AU613907B2 - Creation of Inventions and Patents with Artificial Intelligence

AU613907B2 – New pyrazolo (3,4-d) pyrimidines, processes for the preparation thereof and pharmaceutical compositions containing them
– Google Patents

AU613907B2 – New pyrazolo (3,4-d) pyrimidines, processes for the preparation thereof and pharmaceutical compositions containing them
– Google Patents
New pyrazolo (3,4-d) pyrimidines, processes for the preparation thereof and pharmaceutical compositions containing them

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Publication number
AU613907B2

AU613907B2
AU14506/88A
AU1450688A
AU613907B2
AU 613907 B2
AU613907 B2
AU 613907B2
AU 14506/88 A
AU14506/88 A
AU 14506/88A
AU 1450688 A
AU1450688 A
AU 1450688A
AU 613907 B2
AU613907 B2
AU 613907B2
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Prior art keywords
pyrazolo
cyclopentylamino
pyrimidine
compound
alkyl
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1987-04-15
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AU1450688A
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Walter-Gunar Friebe
Wolfgang Kampe
Otto-Henning Wilhelms
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Roche Diagnostics GmbH

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Boehringer Mannheim GmbH
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1987-04-15
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1988-04-12
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1991-08-15

1988-04-12
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1988-10-20
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1991-08-15
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1991-08-15
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Classifications

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

C07D487/04—Ortho-condensed systems

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P11/00—Drugs for disorders of the respiratory system

A61P11/08—Bronchodilators

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P11/00—Drugs for disorders of the respiratory system

A61P11/16—Central respiratory analeptics

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P37/00—Drugs for immunological or allergic disorders

A61P37/08—Antiallergic agents

Abstract

Pyrazolo[3,4-d]pyrimidines of the formula I

in which
R1 denotes a C1- to C6-alkyl radical, a C2- to C6-alkenyl radical, a C3- to C7-cycloalkyl radical or an aryl radical,
R2 denotes a C2- to C6-alkenyl radical, a C3- to C7-cycloalkyl radical or an aralkyl or hetaralkyl radical having 1 to 6 carbon atoms in the alkyl moiety and which, if desired, is mono- or polysubstituted by halogen, C1- to C6-alkyl, hydroxyl, C1- to C6-alkoxy, C1- to C3-haloalkyl, C3- to C7-alkoxycarbonyl, aminocarbonyl, C2- to C7-alkylaminocarbonyl, C3- to C13-dialkylaminocarbonyl, cyano or C1- to C6-alkylthio and
R3 denotes hydrogen, a C2- to C6-alkyl radical which, if desired, is mono- or polysubstituted by hydroxyl, a tetrahydrofuranyl radical or a tetrahydropyranyl radical,
with the proviso that R2 cannot be unsubstituted benzyl if R1 represents the methyl group,
and their physiologically tolerable salts of inorganic or organic acids are used as medicaments for the treatment of allergic diseases and of bronchospastic and bronchoconstrictive reactions due to inflammation.

Description

61l3 90 7 L TH 11 O A US TR P CO0M MO0N W HA L X A PATENT ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE C I, A S S IIJ’f. CI~ASS Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art-.
NAM{E OF APPLICANT: BO ADDRESS OF APPLICANT: EHRINGER MANNHEIM GMB3H 6800 Mannheim 31, Federal Republic of Germany.
NAME(S) OF INVENTOR(S) Walter-Gunar FRIEDE Wolfgang KAMPE Otto-Henning WILHELMS ADDRESS FOR SERVICE: DAVIES COLLISONl, Patent Attorneys 1 Little Collins Street, Melbourne, 3000.
COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: ‘NEW PYRAZOLOC3,4-d3PYRIMIDINES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM” The following statement is a full description of this invention, including the best method of perforwing it known to us 17CI~ ~i~e~ -2- The present invention is concerned with new pyrazolo[3,4-d]pyrimidines, processes for the preparation thereof and pharmaceutical compositions containing them.
The new pyrazolo[3,4-d]pyrimidines according to the present invention are compounds of the general formula:- R R 1\ 2
N
I(I), NN
R
3 S wherein R 1 is a C 1 to C0-alkyl radical, a C 2 to C- 0 04 10 alkenyl radical, a C 3 to C 7 -cycloalkyl radical or an aryl radical, R 2 is a C 2 to C 6 -alkenyl radical, a C 3 to
C
7 -cycloalkyl radical or an aralkyl or hetaralkyl radical with 1 to 6 carbon atoms in the alkyl moiety and substituted, if desired, one or more times by halogen,
C
1 to C 6 -alkyl, hydroxyl, C, to C 6 -alkoxy, C 1 to C 3 haloalkyl, C 3 to C7-alkoxycarbonyl, aminocarbonyl,
C
2 to C 7 -alkylaminocarbonyl, C 3 to C 13 -dialkylaminocarbonyl, cyano or C, to C 6 -alkylthio and R 3 is a hydrogen atom or a C 2 to C 6 -alkyl radical substituted, if desired, one or more times by hydroxyl or is a tetrahydrofuranyl or tetrahydropyranyl radical, with the proviso that R2 cannot be an unsubstituted benzyl radical when R1 is a methyl radical and the physiologic-
A
-3ally acceptable salts thereof with inorganic and organic acids.
4-[N-(Benzyl)-methylamino]-H-pyrazolo[3,4-d]pyrimidine is known from J. Med. Chem., 1, 588/1962 as a potential antitumour agent.
When compounds of general formula I contain an asymmetric carbon atom, the optically-active compounds and racemic mixtures are also the subject of the present invention.
The new compounds of general formula I display valuable pharmacological properties; in particular, they can inhibit the antigen-caused liberation of mediators from lung tissue samples, as well as the “ontraction of lung tissue strips. Therefore, they can be used for the treatment of allergic diseases, as well as of inflammation-caused bronchospastic and bronchoconstrictory reactions.
The alkyl moieties in the said radicals, as well as the alkenyl, alkoxy, alkylamino and alkylthio radicals, can be straight-chained or branched. Preferred alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and 3-pentyl radicals. An alkenyl radical is preferably the allyl radical. Preferred alkoxy and alkylthio radicals include the methoxy, ethoxy, methylthio and ethylthio radicals.
Cycloalkyl radicals are preferably cyclopentyl and cyclohexyl radicals.
-4- Heteroalkyl radicals are preferably the furfuryl, thenyl and pyridinylmethyl radicals.
Preferred aralkyl radicals include, for example, the benzyl, phenethyl, phenylpropyl, phenylisopropyl and 3-methyl-3-phenylpropyl radicals.
Heteroalkyl radicals contain, for example, fiveor six-membered rings with one or two nitrogen, oxygen or sulphur atoms; in the case of two hetero atoms, these can be th- same or different.
As a rule, an aryl radical is a naphthyl or phenyl radical and preferebly a phenyl radical.
Halogen atoms are especially fluorine, chlorine, bromine and iodine.
R
3 is preferably a hydrogen atom or a 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, tetrahydrofuran-2-yl or tetrahydropyran-2-yl radical.
Apart from the compounds mentioned in the Examples, the present invention also includes, in particular, all compounds which display every possible combination of the substituents mentioned in the Examples.
The compounds according to the present invention can be prepared, for example, by reacting in known manner a compound of the general formula:-
X
N N s (II) IiK
N
wherein X is a reactive residue and R 3 has the abovementioned meaning, with a compound of the general formula:-
HNR
1
R
2
(III),
wherein R 1 and R2 have the above-mentioned meanings, and subsequently, if desired, a radical R 3 is replaced by another radical given by the definition of R 3 and a compound obtained of general formula I is converted, if desired, by neutralisation with a non-toxic acid into a pharmacologically acceptable salt thereof.
The reactive residue X can be, for example, a chlorine or bromine atom or a lower alkylthio radical.
Conversion of a compound of general formula I in which R is a hydrogen atom into a compound of general formula I in which R 3 is other than a hydrogen atom preferably takes place by alkylation with a compound of the general formula R 3 wherein Y is a reactive residue, for example a halogen atom or a methanesulphonyloxy or toluenesulphonyloxy radical, in an acidbinding medium. Hydroxyl substituents possibly present in R 3 can be protected by ether, ester or ketal groups and liberated after the alkylation.
For the removal of a tetrahydrofuranyl or tetrahydropyranyl radical R 3 there can be used an inorganic acid, such as hydrochloric acid or sulphuric acid, in aqueous or organic solution.
On the other hand, by proton catalysis, into -6compounds of general formula I, in which R 3 is a hydrogen atom, there can be introduced a tetrahydrofuranyl or tetrahydropyranyl radical by reaction with excess 2,3-dihydrofuran or 2,3-dihydropyran.
The starting compounds of general formulae II and III are either known from the literature or can be prepared analogously to processes known from the literature.
The pharmacologically acceptable salts are obtained in the usual way, for example by neutralisation of compounds of general formula I with non-toxic inorganic or organic acids, for example hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid or succinic acid.
For the preparation of pharmaceutical compositions, compounds of general formula I are mixed in known manner with appropriate pharmaceutical carrier substances, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or an oil, for example olive oil.
The compounds of general formula I can be administered orally and parenterally in liquid or solid form.
As injection medium, water is preferably used which contains stabilising agents, solubilising agents and/or -7buffers usual in the case of injection solutions. Such additives include, for example, tartrate and borate buffers, ethanol, dimethyl sulphoxide, complex formers (such as ethylenediamine-tetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation and polyethylene derivatives of sorbite anhydrides. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids and high molecular weight polymers (such as polyethylene glycols).
Compositions suitable for oral administration can, if desired, contain flavouring and sweetening agents.
For external use, the compounds I according to the present invention can also be used in the form of powders and salves. For this purpose, they are mixed, for example, with powdered, physiologically acceptable dilution agents or conventional salve bases.
The dosage administered depends upon the age, the state of health and the weight of the recipient, the extent of the disease, the nature of further treatments possibly carried out simultaneously, the frequency of the treatments and the nature of the desired action.
Usually, the daily dose of the active compounds is from 0.1 to 50 mg./kg. body weight. Normally, 0.5 to 40 and preferably 1.0 to 20 mg./kg. per day, in one or more administrations per day, are effective in order to obtain the desired results.
Especially preferred according to the present invention are, apart from the compounds mentioned in the Examples, also the following: 4- [1-C3-bromophenyl )-ethyl I-cyclopentylamino }-lHpyrazolo(3,4-dlpyrimidine (3-bromophenyl )-ethyl) -cyclopentylamino }-lHpyrazolof 3,4-dipyrimidine 4-[N-(3-bromopyridin.-5-yl-tethyl)-cyclopentylamino]-1Hpyrazolo [3 ,4-d Ipyrimidine 4-[N-(3-ethoxycarbonylbenzyl)-cyclopentylamino]-l-(2,3dihydroxypropyl)-lH-pyrazolo 3 ,4-dlpyrimidine 4-[N-(3-atninocarbonylbenzyl)-cyclopentylaminol-l-(2,3dihydroxypropyl H-pyrazolo 4-d Ipyrimidine 4-[N-(3-cyanobenzyl)-cyclopentylaminol-l-(2,3-dihydroxypropyl)-lH-pyrazolo[3,4-d]pyrimidine 4-[N-(2,5-dichlorobenzyl)-cyclopentylamino]-l-(2,3dihydroxypropyl -lH-pyrazolo 4-d ]pyrimidine 4-[N-(3,4-dichlorobenzyl)-cyclopentylaminol-l-(2,3dihydroxypropyl)-lH-pyrazolo3,4-dpyriidile 4-IN-(5-chloro-2-methylbenzyl)-cyclopentylamino]-l- (2,3-dihydroxypropyl)-lH-pyrazolo[3,4-dlpyrimidine 4-IN-(2-chloro-5-methoxybenzyl)-cyclopentylamino]-l- 3-dihydroxypropyl )-lH-.pyrazolo[ 3,4-dlpyrimidine The following Examples are given for the purpose of illustrating the present invention:- Example 1.
4-[N-(3-Chlorob~enzyl)-cyclopentylamino]-lH-pyrazolo- [3 ,4-d~pyrirnidine -9- A ixture of 12.5 g. (80 mmole) 4-chloro-lHpyrazolo[3,4-djpyrimidine, 50.3 g. (240 mn’ole) N-(3chlorobenzyV’-cyclopentylamino and 190 ml. n-butanol is heated to reflux for 16 hours and then evaporated.
The residue is taken up in dilute aqueous sodium hydroxide solution, washed with diethyl ether, the aqueous phase neutralised with hydrochloric acid and the precipitate filtered off. After recrystallisation from ethanol, there are obtained 19.5 g. of the title compound (74% of theory); m.p. 186 187 0
C.
Example 2.
In a manner analogous to that described in Example 1, by the reaction of 4-chloro-lH-pyrazolo[3,4-d]pyrimidine with the appropriate secondary amines, there are obtained the following compounds: designation yield melting point (sol.vent) a) 4-(N-allylcyclohexylamino)- 46 141-143 1H-pyrazolo[3,4-dlpyrimidine (ethanol! water) b) 4-[N-(3-methylbenzyl)-cyclopentylaminol-lH-pyrazolo- 49143-145 [3 ,4-alpyrimidine (ethanol) c) 4-[N-(3-trifluoromethylbenzyl)-cyclopentylamino]- 76 171-172 1H-pyrazolo[3,4-dllpyrimidine (ethanol) d) 4-[N-(3-methoxybenzyl)- 63 169-170 cyclopentylamino I-lHpyrazolo [3 ,4-d ]pyrimidine 4 0 a designation yield melting point 0 C. (solvent) e) 4-[N-(5-chloro-2-methoxy- 40 232-235 benzl)-ycloentlamiol-(dichlorobenzl )-cycopetyl min] -methane/ lH-pyrazolo[3,4-dlpyrimidine methanol) f) 4-[N-(3-bromobenzyl)-cyclo- 55 192-194 pentylamino]-1H-pyrazolo- (ethyl [3 ,4-dlpyrimidine acetate) g) 4-IN-(3-ethoxycarbonyl- 28 135-137 benzyl)-cyclopentylamino]- (ethyl lH-pyrazolo[3,4-dlpyrimidine acetate) h) 4 -N(-mncroy-25 150-160 benzyl)-cyclopentylaminol- amorphous (diethyl 1H-pyrazololl3,4-dlpyrimidine ether) i) 4-[N-(3-cyanobenzyl)-cyclo- 52 178-180 pentylamino]-1H-pyrazolo- (diethyl II3,4-dipyrimidine ether) j) 4-IN-(2,5-dichlorobenzyl)- 32 233-235 cyclopentylamino ]-111- (diethyl pyrazolol3,4-dlpyrimidine ether) k) 4-[N-(3,4-dichlorobenzyl)- 27 168-170 cyclopentylamino]-lH- (ligroin) pyrazolo[ 3,4-dipyrimidine 1) 4-[N-(5-chloro-2-methyl- 33 203-205 benzyl)-cyclopentylamino]-lH- (ligroin) pyrazolo [3 ,4-d ]pyrimidine m) 4-[N-(2-chloro-5-methoxy- 35 213-215 benzyl)-cyclopentylamino]-lH- (diethyl pyrazolo[3,4-dlpyrimidine ether) n) 4-IN-(2,5-dimethylbenzyl)- 41 188-190 cyclopentylamino]-1H- (ligroin) pyrazolo[ 3,4-dlpyrimidine 2 11a I Al
IA,,
*ttI designation yield melting point 0 C. (solvent) o) 4-[N-(2-furylmethyl)-cyclo- 35 125-127 pentylamino]-lH-pyrazolo- (ethanol) 3,4-d jpyrimnadine________ p) 4-[N-(thiophen-2-ylmethyl)- 56 166-169 cyclopentylamino]-1H- (ligroin) pyrazolo 4-d Ipyrimidine________ q) 4-[N-(2–methylpyridin-6-yl- 79 182-184 methyl) -cyclopentylamino I- (ethanol) lH-pyrazolo[ 3,4-dipyrimidine r) 4-[N-(3-bromobenzyl)-2- 31 173-175 propyl)-amino]-lH-pyrazolo- (diethyl [3 ,4-dlpyrimidine ether) s) 4-[N-(3-bromobenzyl)-3- 27 147-148 pentyl)-aminol-11{-pyrazolo- (diethyl [3 ,4-d Ipyrimidine ether) t) 4-[N-(2-bromobenzyl)-cyclo- 29 216-217 pentylaminol-lH-pyrazolo- (diethyl [3 ,4-dlpyrimidine ether) u) 4-[N-(3-bromobenzyl)-cyclo- 24 149-150 hexylamino]-1H-pyrazolo- (diethyl [3 ,4-dlpyrimidine ether) v) 4-[N-(3-b-romobenzyl)-methyl- 55 216-217 amino]lH-pyrazolo[3,4-d]- (methanol) pyrimidine w) 4-[N-allyl-(3-bromobenzyl)- 52 118-120 amino]l1H-pyrazolo[3,4-dI- (ethyl pyrimidine acetate) x) 4-(N-benzylcyclopentylamino)- 28 168-170 lH-pyrazolo[3,4-dlpyrimidine (diethyl I ether) -12designation yield melting point C. (solvent) y) 4-(N-(4-bromobenzyl)-cyclo- 26 112-114 pentylaminob-lH-pyrazolo- (diethyl (3 ,4-dlpyritnidine ether) z) 4-(N-(3-iodobenzyl)-cyclo- 24 182-184 pentylaminol-lH-pyrazolo- (diethyl (3 ,4-d Ipyrimidine ehr aa) 4-IN-(3-hydroxybenzyl)- 43 213-215 cyclopentylaminoj-lH- (diethyl pyrazolo[3,4-dlpyrimidi’ne ehr ab) 4-(N-(3-methylthiobenzyl)- 48 116-118 cyclopentylariinol-ll- (diethyl pyrazolo[3,4-dlpyrimidine ehr ac) 4-[N-(3-t-butylbenzyl)- 37 223-225 cyclopentylamino]-lH- (ethyl pyrazolof3,4-dlpyrimidine acetate) hydrochloride ad) 4-IN-(3,5-dibromobenzyl)- 17 182-184 cyclopentylamino I- lH- (die thyl pyrazolo[3,4-dlpyrimidine ether) ae) 4-[N-(3-bromo-4-methylbenz- 19 200-202 yl )-cyclopentylamino (diethyl pyrazolo[3,4-dlpyrimidine ether) af) 4-EN-(3-bromobenzyl)- 40 194-196 anilino]-lH-pyrazolo- (methanol) 3,4-dlpyrimidine ag) 4-[N-(2-bromothiophen-5-yl- 33 155-156 methyl) -cyclopentylamino] (ethyl 1H-pyrazololl3,4-d~pyrimidine acetate)
C
-13- Example 3.
4-[N-(3-Chlorobenzyl)-cyclopentylamino]-1-(2,3 dihydroxypropyl)-1H-pyrazolo[3,4-d]pyrimidine.
To a suspension of 1.5 g (30 mmole) 50% sodium hydride in 50 ml. N,N-dimethylformamide are added dropwise 9.6 g. (30 mmole) 4-[N-(3-chlorobenzyl)-cyclopentylamino]-1H-pyrazolo[3,4-d]pyrimidine (compound of Example 1) in 25 ml. N,N-dimethylformamide. The reaction mixture is stirred for 1 hour at 80 0 10.0 g. (35 mmole) 4-(4-toluenesulphonyloxymethyl)-2,2-dimethyl-l, 3 dioxolan in 25 ml. N,N-dimethylformamide are added thereto, the reaction mixture is further stirred for 3 hours at 80 0 C. and evaporated in a vacuum. The residue is taken up in water, extracted with dichloromethane and the extract evaporated. The residue is mixed with 300 ml. 0.1N hydrochloric acid, heated under reflux for hours, allowed to cool, washed with diethyl ether and the aqueous phase rendered alkaline with aqueous sodium hydroxide solution. After extraction with dichloromethane and evaporation of the extract, there are obtained 8.2 g. of crude product which is purified by chromatography on silica gel (elution agent: dichloromethane/methanol; 9:1 4.1 g. (34% of theory) of the title compound are eluted which, after trituration with diethyl ether, melts at 98 100 0
C.
Example 4.
In a manner analogous to that described in -14- Example 3, by alkylation with 4-(4-toluenesulphonyloxymethyl)-2,2-.dimethyl-l,3-dioxolan, there are obtained the following compounds:designation yield melting point C. (solvent) a) 4-(N-allylcyclohexylamino)- 38 oil 1- 3-dihydroxypropyl )-lHpyrazolo[13 ,4-dlpyrimidine from the compound of Example 2a) b) 4-[N-(3-trifluoromethyl- 33 122-123 benzyl)-cyclopentylamino]- (diethyl l-(2,3-dihydroxypropyl)-lH- ether) pyrazolo[3 ,4-dlpyrimidine from the compound of 15 Example 2c) c4-[N-(2,5-dimethylbenzyl)- 35 60-70 cyclopentylamino1-1- amnorphous dihydroxypropyl)-lH- (dichloropyrazololl3,4-d]pyrimidine methanol) from the compound of Example 2n) d) 4-IN-(2-furylmethyl)-cyclo- 40 oil pentylaminol 3-dihydroxypropyl -lH-pyrazolo- [3,4-dlpyrimidine from the compound of Example 2o) e) 4-[N-(thiophen-2-ylmethyl)- 44 oil cyclopentylamino1-1- (2,3dihydroxypropyl -lHpyrazolo[3,4-dlpyrimidine from the compound of Example 2 p) 1 7 designation yield melting point C. (solvent) f) 4-[N-(3-methoxybenzyl)- 41 oil cyclopentylarnino)-l-(2,3- hydrochloride: dihydoxypopyl-IH-175-176 dihyroxyropl Ut-(ethyl pyrazolo[3,4-dlpyrimidine acetate) from the compound of Example g) 4-[N-(3-methylbenzyl)- 65 80-82 cyclopentylaminol]-(2,3- (diethyl dihydroxypropyl)-1E- ether) pyrazolo [3 ,4-d Ipyrimidine h) 4-[N-(3-bromobenzyl)-cyclo- 51 107-108 pentylamino]-l-(2,3- (diethyl dihydroxypropyl) U- ether) pyrazolo[3,4-dlpyrimidine i) 4-[N-(5-chloro-2-methoxy- 58 132-134 benzyl)-cyclopentylaminol- (diethyl 1-(2,3-dihydroxypropyl)-1H- ether) pyrazolo [3 ,4-d Ipyrimidine Example 4-[N-(2,5-Dimethylbenzy7l)-cyclopentylamino]-l-(tetrahydrofuran- 2-yl )-l11-pyrazolo 4-d] pyrimidine A mixture of 7.8 g. (35 mmole) 4-chloro-l-(tetrahydrofuran-2-yl)-lH-pyrazolo[3,4-dpyriidile, 20.3 g.
(100 mmole) N-(2,5-ditnethylbenzyl)-cyclopentylamile and 100 ml. n-butanol is heated under reflux for 16 hours.
The reaction mixture is evaporated, the residue is taken up in water and extracted with dichloromethane and the extract is washed with dilute acetic acid and dilute r; i i
I
T~ I7 -16aqueous sodium hydrogen carbonate solution, dried, evaporated and chromatographed on silica gel. 5.0 g.
(37% of theory) of the title compound are eluted with dichioromethane/mnethanol (98:2 v/v) which, after trituration with diethyl ether, melts at 173 1740C.
Example 6.
In a manner analogous to that described in Example 5, by reaction of 4-chloro-l-(tetrahydrofuran- 2-yl)-1H-pyrazolo(3,4-d]pyrimidine with an appropriate amine, there are obtained the following compounds:
L,
P LO t
D
I
I
designation yield melting point 0C. (solvent) a) 4-(N-allylcyclohexylamino)- 29 oil 1-(tetrahydrofuran-2-yl)-1Hpyrazolo[3,4-d]pyrimidine b) 4-[N-(2-furylmethyl)-cyclo- 33 85-87 pentylaminol-l-tetrahydro- (ligroin/ furan-2-yl)-lH-pyrazolo- diethyl ether) [3,4-dpyrimidine c) 4-[N-(thiophen-2-ymethyl)- 46 120-122 cyclopentylamino]-1-tetra- (diethyl hydrofuran-2-yl)-lH- ether) pyrazolo[3,4-dlpyrimidine d) 4-[N-(3-bromobenzyl)-cyclo- 44 118-119 pentylaminol-l-(tetrahydro- (ligroin) furan-2-yl)-lH-pyrazolo- (3,4-dpyrimidine 16A Example 7.
Test Results for Pharmaceutical Activity Activity of the inventive compounds was shown by the following testing in vitro. The testing result show inhibition of antigen-induced constriction of passively sensitized guinea pig pulmonary parenchyma strips in vitro (organ bath). The method employed was as described herewith: Pirbright-White guinea pigs were stunned by a blow to the neck and bled. The lungs were flushed largely free of blood in situ with Kreb’s buffer, pH 7.4.
Then the lung was removed, cut into strips (approx.
20x4x4mm) and the strips were passively sensitized for one hour at room temperatu-e with a 1:50 dilution of a homologous anti-ovalbumin antiserum and then washed once with Kreb’s buffer.
The antiserum had previously been produced as described by Davies et al., (Quantitative studies on anaphylaxis in guinea pigs passively sensitized with homologous antibody. Inter. Arch. Allergy 41, 648-654 (1971) in guinea pigs of the same strain by repeated injection of ovalbumin (2xcrystallized) with the addition of complete Freund’s adjuvant (Until it was used, the antiserum was stored undiluted at -18 0
C).
Then the lung strips were fixed singly with one end to the bottom of 10-milliliter organ baths, and with the upper end to isometric measuring devices for the recording of the constrictions of the lung strips through an amplifier on a plotter. The tenseron was adjusted to 1.2g weight.
Then the baths were filled with Kreb’s buffer and continually gassed at 37 0 C with 02 and CO 2 After a 30 minute equilibration phase, histamine constrol spasms were produced in order to establish the reactivity of the lung specimens, washed, then the test substance was preincubated for 20 minutes at 37 0 C, and the V 910521,ejhspe.022,14506.spe, 16B ovalbumin constriction was produced.
The inhibiting action of the compounds according to the invention was expressed as percentage reduction of the constriction amplitude of the “specimens with the test substance” in proportion to the “untreated control constrictions”.
TABLE 1 Inhibition of the antigen-induced constriction on the passively sensitized strip of pulmonary parenchyma (guinea pig) Substance from Example No.
Inhibition Superfusion Concentration
I
It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments with the spirit and scope of the invention will suggest themselves to those skilled in the art.
910521,ejhspe.022,14506.spe,2

Claims (16)

1. Pyrazolo pyrimidines of the formula: RI R2 (I) N N N R3 wherein RI is a C 1 to C 6 -alkyl, a C 2 to C 6 -alkenyl, a C 3 to C 7 cycloalkyl or a napthyl or phenyl, R 2 is a C 2 to C6-alkenyl, a C 3 to C 7 -cycloalkyl or an unsubstituted or substituted phenyl-Ci-C 6 -alkyl or hetero-C 1 -C 6 -alkyl wherein the hetero radical is a or 6 membered ring selected from the group consisting of furyl, thienyl and pyridinyl and wherein said substituted phenyl-C 1 -C 6 -alkyl or hetero-C 1 -C 6 -alkyl is substituted from the group consisting of halogen, C 1 to C 6 -alkyl, hydroxyl, C, to C 6 -alkoxy, Ci to C 3 -haloalkyl, C 3 to C 7 alkoxycarbonyl, aminocaronyl, C 2 to C 7 alkylaminocarbonyl, C 3 to C 13 -dialkylaminocarbonyl, cyano and C, to C 6 -alkylthion, and R 3 is hydrogen or is an unsubstituted C 2 to C 6 -alkyl or is a substituted C 2 -C 6 alkyl substituted at least once by hydroxyl or is a tetrahydrofuranyl or tetrahydropyranyl, with the proviso that R 2 cannot be an unsubstituted benzyl wherein R i is methyl and the physiologically acceptable salts thereof with inorganic and organic acids and the racemic or optically active forms thereof. 910521,ejbspe.022,14506.spe,17

2. The compound of claim 1 wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and 3-pentyl, the alkenyl is allyl, the alkoxy is methoxy or ethoxy and the alkylthio is methylthio or ethylthio.

3. The compound of claim 1 wherein the cycloalkyl is cyclopentyl or cyclohexyl, the heteroalkyl is furfui’yl, thenyl or pyridinylmethyl, and the aralkyl is benzyl, phenethyl phenylpropyl, phenylisopropyl or 3-methyl-3- phenylisopropyl.

4. The compound of claim 1 wherein R 2 is benzy. is phenyl. The compound of claim 1 wherein R 3 is selected from the group consisting of hydrogen, 2-hydroxyethyl, 2- hydroxypropyl, 2, 3-dihydroxylpropyl, tetrahydrofuran-2-yl and tetrahydropyran-2-yl.

6. A pyrazolo[3,4-dlpyrimidine compound designated 4-[N- (3-trifluoromethylbenzyl )-cyclopentylamino] dihydroxypropyl -H-pyrazolo 4-d] pyrimidine.

7. A pyrazolo[3,4-d]pyrimidine compound designated 4-[N- (3-methoxybenzyl )-cyclopentylamino] -1H-pyrazolo[3, 4- d] pyrimidine. S. A pyrazolo(3,4-d]pyrimidine compound designated 4-[N- (3-ethoxycarbonylbenzyl )-cyclopentylamino] -lH- pyrazolo 4-d] pyrimidine.

9. A pyrazolo[3,4-dlpyrimidine compound designated 4-[N- (3-cyanobenzyl )]cyclopentylamino] -1H-pyrazolo- [3,4- d] pyrimidine. 910521,ejhspc.022,14506.spe,18 A pyrazolo[3,4-d~pyrimidine compound designated 4- 2, 5-dichlorobenzyI.)-cyclopentylaminoJ -1H- pyrazolo[3, 4-d~pyrimidine.

11. A pyrazolo[3,4-d~pyrimidine compound designated 4- 3, 4-dichlorobenzyl.)-cyclopentylamino]l H- pyrazolo [3,4 pyrimidine.

12. A pyrazolo[3,4-d]pyrimidine compound designated 4- 5-chloro-2-methylbenzy.)-cyclopentylamino] -lH- pyrazolo[3, 4-djpyrimidine.

13. A pyrazolo[3,4-dlpyrimidine compound designated 4- 2, 5-dimethylbenzyl )-cyclopentylamino-lH-pyrazolo[3, 4- dJ pyrimidine.

14. A pyrazolo[3,4-djpyrimidine compound designated 4- [N-2-furylmethyl )-cyclopentylamino] -1H-pyrazolo[3, 4- d] pyrimidine. A pyrazolo[3,4-d]pyrimidine compound designated 4- [N-C thiophen-2-ylmethyl )-cyclopentyl amino] -1H- pyrazolo[3, 4-d]pyrimidine.

16. A pharmaceutical composition for treating histamine- medicated allergic disease comprising an effective amount of the compound of claim 1 in a pharmaceutically acceptable carrier.

17. A pharmaceutical composition for treating histamine- medicated allergic disease comprising an effective amount on a compound in a pharmaceutically acceptable carrier wh’,rein the compound is selected from at least one of the group consisting of 4- [N-(3-trifluoromethyl-benzyl) cyclopentylamino] 2, 3-dihydroxypropyl )-lH- pyrazolo[3,4-d]pyrimidine, 4-[N-(3-methyoxybenzyl)- 910521,ejhspe.022Z14506.spe,19 _202 cyclopentylaminoj -1H-pyrazolo[3,4-dlpyrimidine, ethoxycarbonyl-benzyl )-cyclopentylamino] -lH-pyrazolo[3 ,4- djpyrimidine, 4- EN-(3-cyanobenzyl )-cyclopentylamiinoj -lH- pyrazolo[3,4-djpyrimidine, 5-dichlorobenzyl cyclopentylamino]-lH-pyrazolo[3,4-d]pyrimidine, 4-[N- 4-dich:lorobenzyl )-cyclopentylamino] -lH-pyrazolo 4- d~pyrimidine, 5-chloro-2-methyl-benzyl)- cyclopentylamino]-1H-pyrazolo[3,4-d]pyrimidine, dimethylbenzyl )-cyclopentylamino] -1H-pyrazolo[3, 4- djpyrimidine, 4- 2-furylmethyl )-cyclopentylamino] -lH- pyrazolo[3, 4-d]pyrimidine and 4- thiophen-2-ylmethyl cyclopentylamino] -1H-pyrazolo[3, 4-d]pyrimidine.

18. A method for treating histamine-medicated allergic disease in a patient having an allergic disease comprising administering an effective amount of a compound of claim 1 in a pharmacologically acceptable carrier.

19. A method for treating histamine-medicated allergic disease in a patient having an allergic disease comprising administering an effective amount in a pharmacologically acceptable carrier of at least one compound selected from the group consisting of trifluoromethyl-benzyl )-cyclopentylamino] dihydroxypropyl)-lH-pyrazolo[3,4-d]pyrimidine, methoxybenzyl )-cyclopentylamino] -lH-pyrazolo [3,4- d]pyrimidine, 4- 3-ethoxycarbonyl-benzyl cyclopentylamino]-lH-pyrazolo[3,4-d]pyrimidine, cyanobenzyl )-cyclpentylamino] -lH-pyrazolo[3, 4- d]pyrimidine, cyclopentylamino] -lH-pyrazolo[3,4-djpyrimidine, 4-[N- 4-dichlorobenzyl )-cyclopentylamino] -lH-pyrazolo[3, 4- dipyrimidine, 5-chloro-2–methyl-benzyl)- cyclopentylaminoll-lH-pyrazolo[3,4-dlpyrimidine, dimethylbenzyl )-cyclopentylamino] -lH–pyrazolo[3, 4- 910521,ejhspe.02,14506.spe,20 fNT 0O 1 lit, 21 d]pyrimidine, 4- (2-furylmethyl )-cyclopentylamino] -1H- pyrazolo[3, 4-dipyrimidine and 4- thiophen-2-ylmethyl cyclopentylamino] -lH-pyrazolo[3, 4-dilpyrimidine. The method of claim 18 wherein 0.1 to 50 mg/kg body weight is administered daily.

21. The method of claim 19 wherein 0.1 to 50 mg/kg body weight is administered daily. DATED this 27th day of May, 1991 B0EHRINGER MANNHEIM GmbH By Its Patent Attorneys DAVIES COLLISON 910527,ejhspe.022,14506.spe,21

AU14506/88A
1987-04-15
1988-04-12
New pyrazolo (3,4-d) pyrimidines, processes for the preparation thereof and pharmaceutical compositions containing them

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