIR PRODUCTION AND THEIR USE |
| US5407938A (en) * | 1990-04-10 | 1995-04-18 | Israel Institute For Biological Research | Certain 1-methyl-piperidine-4-spiro-4'-(1'-3'-oxazolines) and corresponding -(1',3' thiazolines) |
| JP2800953B2 (en) * | 1990-07-06 | 1998-09-21 | 住友製薬株式会社 | New imide derivatives |
| BE1007765A5 (en) | 1994-06-27 | 1995-10-17 | Blagden Ind Plc | Total metal was open. |
| AU2206699A (en) * | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| US8257680B1 (en) | 2004-02-24 | 2012-09-04 | The General Hospital Corporation | Catalytic radiofluorination |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1211646B (en) * | 1959-03-25 | 1966-03-03 | Sandoz Ag | Process for the preparation of spirosuccinimides and their salts |
| GB936477A (en) * | 1959-03-25 | 1963-09-11 | Sandoz Ltd | Improvements in or relating to substituted succinimides |
| US3198800A (en) * | 1964-05-07 | 1965-08-03 | Sandoz Ltd | 2, 8-(para-f-4-oxo-butyl)-diazaspiro[4, 5]-decane-1, 3-diones |
| BE897058A (en) * | 1982-06-25 | 1983-12-16 | Sandoz Sa | USE OF A SPIRO-SUCCINIMIDE DERIVATIVE IN THE TREATMENT OF ALZHEIMER-TYPE DEMENTIA |
-
1984
- 1984-06-15 HU HU842326A patent/HUT36793A/en unknown
- 1984-06-15 NL NL8401907A patent/NL8401907A/en not_active Application Discontinuation
- 1984-06-16 DE DE3422411A patent/DE3422411A1/en not_active Withdrawn
- 1984-06-18 WO PCT/CH1984/000099 patent/WO1985000171A1/en unknown
- 1984-06-22 FR FR8410017A patent/FR2549061A1/en active Pending
- 1984-06-25 PT PT78787A patent/PT78787B/en unknown
- 1984-06-25 AU AU29833/84A patent/AU2983384A/en not_active Abandoned
- 1984-06-25 SE SE8403376A patent/SE8403376L/en not_active Application Discontinuation
- 1984-06-25 FI FI842547A patent/FI842547A/en not_active Application Discontinuation
- 1984-06-25 GR GR75100A patent/GR82274B/el unknown
- 1984-06-25 DK DK310184A patent/DK310184A/en not_active Application Discontinuation
- 1984-06-25 GB GB08416172A patent/GB2142332A/en not_active Withdrawn
- 1984-06-25 IL IL72218A patent/IL72218A0/en unknown
- 1984-06-26 IT IT48458/84A patent/IT1199148B/en active
- 1984-06-26 ES ES533735A patent/ES533735A0/en active Granted
- 1984-06-27 LU LU85434A patent/LU85434A1/en unknown
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0273659A1 (en) * | 1986-12-27 | 1988-07-06 | Takeda Chemical Industries, Ltd. | Azaspiro compounds, their production and use |
| US4804665A (en) * | 1986-12-27 | 1989-02-14 | Takeda Chemical Industries, Ltd. | Azaspiro compounds and their use |
| KR101052287B1 (en) * | 2002-07-05 | 2011-07-27 | 타가셉트 인코포레이티드 | N-aryl diazaspirocyclic compound, preparation method thereof, and use thereof |
| WO2004005293A2 (en) * | 2002-07-05 | 2004-01-15 | Targacept, Inc. | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
| WO2004005293A3 (en) * | 2002-07-05 | 2004-05-13 | Targacept Inc | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
| US6956042B2 (en) | 2002-07-05 | 2005-10-18 | Targacept, Inc. | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
| US7923559B2 (en) | 2002-07-05 | 2011-04-12 | Targacept, Inc. | N-aryl diazaspirocyclic compounds and methods of preparation and use thereof |
| US7291731B2 (en) | 2002-07-05 | 2007-11-06 | Targacept, Inc. | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
| EA009789B1 (en) * | 2002-07-05 | 2008-04-28 | Таргасепт, Инк. | N-aryl diazaspirocyclic compounds and methods of preparation and use thereof |
| US7375110B2 (en) | 2002-07-05 | 2008-05-20 | Targacept, Inc. | N-aryl diazaspiracyclic compounds and methods of preparation and use thereof |
| US7288548B2 (en) | 2003-09-10 | 2007-10-30 | Virochem Pharma, Inc. | Spiro compounds and methods for the modulation of chemokine receptor activity |
| WO2005023809A1 (en) * | 2003-09-10 | 2005-03-17 | Virochem Pharma Inc. | Spiro compounds and methods for the modulation of chemokine receptor activity |
| US10058625B2 (en) | 2004-02-24 | 2018-08-28 | The General Hospital Corporation | Catalytic radiofluorination |
| US10695449B2 (en) | 2004-02-24 | 2020-06-30 | The General Hospital Corporation | Catalytic radiofluorination |
| US7612056B2 (en) | 2004-04-06 | 2009-11-03 | Jenssen Pharmaceutica N.V. | Substituted diaza-spiro-[4.5]-decane derivatives and their use as neurokinin antagonists |
| US8604200B2 (en) | 2005-03-08 | 2013-12-10 | Janssen Pharmaceutica N.V. | Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists |
| US9005578B2 (en) | 2008-03-21 | 2015-04-14 | Fluoropharma, Inc. | Compounds and compositions for the detection and treatment of Alzheimer's disease and related disorders |
| US10857247B2 (en) | 2008-03-21 | 2020-12-08 | The General Hospital Corporation | Compounds and compositions for the detection and treatment of Alzheimer's disease and related disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| DK310184D0 (en) | 1984-06-25 |
| ES8601202A1 (en) | 1985-10-16 |
| IT1199148B (en) | 1988-12-30 |
| LU85434A1 (en) | 1985-03-26 |
| GR82274B (en) | 1984-12-13 |
| SE8403376L (en) | 1984-12-28 |
| GB8416172D0 (en) | 1984-08-01 |
| FR2549061A1 (en) | 1985-01-18 |
| PT78787B (en) | 1986-06-05 |
| ES533735A0 (en) | 1985-10-16 |
| FI842547A (en) | 1984-12-28 |
| NL8401907A (en) | 1985-01-16 |
| DE3422411A1 (en) | 1985-01-03 |
| IT8448458A0 (en) | 1984-06-26 |
| WO1985000171A1 (en) | 1985-01-17 |
| FI842547A0 (en) | 1984-06-25 |
| PT78787A (en) | 1984-07-01 |
| IL72218A0 (en) | 1984-10-31 |
| SE8403376D0 (en) | 1984-06-25 |
| HUT36793A (en) | 1985-10-28 |
| AU2983384A (en) | 1985-01-03 |
| DK310184A (en) | 1984-12-28 |
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Legal Events
| Date | Code | Title | Description |
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| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |