DE2103296A1 - Substituted tetrahydroquinolines - Google Patents

Description

Applicant: PIi ¹ IZBS CORPORATION, Colon, Panama

Substituted tetrahydroquinolines

The invention relates to substituted tetrahydroquinolines and particularly relates to new derivatives of the substituted Tetrahydroquinolinej which is the subject of the British Patent Hr «1 166 558 corresponding to the German Patent application P 17 70 595 form “The present invention is an improvement or modification of this older one Invention, The compounds of the present invention, like those described in the aforementioned British patent "have antischistosomal activity and are useful in the treatment of schistosoraiasis » In addition, the compounds according to the invention have advantages during administration, as will be shown in the following ο

British Patent 1,166,558 relates to compounds of the following formula:

109834/1685

<~ 2

1 ?
where R and R "are hydrogen, lower-alkyl, hydroxy-lower-alkyl or cyclo-lower-alkyl, or together with the nitrogen atom to which they are attached _{; form} a saturated heterocyclic group, which may with one or more lower alkyl . or hydroxy-lower-alkyl groups can be substituted,

R ^ and R are hydrogen or lower alkyl _? .

R is Liethyl.j hydroxymethyl or formyl * R- ^{3 is} a nitro or oyan group or a halogen and η is 1 or 2;

as well as the N ~ oxides of those compounds in which neither R nor

R is hydrogen and the pharmaceutically acceptable acid addition salts such connections *

The compounds of the present invention are ethers and esters of such compounds of the British patent 1,166,538 - in which R is hydroxyethyl and certain analogues Compounds such as # B-> Ither and esters of the formula

1.2 CID

109834/1685

2103298

Λ Ρ ^ τ 6
wherein RV. 3. ". R,. R, R and π have the same meaning v / ie

η
defined above "have., R> 7asi.erstof.f or lower alkyl

and R is a lower alkyl group or a lower alkanoyl group is;

as well as ίΤ-oxides of such compounds, in which neither R nor R V. hydrogen is, the lower alkyl & ethers and lower al-

1 2 lcanoyl ester of "compounds ^, in which R rind R ed.ne Hydroxynieder-Alkjl-Gnippe is and the piip.rmaseutisch? uläasigen Acid additives of such compounds.

Preferably, v / ie in British Patent 1,166

12th

C, H _o "is an ethylene group . _} contains either R or R η cxi f, p

2 to 4 carbon atoms and contain R and R together not more than M carbon atoms _o

The term "lower" in this description «. when applied to an alkyl or alkanoyl group means that such a group does not nehr than 6 carbon atoms contains "! 's λ

Iithers according to the invention in which R ^{ö is} a lower alkyl group can be formed from compounds of the formula:

H ⁶

\
HIGH,

_σ _ 12

by conventional etherification methods, for example, by heating a solution of the compound of the formula III with the suitable alkanol R OH in the presence of a strong acid ₈ S ₁₃ B ₀ hydrochloric acid or ethanesulfonic acid. The product can then be used

109834/1665

are recovered by precipitation and filtration as a salt of the acid and can then be recrystallized from a suitable solvent; it can performed by releasing the base in situ and be recovered by extraction with a suitable solvent, for example diethyl ether _{0 s} and anschließsende evaporation or conversion into an acid addition salt by means of conventional llethoden also in the free base *

Instead, an acid addition salt of the compound of formula III with the strong acid can be heated under reflux with the appropriate alkane1 R OH ₅ . to the acid addition salt form of Froduktes, which then won or mentioned in the free base ₅ as previously ·, wird.- converted.

Esters according to the invention in which R is a lower alkanoyl group can be prepared from those compounds of the formula III in which neither R nor R is hydrogen, by customary esterification _{methods, Z 9} B = by treating the compound with the anhydride or an acid halide of the appropriate alkanoic acid, addition of Vasser to hydrolyze about ~ scaüssiges anhydride or acid halide, neutralizing the free acid with an alkali and extracting the Froduktes as a free base with a suitable solvent which is then evaporated _e the product is recrystallized it from a suitable solvent »Or converted into an easily crystallizable salt by conventional means»

Esters of the invention wherein R and / or R is hydrogen cannot easily be prepared by this process because acylation of the primary or secondary aminoalkyl group will usually occur simultaneously with the acylation of the hydroxyethyl group * and selective development

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removal of the acyl group attached to the aminoalkyl group will be difficult * However, such esters can be made by doing this become »that first the compound of formula III,

Λ ?

wherein R and / or R is hydrogen, to an ilexahydroimidazoquinoline converted by reaction with an aldehyde (as described in DOS 20 07 3 ^ 5) “then as described above acylated and then the imidazoquinoline is hydrolyzed to regenerate the aminoalkylquinoline «

The ilethode for the preparation of compounds of the formula III (which are used as starting materials for the production of the compounds according to the invention) from the corresponding 6-LIethylverbindungen is in the British patent 1 166 533 described

The preparation of compounds according to the invention is illustrated by the following examples, in which the temperatures are given in ° C _o

example 1

His solution of 6-hydroxymethyl-2 ~ isopropylarainomethyl ~ 7- ■ nitro-1,2 _e 3,4-tetrahydroquinoline (1.0 g) in ethanol (50 ml) was treated with an excess of ethanol saturated with hydrogen chloride, - The dnnkelrote obtained solution was added to dry Diathyläther (500 ml) and filtered This -rareds to a light yellow liasse triturated »and recrystallized from ethanol what _t O ₄ 4-5 g of 6-ethoxymethyl ~ 2 ~ 7 ~ iBopropylaminomethyl-nitro ~ 1 * , 2.3 _; 4-totrahydro ~ chiiiolin-hydrochloria as a light yellow downy solid substance with a melting point of .1QMr «185 ⁰ C resulted in ₀

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Analysis:

found: O 55 _s 99ϊ H 7.55; IT '''2

requires: G 55.90; H 7.57; IT 12 * 25 ft

Example 2

A warm solution of 6-Hydro: xymethyl-2-'isopropylaminomethyl · ·· 7-nitro- »1 ₂ 2,3i ^{i {} - * ^ et37aliydroquinoline (C £ g) in dry toluene (40 ml) was saturated with dry hydrogen chloride _s vn the Hydrochloridsala as a same-solid precipitate, which was filtered, thoroughly washed with dry ether and was then dissolved in ethanol under Euckflass ₀ crystallization from ethanol afforded on cooling, 0.25 g of 6-ethoxymethyl-2-.7 ° -isopropylaminomethyl '--nitro =''l, 2, $ o' ⁱ i- * tetrahydroquinoline hydrochloride.,. which was identical to the product of Example 1,

Example 3

6 ~ Uethoxymethyl ~ 2-isopropylaminomethyl-7-nitro-i .2 * 3., ^ - betrahydroquinoline hydrochloride was after the verf slxrexi of. Example 2 made with methanol instead of ethanol, that The product had a melting point of 184 - 186 ° C.,

Analysis:

found: C 5-22; H? Λ9; IT 12 ₅ 22? "I

C ₁ ^ Hp-N ₅ O ₅ .HOl requires: C 5'ΚδΟ; II 7.28; 1Ϊ 12 «76%

To a warm solution of 6 "hyd7? Oaiymethyl-2-isoj) ropylani- noj! Etb.yl" -7 "nitro-1,2 3. ^ - L-etraliydroohinoIin (5 g '. ¹ in n-Buv ;.; aol (25Ο inl) v / m. * do sine T.ÖEJung by lue'i-'Af. nimlZonskhvee ^c "\, 72, g) in n-ButanoJ. (20 nil) suKeß ^et > 6ii Hie solution vmrdö

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r ^? heated to reflux for 24 hours., to 50 ml can crierts with sodium hydroxide solution "basic, made and extracted with ether. The ethereal solution was washed with water and with a solution of laleic acid in n-butanol "Treated ο The crystals obtained were filtered off and recrystallized from butane 1 to give 3.0 g of 6-n-Bui-ox3Tneth; fl- '

malsa-fc with a melting point of 159 - 160 ° C results in «

Analysis:

found: G 58 * 16; H 7.39; IT 9.28%

C ₁₈ H ₂₉ H ₅ O ₅ CC ₄ H 1 O ₄ requires: G 58.55; H 7 * 51; H 9.31 *

Similarly, the compounds of Examples 5 and 6 were prepared from 6-! IydroxyEieth3rl ~ 2 "iaopropylamiiiomethyl-7" nitro "-1 _{i 2>} 3,4-tetrahydroquinolin and the appropriate alkenol

R ⁸ OH,

AIIF 3ede implementation, including that of the case · », game _4-t followed TLC a Uusters,

to determine the completeness of the heaction., M

10983 ^ / 1665

Example R '

oalzform melting point

analysis
(Theory in lilammerrO

; j ο

iS ε

% ή

a-propyl haleate

S isopropyl Kaleate

163 ° 0

57.84 7.36 9.04 (57.66X7.15X9.61)

57.45 7.16 9 _S 9 (57 * 66X7.15X9.61)

Example 7

A mixture of 2 ~ Mäthylaminomethyl-6 "hydroxymethyl - 7-nitro-1J2 ^ is4-tetrahydroquinoline (1.4 g) xtit an excess of acetic anhydride (0.75 s) was warmed gently to * solution to _bexvirken% and the reaction . "was left at room temperature for '16 hours · the viscous Roaktions" - product was added to an excess stirred in cold, üasser added and _$ 2 hours to hydrolyze the excess anhydride ,. the aqueous solution was then passed through Zusats of potassium carbonate just made alkaline · and the organic material with .Mther extrahiert-, the dried ethereal extract was evaporated over IJagmjsiumsulfat and further dried in Yairaum to give an orange-colored solid which ₅ as a mixture of starting material and Realitionsprodukt by Dünnschichtch.t- omatographic analysis was found _o Fractionated crystallization of the crude mixture from n-hexane gave O _f 4 g of 6-acet-O3Q-KethyX-2-diethylaminome thy l-7 »not ro-1.2,3- 4-th trahydro as orange needles ait Sc! biDel2; point 60 - 62 ° C

Analysis: , requires: C. 60 77; H 7th .05; II 12th , 10 found: G 60 .'3Oi H 7th , 46; H 12th , 44

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Example 8

Yaleric anhydride (0 ^ 23 g) was added to a solution of 2 - D: Läthyl-aiainomet: b. ^: = ^ - 6-hydrox3imethyl - 7 «» nitro - 1 ₁ 2 _t 3 hydroquinoline (Ov , 4 gj in dry pyri & in added (2 ml) and the Reaktionsmisoiiimg by! room temperature kept for 4 days * Me solution was poured into water ,,, extracted with ether and the ethereal © extract then V 'aES3r _s iiatriunibica-cDonatlösung and Finally washed with water., The dried ether solution was further dried over agnesita sulfate and evaporated in vacuo. of dry ether and cooling to 0 ° G gave an orange-colored solid substance, which was then recrystallized from ethyl acetate / ether by 0 _% 35 S 3-diethylaminomethyl-7'ßi tro-6- (n'pe: atanoyloxyne tlryl) -1 ., 2,3, 4 ^ te trahydrochrLnolin-hydrogemnaisat with chmsl point 8.5 * - 87 ^C C to

Analysis:

found; C 58 ,! 53 \ H 6.81; IT 8.09 %

₄ O ₄ requires: G 58 * 40 ", H 7.15; ΪΤ 8.50 il

The activity of the compounds according to the invention as schiktosomiziae was confirmed; by a process which is based on the movement of grown-up bchistosomes out of their nor- ν> ΐlan places in the riCi3enterialjjj, 3fäßseri? .ur Lebor ,, lie-.i works by cheiü'jthe.'iapoutisch active Ve-i? bindur! .ger.u Die '» ■ ädti decay /. ··?.;:.! v / urdo ir · Journal of Tropical). Medicine & IIygd.ene _s r>j«; d 71-, C ^ i-, sn Ί39 · '! ^ 5 (June 1968).

1 0 9 8 3 Λ / 1665

ίο ~

In the present case, white lice, 3-4 y / o old, were infected percutaneously with 20 cercariae of Schistosoma mansoni (East African strain) 25 ng / kg daily for M- days3 or 50 mg / kg administered in a single dose * and the efficacy was determined after different times after dosing. vässenj the liver portal artery and from the veins within the liver. The proportional movement of the worms from the portal vein and the hesenteric vessels to the liver forms the basis for the test *

Based on these tests in mice, the compounds of the present invention were found to generally have relative activities as schistosomal agents similar to those of the corresponding e-hyxymethyl compounds from which they are derived. When tested intramuscularly, their abso3. utes activities similar to those of the corresponding 6 ~ ^ ydro2cymethy links and much larger than those of the corresponding 6-LIethylverbindungen, "which are a 2iem * ~ lent low activity have when administered in this way," V / hen when administered orally tested _s! Activities of the compounds according to the invention, in which R

Ethyl or isopropyl (s _{0 Q} B, the compounds of Examples 3 ",. 1 and 6) _v, considerably larger than those of the corresponding 6-Iiydrosynethy3.verbindungen and comparable with those of the corresponding 6-lle thy! Compounds, many of which are strongly active in this VeriObreiclmns »

1 0 9 8 3 Λ / 1 665

Compounds according to the invention were also tested in Oebus and Vervetaffen and, in particular, it was found that the compound of Example 1 has a strikingly greater antiseid.stosomal activity (measured as a reduction in the fecal egg count) * when on oral V / eg in a dosage of 15 to 25 mg / kg (expressed as free base) is administered _$ than either the corresponding .delta.-hydroxy methyl compound or the corresponding 6-methylene compound.,

The compounds according to the invention are more stable in acidic compounds as the corresponding e-Hydrox ^ aaethylverbin "- fertilize, and it is believed that this is due to their enlarged Effectiveness contributes "when administered on oral" sweeping s and also gives them the other advantages “if they are used in dosage forms *

10983 ^ / 1665

Claims (1)

Claims Compounds of the formula Ε ⁵ R ⁸ OOH ₂ (II) where R and R .. hydrogen _s lower alkyl, Ilydroxynieder-alkyl or Oyclo-lower-alkyl 3ind, or together with the nitrogen atom to which they are attached _{9 form} a saturated heterocyclic group, which with one or more lower alkyl or Ilydroxynieder-alkyl groups can be substituted, Bri R and R 'are hydrogen or lower alkyl, R is a lower alkyl or a lower alkanoyl group is _s R- ^{7 is} a nitro or cyano group or a halogen and η is 1 or 2; 1
and IT oxides of such compounds in which neither R nor ρ
Hydrogen is the lower and lower alkyl ethers 1 2 Alkanoyl esters of compounds in which R or R is a hydroxy-lower alkyl group and the pharmaceutically acceptable acid addition salts of such compounds are _β 2 "A compound according to claim 1, characterized in that _s Br ₉ ^ r, E VND. B ^ hydrogen sindo β A compound according to claim 1 or 2, characterized in that that G-Hp ^ is a methylene groupa 109834/1665 4β A compound according to any one of the preceding claims, characterized in that either R or R contain from 2 to 4 · carbon atoms and R and R ^ together contain no more than 4 carbon atoms « 5β A compound according to claim 4, characterized in that that R and R are ethyl groups » A compound according to claim 4, characterized in that Jj that R is an isopropyl group and R is hydrogen 7 «A connection according to one of the preceding claims, characterized in that R is an IJethy 1-, ethyl or Isopropyl group isto 6-Ethylene-methyl-2- (N-isopropylaminomethyl) 7-3iitro-1,2,3, tetrahydroquinoline and its pharmaceutically acceptable acid addition salts. 9β drug containing a compound «, as in one of the preceding claims claimed, and a pharmaceutical carrier *, 109834/1665