KR800000089B1 - Method for preparing 2-acyl-4-oxo-hexahydro-4H-pyrazino [2, 1-a] isoquinoline derivative - Google Patents

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Description

Method for preparing 2-acyl-4-oxo-hexahydro-4H-pyrazino [2, 1-] isoquinoline derivative

The present invention relates to novel 2-acyl-4-oxo-hexahydro-4H-pyrazino [2, 1-a] isoquinoline derivatives and methods for their preparation.

The novel isoquinoline derivatives of the present invention are the following general formula (I) compounds and their physiologically acceptable salts and quaternary ammonium salts.

COR is an acyl group having up to 26 carbon atoms, where R is substituted when R is a phenyl group.

The abbreviation “HPI” used for convenience in the description below is 4-oxo-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino 2, 1-aisoquinoline and “HPI” is 4-oxo -1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinoline was shown. Therefore, general formula (I) compound can be represented as "2-acyl-HPI."

We found that the general formula (I) compound had excellent applicability and excellent pharmacological action. This compound is particularly useful as an antiparasitic agent, and has a wide range of activities, especially for tapeworms and dystomies. Moreover, some of the new substances have properties that affect neurological diseases and blood pressure. Therefore, general formula (I) compounds can be used as human or animal medicines, especially insect repellents. These materials are also useful as intermediates for the manufacture of other pharmaceuticals.

Not only the racemic compound of formula (I) but also the optical colon thereof are useful, and in particular, it is more useful to correspond to the left-handed HPI in terms of optical structure.

Among the 2-acyl-HPIs of formula (I) belong to the recognition (I) compound, wherein the acyl group (-CO-R) is the following general formula (Ia)-(Ik) compound and physiologically acceptable More preferred are salts, quaternary ammonium salts, and optically substituted.

Ia: fluorine at the 0-position or fluorine, chlorine, nitro, hydroxy, amino, formylamino, acetylamino, pentanoylamino, hexanoylamino, octanoylamino, oleoylamino, at the m- or -p position; Benzoyl group once substituted with methoxy-acetyl amino, methylamino, dimethylamino or allylamino

Ib: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptylcarbonyl groups (each is fluorine, chlorine, nitro, hydroxyamino, formylamino, acetylamino, pentanoylamino, hexanoylamino, octanoylamino, May be substituted once more with oleoylamino, methoxyacetylamino, methylamino, dimethylamino or allylamino.)

Ic is an alkanoyl group having up to 8 carbon atoms which may be further substituted with methoxy or ethoxy

Id: furyl-2-carbonyl, furyl-3-carbonyl, thienyl-2-carbonyl, thienyl-3-carbonyl or 2-thienyl mercaptomethylcarbonyl

Ie: can be substituted once more with fluorine, chlorine, hydroxy, amino, formylamino, acetylamino, pentanoylamino, hexanoylamino, octanoylamino, oleoylamino, methoxyacetylamino, methylamino or dimethylamino 2-, 3- or 4-pyridylcarbonyl or 2-, 3- or 4-N-oxido-pyridyl-carbonyl groups

If: aminoalkanoyl having up to 4 carbon atoms, aminocycloalkyl carbonyl having 6-8 carbon atoms, or benzylidene at 2-atom atoms, 2-hydroxybenzylidene, 2-hydroxy-3-methoxy-benzyl Amino benzoyl- or aminopyridyl carbonyl groups substituted with lidene, carboxymethylidene, 3-phenyl-prop-2-enylidene or furfurylidene

Ig: The phenyl group at the terminal is hydroxy at the P-position, alkoxy having up to 4 carbon atoms, amino, alkoxy having up to 4 carbon atoms, amino, alkylamino having up to 4 carbon atoms or up to 8 carbon atoms A phenyl azobenzoyl group which may be further substituted with an aliphatic acylamino, halogen, sulfo having up to 4 carbon atoms, or an alkyl having up to 4 carbon atoms;

Ih: amino-cycloalkyl-carbonyl group having 6-8 carbon atoms, aminobenzoyl group or aminopyridylcarbonyl group, amino group protected with benzyl group which may be substituted with hydroxy or methoxy;

Thiazolyl-, isothiathiazolyl-, oxazolyl-, or isoxazolylcarbonyl groups which may be further substituted with Ii methyl or nitro;

Ik: formyl, acetyl, pentanoyl, hexanoyl, octanoyl, oleoyl, methoxyacetyl, carboxymethyl, allyl, benzyl (which may be further substituted with hydroxy or methoxy) or 3-phenylpropyl at the nitrogen atom 2-, 3- or 4-piperidyl carbonyl group substituted with;

In particular, compounds of general formula (I) have R groups cyclohexyl, 0-, m- and P-fluorophenyl, P-chlorophenyl, m- and P-aminophenyl, m- and P-formylaminophenyl, P- Nitrophenyl and 3-pyridyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, m-chlorophenyl, m- and P-hydroxyphenyl, m- and P-methylaminophenyl, m- and P-dimethylaminophenyl, m- and P-acetylaminophenyl, m- and P-methoxyacetylaminophenyl, 2-thienyl, 3-thienyl-2-thienylmercaptomethyl, 2-furyl, 2- And 3-pyridyl and 1-oxido-3-pyridinio.

Compound (I) is 4-oxo-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinoline (HPI). Compounds obtained by reacting with functional derivatives thereof or by cyclization of the compound of formula (III) with a cyclizing agent in the state of separating HX, or by treating the compound of formula (IV) with a reducing agent, and if desired The R group in the compound is converted to another R group, or the racemate of the obtained compound (I) is transformed into its optical colon or the base of formula (I) is converted into its physiologically acceptable acid addition salt or quaternary ammonium salt. Or base (I) is free from its acid addition salts.

In which R is as defined above

X is fluorine, chlorine, bromine, iodine, methylsulfonyloxy or arylsulfonyloxy having 6 to 10 carbon atoms, preferably P-toluene sulfonyloxy, and the dotted line double bonds at the 6 and 7-positions of the ring. This means you can survive.

Generally speaking, the R group represents, for example, one of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl or heterocyclic group.

The alkyl group may be straight or branched and may have up to 17 carbon atoms, in particular up to 6 carbon atoms, and the cycloalkyl group may have 3-12 carbon atoms, preferably 3-7 carbon atoms, and 2 or 3 carbon atoms may be endoalkylene. It may be connected to each other by a connection. Cycloalkylalkyl groups can in particular have up to 8 carbon atoms and aralkyl groups preferably have up to 10 carbon atoms. The aryl group can be partially hydrogenated, in part or in the case of a napryl group, and can have up to 10 carbon atoms. Finally, the cyclic group may have up to 15 carbon atoms, which may be linked to adjacent carbonyl groups by straight or branched chain alkyl or trialkyl groups having up to 4 carbon atoms.

Double or triple bonds can also be present in alkyl, cycloalkyl, cycloalkylalkyl, aralkyl aryl and heterocyclic groups and these groups may be substituted.

R preferably has one of the following meanings.

Alkyl groups having up to 8 carbon atoms which may be substituted with alkoxy having up to 4 carbon atoms; Fluorine, chlorine, nitrile, amino, alkylamino or dialkylamino (the alkyl group contains up to 4 carbon atoms), allylamino, benzylamino (may be substituted by hydroxy or methoxy), up to 18 Cycloalkyl groups having up to 7 carbon atoms which may be substituted with saturated and unsaturated aliphatic acylamino with carbon atoms, amino protected with Schiff base, hydroxy or alkoxy having up to 4 carbon atoms; Fluorine, chlorine, nitro, amino, alkylamino or dialkylamino (each containing up to 4 carbon atoms in the alkyl group) allylamino, benzylamino (which may be substituted by hydroxy or methoxy) Saturated or unsaturated aliphatic acylamino, amino protected as a Schiff base, hydroxy or alkoxy having up to 4 carbon atoms, phenylazo (hydroxy, methoxy, amino, methylamino, dimethylamino, fluorine, chlorine or lower) Carboxymethylamino or alkoxymethylamino containing up to 4 carbon atoms in the alkoxy group; Thienyl, thienyl mercaptomethyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or pyridyl groups; Or a piperidyl group which may be substituted with an alkyl group having up to 4 carbon atoms, benzyl or a saturated or unsaturated aliphatic acyl having up to 18 carbon atoms.

More detailed description of the R group is as follows;

Alkyl groups preferably have up to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, isopentyl, 1-ethyl-propyl, 1, 1-dimethyl-n-propyl, tert-pentyl, n-hexyl, 1, 1-dimethyl-n-butyl 2, 2-dimethyl- n-butyl, isohexyl, n-heptyl, 1, 1-dimethyl-n-pentyl, n-octyl or 2-ethylhexyl group but can also be n-noyl, 1- (n-butyl) -n Such as pentyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-detradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl or isodedecyl, isododecyl, etc. It may be another isomer of yigi; Cycloalkyls may have 3-12 carbon atoms, preferably 3-7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclodecyl or There is cyclododecyl; Two or three carbon atoms in a cycloalkyl group may be linked together by an endoalkylene, for example by an endoalkylene bridge having eight, preferably one or two carbon atoms. For example, -CH ₂ , -CH ₂ -CH ₂ , -C (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₂ -CH ₂₁ -C (C ₂ H ₅ ) ₂ -or CH (CH ₃ ) -CH Examples of the cycloalkyl group which are (CH ₃ ) and thus bonded are bicyclo [2, 2, 1] heptyl-2, bicyclo [2, 2, 2] octyl-2-, bicyclo [3, 2, 2] Nonyl-2, -3 and -6, bicyclo [4, 2, 2] decyl-2, -3 and -7, bicycl [4, 3, 2] undecyl-2, -3,, -7, -8 and -10 or adamantyl as well as alkylated bicyclic systems such as 7-methyl-bicyclo [2, 2, 1] heptyl, 7-ethyl-bicyclo [2, 2, 1] heptyl, 7, 7-dimethyl-bicyclo [2, 2, 1] heptyl, 7, 7-diethylbicyclo [2, 2, 1] heptyl, [1, 7, 7] -trimethyl-bicyclo [2, 2, 1 ] Heptyl, 1-methyl-bicyclo [2, 2, 2] octyl and 1, 2, 3-trimethyl-bicyclo [2, 2, 2] octyl:

The cycloalkyl group preferably has up to 8 carbon atoms, for example cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

Alkyl and cycloalkyl groups may have unsaturated bonds, for example ethenyl, ethenyl, 1-propynyl, 2-propenyl, 8-heptadecenyl, 1-cyclopentinel, 2-cyclopentinyl, 3- Cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 4-cycloheptenyl, 1-part Tail, 2-butenyl, 3-butenyl, 1-cyclooctenyl, 2-cyclooctenyl, 3-cyclooctenyl, 4-cyclooctenyl, 5-cyclocolococtenyl, 1-propynyl and 2- Propynyl.

Aralkyl is preferably up to 10 carbon atoms, for example benzyl, 1- or 2-phenylethyl, 3-phenylpropyl, 1-methyl-1-phenylethyl or 1-methyl-2-phenylethyl .

Aryl preferably has up to 10 carbon atoms, for example substituted phenyl, naphthyl-1, naphthyl-2 or phenanthryl-1 (or -2, -3, -4, -9). Some or all of the naphthyl groups may be hydrogenated, for example 1, 2-dihydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl or decalinyl (cisna trans).

The heterocyclic group can be, for example, a 5- or 6-membered aromatic heterocyclic system which can be condensed with one or two benzo groups or a second 5 or 6-membered heterocycle, for example pyryl 1- (or- 2na-3), thienyl-2 (or -3), furyl-2 (or 3) anddolyl-1 (or -2, -3, -4, -6 or -7), benzofuryl-2 ( Or -3, -4, -5, -6 or -7), benzothienyl-2 (or -3, -4, -5, -6 or -7) pyridyl-2 (or -3 or -4) ), α- or γ-pyranyl-2 (or -3 or 4) α- or γ-thiopyranyl-2 (or -3 or -4), quinolyl-2 (or -3, -4,- 5, -6, -7 or -8), isoquinolyl-1 (or -3, -4, -5, -6, -7 or -8), carbazolyl -1 (or -2, -3, -4 or -9) pyrazolyl -1 (or -3, -4 or -5), imidazolyl -1 (or -2, -4 or -9) benzpyrazolyl-1 (or -2, -4 , -5, -6 or 7), benzimidazolyl-1 (or -2, -4 or -5) oxazolyl -2 (or -4 or -5), benzoxazolyl-2 (or -4, -5, -6 or -7) thiazolyl -2 ( Is -4 or -5) benzthiazolyl -2 (or -4, -5, -6 or -7) isoxazolyl -3 (or -4 or -5) isothiazolyl -3 (or -4 i- 5), 1, 2, 3-triazolyl-1 (or -2 or -4) 1, 2, 4-triazolyl-1 (or -3 or -5) tetrazolyl-1 (or -2 or -5) ) 1, 2, 3- or 1, 2, 4-oxadiazolyl, 1, 2, 4-, 1, 3, 4- or 2, 1, 5-thiadiazolyl, 2, 1, 3-benzo- Thiadiazolyl-5, acridinyl-1 (or -2, -3, -4, -5, -6, -7, -8 or -9) pyrazazinyl-3 (or -4) pyrimidinyl -2 (or -4 or -5), pyrazinyl, phenazinyl-1 (or -2), phenoxazinyl-1 (or -2, -3, -4 or -9) phenothiazinyl-1 (or -2, -3, -4 or -9), thianthrenyl-1 (or-2) 1, 2, 5-, 1, 2, 4- or 1, 2, 3-triazinyl, 1, 2, 3, 4- or 1, 2, 4, 5-detrazinyl, furinyl-2 (or-6, -7, -8 or -9) pyrazolo [3, 4-d] pyrimidinyl-2 ( Or -6, -7 or -9), putridinyl, cynolinyl-3 (or -4, -5, -6, -7 or -8) phthal Lazinyl-1 (or -5 or -6), quinizolinyl-2 (or -4, -5, -6, 7 or -8) quinoxazolinyl-2 (or -5 or -6), 1 , 5-naphthyridinyl-2 (or -3 or -4) or naridixinyl. Heterocyclic groups may also be partially or wholly hydrogenated, for example 1, 4-dioxanyl, morpholinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl , 1, 2, 3, 4-tatrahydropyridyl, 1, 2, 5, 6-tetrahydropyridyl, piperidyl, tetrahydropyranyl, 1, 2, 3, 4-tetrahydroquinolyl, 1, 2, 3, 4-tetrahydroisoquinolyl, hexahydropyridanyl, hexahydropyrimidinyl, piperazinyl, 1, 3-dioxanyl, pyrrolinyl, dihydrofuryl, pyrazolinyl, already Dazolinyl, oxazolinyl, oxazolidinyl, thiazolidinyl, thiazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, 2, 3-dihydrobenzthiazolyl, dihydropyridyl , Dihydropyranyl, tetrahydrothiopyranyl, 1, 2-dihydroquinolyl, 3, 4-dihydroqui Reel, 1, 2-dihydroisoquinolyl, 3, 4-dihydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, chromenyl, chromanyl, dihydropyridazinyl, tetrahydropyridazinyl , Dihydropyridinyl, tetrahydropyrimidinyl, dihydropyrazinone, tetrahydropyrazinyl or 1,4-thiazinyl.

Such alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl or heterocyclic groups may also be substituted more than once and several substituents may also be on one carbon atom or if possible the substituents may be cis or trans. . Such substituents are for example one or more of the following groups; In other words

Alkyl having up to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; Haloalkyl with up to 4 carbon atoms such as fluoromethyl, trifluoromethyl, and chloromethyl: hydroxy alkyl with up to 4 carbon atoms such as hydroxy methyl and hydroxyethyl; Aminomethyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminomethyl, diethylaminomethyl, ethylaminoethyl, diethylaminoethyl, methylamino-n-propyl, dimethylamino-n-pr Aminoalkyl having up to 4 carbon atoms such as mono- and di-ethyl as well as mono- and di-methylamino such as fill and diethylamino-n-butyl and the like; Aryl having 6-10 carbon atoms such as phenyl; Aralkyl having 7 to 19 carbon atoms such as benzyl and triphenylmethyl; Halogen such as fluorine, chlorine, bromine and iodine;

Hydroxy; Alkoxy having up to 4 carbon atoms such as methoxy, ethoxy, h-propoxy, isopropoxy, n-butoxy isobutoxy, sec-butoxy and tert-butoxy; Acyloxy having up to 4 carbon atoms such as formyloxy, acetoxy and propionyloxy; Substituted acetoxy such as trifluoroacetoxy and methoxy acetoxy; Aryloxy having 6-10 carbon atoms, such as phenoxy; 0-, m- and P-fluorophenoxy, 0-, m- and P-chlorophenoxy, 0-, m- and P-aminophenoxy, 0-, m-, and P-methylaminophenoxy Substituted aryloxy such as 0-, m- and P-dimethylaminophenoxy, 0-, m- and P-formylaminophenoxy and 0-, m- and P-acetylaminophenoxy; Amino, alkylamino having up to 4 carbon atoms such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino and tert-butylamino; Dimethylamino, diethylamino, methylethylamino, methyl-n-propylamino, methyl-isopropyl-amino, methyl-n-butylamino, ethyl-n-propylamino, ethylisopropylamino, ethyl-n-butyl amino Dialkylamino having an alkyl group of up to 4 carbon atoms, such as di-n-propylamino, diisopropylamino and di-n-butylamino; Trialkylammonium having alkyl groups of up to 4 carbon atoms, such as trimethylammonium and triethylammonium; Alkenylamino having up to 4 carbon atoms such as vinylamino, 1-propenyl amino, allylamino, 1-butenylamino2-butenylamino and 3-butenylamino; Aralkyl optionally substituted with hydroxyl, methoxymethylamino, dimethylamino, methylthio, methyl or ethyl, such as benzylamino, 2-hydroxybenzylamino, and 2-hydroxy-3-methoxybenzylamino; Formylamino, acetylamino, propionylamino, butyrylamino, pentanoylamino, hexanoylamino, heptanoylamino, octanoylamino, decanoylamino, dodecanoylamino, palmitoylamino, stearoylamino, oleic Acylamino having up to 18 carbon atoms in which acyl groups such as oilamino, linoloylamino, linolenoylamino are derived from saturated or unsaturated fatty acids and preferably derived from fatty acids and having up to 18 carbon atoms; Acyl groups such as trifluoroacetylamino, methoxyacetylamino, ethoxyacetylamino, propoxyacetylamino, isopropoxyacetylamino, butoxyacetylamino and tert-butoxyacetylamino may be substituted with trifluoroacetic acid or lower alkoxyacetic acid ( Wherein alkoxy is acylamino derived from up to 4 carbon atoms); 3-carboxypropionylamino (succinoylamino) 3-carboxy-cis-prop-2-enoylamino (maleoylamino), 2-carboxy-cyclopentylcarbonylamino, 2-carboxy-cyclohexylcarbon Acyl groups can form cyclic anhydrides such as nylamino, phthaloylamino, 2- and 3-carboxy-pyridyl-3- and-2-carbonylamino and 3- (carboxyethyl-mercapto) -propionylamino Acylamino derived from dicarboxylic acids having 4-8 carbons present; Sulfamino; Ethoxycarbonylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, 3, 5-dimethoxybenzyloxycarbonylamino, cyano-tert-butoxycarbonylamino, 2-biphenylyl- ( 4) -isopropoxycarbonylamino, 2, 2, 2-trichloroethoxycarbonylamino, fluorenyl- (9) -methoxycarbonylamino, P-nitrobenzyloxycarbonylamino, P-chloro Substitution with organic groups of up to 15 carbon atoms, such as benzyloxycarbonylamino, P-phenylazobenzyloxycarbonylamino, P- (P-methoxyphenylazo) -benzyloxycarbonylamino and cyclopentyloxycarbonylamino Oxycarbonylamino; Benzylideneamino, P-methylbenzylideneamino, 0-hydroxybenzylideneamino, P-methoxybenzylideneamino, 3, 4-dimethoxybenzylideneamino, 2-hydroxy-3-methoxybenzylideneamino, Up to 9 such as isopropylideneamino, sec-butylideneamino, carboxymethyleneamino, 3-phenyl-2-propene-1-ylideneamino, furfurylideneamino and 5-nitrofurfurylideneamino Alkylidene- and aralkylideneamino having carbon number; α-sulfo-benzylamino, α-sulfo-2-hydroxybenzylamino, α-sulfo-2-hydroxy-3-methoxybenzylamino, sulfomethylamino, 1-sulfoethylamino, 1-sulfo-1- Sulfo and disulfo groups obtained by adding bisulfite to a disulfo group, such as carboxymethylamino and (1,3-disulfo-3-phenyl) propylamino; Alkyl having up to 4 carbon atoms like hydroxy, methoxy or ethoxy, alkylamino having up to 4 carbon atoms like methylamino or ethylamino, and up to 8 carbon atoms like dimethylamino or diethylamino Dialkylamino, acylamino having up to 4 carbon atoms such as naphthylazo-1 or -2 which may be substituted by carboxy, lower alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl, formylamino and acetylamino Preferably substituted with halogen, sulfo, alkoxysulfonyl, such as methoxysulfonyl or ethoxysulfonyl, or alkyl having carbon numbers up to methyl, ethyl, propyl, isobutyl and tert-butyl, such as fluorine or chlorine and bromine P-substituted, phenylazo, for example 3-carboxy-4-hydroxyphenylazo, 4-dimethylaminophenylazo, 4-diethylaminophenylazo, 2-methyl-4-hydroxy-phenylazo, 4 -Methoxy-and 4-ethoxy-phenylazo; Glunoylamino, Glucuronoylamino, Cycloylamino, Galactonoylamino, Galacturnoylamino, Mucoylamino, Mannonoylamino, Manno-saccharoylamino, Arabinonoylamino, Ribonoylamino , Mono- or di-saccharides having 5 to 12 carbon atoms, such as maltobionoylamino, lactobionoylamino and zaccarbionoylamino, preferably oxidized at the terminal carbon atom or the first carbon atom of the corresponding carboxylic acid Amino group, mercapto, methyl mercapto, ethyl mercapto, n-propyl mercapto, isopropyl mercapto, n-butyl mercapto, isobutyl mercapto, sec-butyl methyl capto Alkylmethylcapto with up to 4 carbon atoms like tert-butyl mercapto, aryl mercapto with 6-10 carbon atoms like phenyl mercapto, formyl mercapto, acetyl mercapto and propionylme Acylmercapto with up to 4 carbon atoms like lecapto, thienyl-2-mercapto, thienyl-3-mercapto, nitro, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, n-pro Alkoxycarbonyl having up to 4 carbon atoms in the alcohol component, such as epoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl, Hydrazino, 1-methylhydrazino, 2-methylhydrazino, 1-ethylhydrazino, 2-ethylhydrazino, 1, 2-dimethylhydrazino, 2, 2-dimethyl-hydrazino Alkyl- and acyl-hydrazinos such as 1, 2, 2-trimethylhydrazino and 2-phenylhydrazino, azido, sulfo, methoxysulfonyl, ethoxysulfonyl, and P-tolueneoxasulfonyl Alkoxysulfonyl and aryloxysulfonyl having a carbon number up to, Sulfur as a thiono group, or Acid as a ketone or N-oxide (N-oxide) group A.

If there is a secondary amino group in the R group, it may be a different acyl group, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, deca Saturated or unsaturated aliphatic acyl with up to 18 carbon atoms, such as noil, dodecanoyl, palmitoyl, stearoyl, oleoyl, linoloyl or linolenoyl, methoxyacetyl, ethoxyacetyl, propoxyacetyl, Alkoxy acetyl groups having up to 4 carbon atoms, gluconoyl, glucuronoyl, saccharoyl, galactonoyl, galacturonoyl, mucoyl such as butoxyacetyl, isobutoxyacetyl, tert-butoxyacetyl Mono- or oxidized at the first carbon or at the end carbon of the corresponding carboxyl group, such as mannonoyl, manno-cyclocaryl, arabinoyl, ribonyl, maltobionoyl, lactobionoyl or zaccarbionoyl Di-saccharide group , 3-carboxypropionyl (succinoyl), 3-carboxy-cis-prop-2-enoyl (maleinoyl), 2-carboxy-cyclohexyl, carbonyl, phthaloyl, 2 or 3-carboxy Substitution by acyl or sulfone groups of dicarboxylic acids having 4 to 8 carbon atoms which can form cyclic anhydrides such as pyridyl-3- or-2-carbonyl or 3- (carboxyethylmercapto) -propionyl Can be. If the R groups contain carboxy or sulfo groups, they may be present in the form of their alkali metal, alkaline earth or ammonium salts, preferably sodium or potassium salts.

Formula (II) compounds used as starting materials may be used in the form of free acids or functional derivatives. Examples of such functional derivatives are alkylesters, lactones, halides, azides and anhydrides. The alkyl group of the ester group may have up to 4 carbon atoms, for example medyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl. As the lactone, for example 4-butyrolactone, 4- and 5-valerolactone and 3-hydroxy-3-methyl-5-valerolactone can be used. The halide is preferably chloride or bromide, but fluoride or iodide may also be used.

As anhydrides, mixed, cyclic and Leuchs anhydrides can be used as well as symmetric anhydrides as long as they can be formed. The acyloxy group in the mixed anhydride (compound 2 in which the hydroxy group is substituted with the acyloxy group) is preferably trifluoroacetoxy, acetoxy, formyloxy, propionyloxy, butyryloxy or isobutyloxy. Cyclic anhydrides are, for example, dicarboxylic acids such as glutaric acid, maleic acid, succinic acid, cyclobutane-1, 2-dicarboxylic acid, cyclopentane-1, 2-dicarboxylic acid, cyclohexane-1, 2-dicarboxylic acid and phthalic acid. Can be derived from.

Leihi anhydrides are formed from aliphatic amino acids such as glycine, leucine, isoleucine, as well as amino acids and phosgene such as 1-amino-1-carboxylic acids of cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane or thiopitane.

When the X group is an arylsulfonyloxy group, this is preferably a phenylsulfonyloxy, P-tolylsulfonyloxy, naphthyl-1-sulfonyloxy or naphthyl-2-sulfonyloxy group.

The preparation of novel compounds of general formula (I) and the conversion to other compounds of general formula (I) are described in the literature (see, eg, Houben Weyl, Methoden der organischen Chemie Pnb, Georg-Thieme-) under known reaction conditions suitable for each reaction. Verlag, Stuttgart).

All starting materials necessary for the preparation of novel substances of general formula (I) can be produced in themselves, such as if desired, without further separation from the reaction mixture and immediately further reaction to obtain the desired compound of general formula (I).

The compound of formula (I) can be prepared by reacting HPI with a carboxylic acid of formula (II) or a functional derivative thereof. Preferred functional derivatives include carboxylic acid anhydrides, mixed carboxylic acid anhydrides such as p-fluorobenzoic acid-formic anhydride, carboxylic acid halides and azides such as fluorides, chlorides, bromide and iodides. Excess carboxylic acid derivatives may be used as solvents or the reaction may be carried out with aromatic hydrocarbons such as benzene or toluene, diisopropyl ether, ethers such as tetrahydrofuran or dioxane, nitriles such as acetonitrile, dichloromethane, chloroform, halogenated carbons or chlorobenzenes. It is carried out in the presence of an inert solvent such as a hydrocarbon.

When acylating, it is preferable to add organic or inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, pyridine, triethylamine or triisopropylamine. The reaction with the acid (II) itself is preferably carried out at 0-200 ° C., and its functional derivative is preferably between 0 ° C. and the boiling point of the solvent used, preferably 0 ° C.-80 ° C. The reaction time is 10 minutes-48 hours, preferably 30 minutes-5 hours.

From the corresponding carboxylic acids (II) with halogenating agents such as silicon tetrachloride, phosphorus trichloride, bromide, phosphorus oxychloride, thionyl chloride or phosphorus pentachloride, preferably in one of the above solvents or the organic bases mentioned above One can also be added to produce carboxylic acid halides, in particular chlorides, in-house. In this case, 40-200 ° C. is particularly preferable.

The reaction of HPI with free carboxylic acid (II) is preferably carried out at low temperature (eg 0-20 ° C.), for example in the presence of dicyclohexylcarbodiimide in one of the inert solvents or in pyridine.

HPI and the above at about 0 ° -200 ° C. in the presence or absence of a basic catalyst such as sodium or potassium hydride and usually in the presence of xylene, dimethylformamide, dimethylsulfoxide, sulfolane, dioxane, tetrahydrofuran or diethyl ether One of the lactones can be reacted.

In addition to the racemic HPI as starting material, one of the two optical isomers, in particular the (-) symmetry, can be converted into an optically active (I) pharmacologically valuable compound by acetylation.

Starting materials (as well as carboxylic acid (II) as well as HPI) can be prepared as well as known materials by known or representative methods.

Compounds of formula (I) may also be prepared by cyclization of compounds of formula (III) in the presence of cyclizing agents under conditions separating HX. As cyclizing agents, alcohols such as butyllithium, potassium-tert-butylate, phenyllithium, sodium hydride, sodium or potassium methylate, ethylate, propylate, isopropylate, n-butylate and tert-butylate, lithium Strong bases such as isopropylamide or the corresponding amides such as sodium or potassium amide may be used. This reaction is usually carried out under nitrogen stream if desired in an inert solvent such as benzene, hexane, tert-butanol, tetrahydrobutan, hexamethylphosphoric acid, triamide, dioxane, ether, dimethylformamide, dimethylsulfoxide or acetonitrile. do. The reaction temperature is good between the boiling point of the solvent used at -20 ° C- and the reaction proceeds for 15 minutes to 30 hours, preferably 10 to 14 hours. Cyclization is carried out using optically active compound (III) as a starting material, thereby obtaining an optically active isomer (I) compound.

Starting materials of the general formula (III) are, for example, corresponding 1-cyano-1 substituted in the 2-position with an R-CO- group (which has the same meaning as in general formula I) according to methods known in the literature. , 2-dihydro- or 1-cyano-1, 2, 3, 4-tetrahydro-isoquinoline. It is reduced by separating the R-CO- group in the presence of tannickel under high temperature and pressure to give the corresponding N- (1, 2, 3, 4-tetrahydroisoquinolyl-1-methyl) acylamide, which continues to be an example. For example, the compound may be converted into a general formula (III) compound together with the general formula X-CH ₂ -CO-X compound such as chloroacetyl chloride.

In addition, the compound of formula (I) may be obtained by reducing the compound of formula (IV), preferably by catalytic hydrogenation. As catalysts for this purpose, conventional catalysts known in the literature, preferably noble metal catalysts, but not only nickel and cobalt catalysts but also copper-chromium oxide catalysts can be used.

Precious metal catalysts can be used, for example, on a carrier (eg palladium on activated carbon) or as an oxide catalyst (eg platinum oxide) or as a finely ground metal catalyst (eg platinum sponge). Nickel and cobalt catalysts are preferably used as Raney metals, and nickel may also use diatomaceous earth or pumice as a carrier. The hydrogenation reaction is carried out at about 1-200 atm, preferably 0-200 ° C., preferably alcohols such as methanol, ethanol, isopropanol or tert-butanol, ethers such as ethyl acetate, dioxane or tetrahydrofuran, water or solvents such as alkaline solutions. It is recommended to carry out under.

If desired, the hydrogenation can also be carried out in a homogeneous phase. As a catalyst for this purpose, for example, heavy metal complexes such as soluble rhodium complexes such as hydrido-carbonyl-tris (triphenyl-phosphine) rhodium can be used. Reduction of compound (IV) can also be carried out, for example, by asymmetric hydrogenation so that all or most of the compound is isomer of compound (I). Catalysts for this purpose include, for example, an aqueous solution of optically active hydroxy, or a rannickel pretreated with an asymmetric modifier such as amino acids such as tartaric acid, citric acid, alanine, isorucine, lysine, phenylalanine, valine or leucine. Can be used.

For asymmetric hydrogenation, heavy metal catalysts acting on natural or synthetic polymers can be used as described in the literature. Palladium or platinum, for example, is used on silk or specially prepared silica gel or polyamino acid carriers. Asymmetric hydrogenation in a homogeneous phase can be carried out, for example, as an optically active and soluble rhodium complex salt. The asymmetric hydrogenation reaction is preferably carried out at 20-50 ° C. at 1-3 atmospheres under the above-mentioned conditions.

Starting material (IV) can be prepared, for example, by dehydrogenation of the corresponding compound of formula (I) saturated at the 11b (1) -position with sulfur, selenium, chloranyl or other dehydrogenating agents known from the literature. This reaction is of particular interest when the compounds saturated at the 11b (1) -position are optically active isomers and are less effective than other possible isomers. In this case, less effective isomers can be dehydrogenated to convert to compound (IV) and continue to hydrogenate to obtain racemic form of the more saturated saturated formula (I), or asymmetric hydrogenation to almost completely more effective formula (I). Can be converted to isomers.

The R group of the obtained compound of formula (I) may be converted to another R group according to the method described in the literature, if desired. For example, existing substituents can be converted to other substituents.

Such reducible substituents, such as nitro groups, can be catalytically hydrogenated or chemically reduced. Catalytic reduction can be carried out under the conditions described above. To carry out this reduction reaction, for example, metals (eg iron, zinc) and acids (eg hydrochloric acid or acetic acid) or tin chloride can be used.

Additional keto groups in the acyl group of compound (I) can be hydrogenated or chemically converted to hydroxyl groups. This hydrogenation reaction is easily carried out according to the method described above. Furthermore, keto groups can be reduced to hydrogen gas by treatment with, for example, an aqueous solution of zinc / acid (eg acetic acid) or zinc / alkali metal hydroxide. Sodium or other alkali metals may be used in lower alcohols such as ethanol, isopropanol or isoamyl alcohol. Keto groups may also be metal hydrides, preferably amides such as sodium borohydride, sodium borohydride, potassium tri (sec-butyl) -brohydride or potassium trimethoxyborohydride. Complex salt metal hydrides which do not attack groups can be reduced in the presence of an inert solvent, for example ethers such as diethyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxyethane or diglyl. The reaction can be carried out between -80-100 ° C., in particular between -20 ° C. and the boiling point of the solvent.

Furthermore, keto groups can be converted to methylene groups, for example, by the Wolff-Kishner method, which reacts with hydrazine and decomposes the formed hydrazone. In addition, under the above conditions, the double bond may be reduced to a single bond or the triple bond may be reduced to a double bond or a single bond. N-oxide groups in the R group can be reduced to the corresponding tertiary amines according to known methods using hydrogen / palladium. Compounds (I) having tertiary nitrogen atoms in acyl groups are for example hydrogen peroxide (preferably a 30% aqueous solution or a mixture of hydrogen peroxide and formic acid). It can be converted to commercially available N-oxides by reacting with inorganic or organic peroxides such as peracetic acid, perbenzoic acid, 3-chloro perbenzoic acid or tert-butylhydroperoxide.

As a solvent of the organic peroxide, for example, methylene chloride, chloroform, or alcohols such as methanol or isopropanol can be used, and the reaction can proceed at 0-50 ° C, preferably at room temperature, and the reaction time is 1-48 hours.

Compounds (I) having a mercapto group in the R group can be oxidized with nitric acid to form the corresponding sulfo compound. Similarly, the corresponding alkylthio group can be, for example, sulfonic acid as an aqueous solution of nitric acid, hydrogen peroxide or 3-chloroperbenzoic acid. Can be converted to sulfoxide. The alcohol group in the R group can be converted to a carbonyl group by oxidation with manganese dioxide or chromic acid.

Compound (I) having one or more free hydroxy, mercapto, amino or monoalkylamino groups as substituents may be alkylated or correspondingly substituted with the corresponding alcohol, alkylthio, monoalkylamino, dialkylamino or trialkylammonium compounds. Acylates can be acylated.

For the 0- and S-alkylation reactions the starting materials are preferably converted to the corresponding salts by the addition of a base of, for example, sodium hydroxide, potassium hydroxide or potassium carbonate aqueous solution. Examples of alkylating agents that may be used are methyl chloride bromide, alkyl halides such as iodide, ethyl chloride, bromide or iodide, dimethyl sulfate, diethyl sulfate or corresponding dialkyl sulfates or alkyl sulfides such as methyl P-toluenesulfonate Diazo compounds such as phonic acid or diazomethane. The amino compound can be reductively alkylated with formaldehyde or acetaldehyde in the presence of hydrogen and a catalyst or in the presence of formic acid. As a solvent, for example, water or an aqueous solution of sodium hydroxide, alcohols such as methanol, ethanol or n-butanol: hydrocarbons such as benzene or xylene, ethers such as tetrahydrofuran or dioxane and amides such as dimethylformamide may be used. The alkylation reaction is preferably carried out between -10-150 ° C., in particular between room temperature and the boiling point of the solvent used.

Corresponding acylation reactions are preferably carried out with carboxylic acids or carboxylic acid derivatives under conditions as described, for example, in the acylation of HPI. The acylation reaction may also be carried out with a curtain, preferably in an inert solvent such as ether, dichloromethane, chloroform, benzene or toluene. It is also possible to add an acid catalyst such as sulfuric acid or P-toluene sulfonic acid. That is, for example, 2- (4-acetoxy benzoyl) -HPI is obtained from 2- (4-hydroxybenzoyl) -HPI and ketene. The obtained general formula (I) compound having a primary or secondary amino group in the R group can be reacted with a sugar derivative under the above-described conditions to prepare a compound in which the amino group in the R group is protected with sugar acid. As a sugar derivative, sugar lactone, such as gluconate lactone and glucuronic acid lactone, can be used, for example. The amino groups in the R groups can also be reacted with sugar acids or functional derivatives thereof, for example other hydroxyl groups protected by benzyl groups, for example separated again by hydrogenation. Thus for example 2- (4-aminobenzoyl) -HPI is reacted with 2, 3, 4, 5, 6-penta-0-benzyl-gluconoyl chloride and the resulting 2- [4- (2, 3, The benzyl group in 4, 5, 6-penta-0-benzyl-gluconoylamino) -benzoyl] -HPI can be hydrolyzed to obtain 2- (4-gluconoylaminobenzoyl) -HPI.

Compound (I) in which the amino group in the R group is protected by at least one sulfo group, for example, reacts the compound (I) having one or more free amino groups in the R group with chlorosulfonic acid under the reaction conditions described when reacting HPI with an acid halide. It can be obtained by reacting. Acyloxy (eg, formyloxy, acetoxy, trifluoroacetoxy, phthaloyloxy or other readily saponifiable groups) in the compound of formula (I) obtained by solvolysis preparation treatment. An acyl merbetto group or an alkoxycarbonyl group (for example, methoxycarbonyl or ethoxycarbonyl) can be converted into a hydroxyl, mercapto or carboxyl group. For this purpose, acids such as hydrochloric acid or acetic acid, or preferably bases such as sodium or potassium carbonate or calcium, barium, sodium or phosphium hydroxide can be used, for example, in aqueous methanol solution.

In order to avoid attacking acid amide groups, it is better to use mixed reaction conditions. In general, the reaction proceeds for 2-50 hours at -40-90 ℃.

The cyano group in the compound of formula (I) is in an acidic medium (e.g. aqueous hydrochloric acid or sulfuric acid solution, methanol, ethanol, dioxane or acetic acid aqueous solution) or an alkaline medium (e.g. ethanol aqueous solution or potassium hydroxide in cyclohexanol). Carbamoyl groups can be hydrolyzed. Hydrogen peroxide can also be used in alkaline solutions, typically at room temperature to 80 ° C. for 1-5 hours.

Compounds in which the amino group in the acyl group is protected in the form of a schiff base can be converted to the corresponding secondary amine by the hydrolysis method. Schiffbases are more easily derived from, for example, ketones such as aldehydes such as formaldehyde, benzaldehyde or glyoxylic acid or acetone.

For hydrogenation, hydrogen may be used, for example, in the presence of platinum or nickel, at room temperature under atmospheric pressure.

Benzylamino compounds can be decomposed with hydrogen, for example in the presence of a noble metal catalyst such as palladium to obtain the corresponding primary amine.

It is also possible to convert the Schiff base obtained into a corresponding bisulfide whole by reaction with bisulfite. Bisulfite inner parts can also be obtained by directly reacting an aldehyde-bisulfite addition product with a compound having a free amino group in the R group.

The urethane group in the R group of compound (I), for example, N-ethoxycarbonyl or N-benzyloxycarbonyl group, can be separated by reaction with hydrogen chloride in acetic acid. The corresponding amino group is liberated from the piouureban group in the R group of compound (I), for example, with an alkali metal acetate or lead diacetate in an alcohol such as methanol or ethanol, or with an alkali metal hydroxide solution in the presence of lead dihydrate or lead carbonate. You can. Theoretically, as the amino protecting group in the acyl group of the compound of formula (I), there may be everything that is successfully used for peptide synthesis.

Thus, methods known in the literature raising this protecting group can also be used. The alkylamino substituents of compound (I) can also be converted to 1-alkylhydrazino substituents by, for example, reacting with nitrous acid and reducing the resulting nitrosoamino compound to hydrogen chloride (eg from zinc / acetic acid) tin chloride. have. Furthermore, the keto group in the (R) group of compound (I) can be converted to an amino group, for example by reacting ketones with hydroxylamine or hydrazine and reacting the resulting oxime or hydrazone at 1-50 atm in the presence of nickel. Hydrogenation. Alternatively, the ketone is hydrogenated in the presence of ammonia or primary or secondary amines to yield primary, secondary or tertiary amines (I). The reaction is preferably carried out in -40-150 ° C. at 1-200 atm, for example in methanol, ethanol, isopropanol tetrahydrofuran or liquid ammonia.

The keto groups in compound (I) can also be converted to CF ₂ groups according to conventional methods, for example by reacting with sulfur tetrafluoride or phenyl trifluoride in the presence of hydrofluoric acid or with carbonyldifluoride in the presence of pyridine. . This reaction is preferably carried out at 0-150 ° C. in an inert solvent such as methylene chloride, chloroform and tetrahydrofuran at slightly high pressure in the autoclave.

The alkoxy or alkylthio group in compound (I) may be separated to obtain a hydroxyl group or a mercapto group. This reaction condition should be chosen with a safe acid amide group. It is recommended to use Lewis acids such as borontribromide at about -40-50 ° C in an inert solvent such as dichloromethane, chloroform or carbon tetrachloride.

Compound (I) having one or more amino groups is converted to the corresponding diazonium compound according to a conventional diazotization method, and then this diazonium group is, for example, fluorine, chlorine, bromine, iodine, cyano, hydroxyl , May be substituted by mercapto, 0-alkyl or S-alkyl.

Diazolation of amino compounds can be carried out, for example, by addition of inorganic nitrates such as sodium or potassium nitrate at -20-10 ° C in aqueous sulfuric acid, hydrochloric acid, bromic acid or tetrafluoroboric acid.

In addition, organic nitrile such as n-butyl nitrile, n-amyl nitrile or isoamyl nitrile may be used at -20-50 ° C. in an inert organic solvent such as diethyl ether tetrahydrofuran or dioxane.

In order to introduce fluorine atoms, the diazotization reaction is carried out by heating anhydrous hydrofluoric acid solution, or the diazonium salt is reacted with tetrafluoroboric acid to obtain diazonium tetrafluoroborate which is partially dissolved.

This compound can be separated by heating in an inert solvent and converted to the desired fluorine compound while generating heat. However, diazonium tetrafluoroborate, especially a heterosulfur compound, is irradiated with mercury or the like in a suspension solution without separation to obtain a desired fluorine compound. This diazonium group may be substituted with chlorine or bromine in a hot aqueous solution, preferably in the presence of copper chloride or copper bromide.

Substitution of the diazonium iodide group with iodine occurs even with a slight warming with addition of copper iodide, copper bromide or copper chloride.

Substitution of the diazonium group with a cyano group occurs at about 0-50 ° C. in the presence of alkali metal cyanide and copper cyanide, such as, for example, sodium or potascyanide. Diazonium groups may be substituted with alkoxy groups by heating an alcoholic solution.

Substitution with the mercapto group is readily accomplished by reacting the diazonium compound with sodium with an alkali metal xanthogenate, such as thylkanthogenate, and with an alkaline gum. Diazonium compounds may also be coupled with suitable coupling agents to obtain the corresponding diazo dyes. As the coupling agent, it is particularly preferable to use benzene compounds having active substituents such as amino, alkylamino, dialkylamino, hydroxy or alkoxy groups and also substituents such as carboxy, halogen (preferably fluorine or chlorine), sulfo or alkyl groups. It is better to have more.

Basic compound (I) can be converted to its physiologically acceptable acid addition salt, if desired. For this purpose, for example, inorganic acids such as hydrochloric acid, bromic acid, iodic acid, sulfuric acid, nitric acid orthophosphoric acid or sulfamic acid: formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, diethyl acetate, oxalic acid, malonic acid, succinic acid, Pimelic acid, fumaric acid, maleic acid, citric acid, gluconic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, phenylpropionic acid, ascorbic acid, isnicotinic acid, methanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid (Ise Ionic acid), organic acids such as P-toluene-sulfonic acid, naphthalene-mono or disulfonic acid (e.g., naphthalene-1- or-2-sulfonic acid or naphthalene-1, 5-or-2, 6-disulfonic acid) Inorganic or organic acids such as aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic-mono or polybasic carboxylic acids or sulfonic acids can be used.

Compound (I) having a free carboxyl group or a free sulfo group can be reacted with a base and converted into its physiologically acceptable metal salt or ammonium salt. However, examples of salts include sodium, potassium, magnesium, potassium and ammonium salts and dimethyl and diethyl ammonium, cyclohexyl ammonium, dicyclohexyl ammonium, N-alkyl- or N-aryl-substituted piperazinium salts (e.g. methyl- Substituted ammonium salts such as piperazinium and ethyl-piperazinium salts), N, N-dibenzyl-ethylene-diazomium salts.

The basic substance (I), on the other hand, can be freed from other acid addition salts by treatment with sodium or potassium hydroxide or with a base such as sodium carbonate or potassium, and acidic from its metals and ammonium salts by treatment with acids, especially inorganic acids such as dilute hydrochloric or sulfuric acid. Compound (I) may be liberated. Compound (I) having a primary, secondary or tertiary amino group can be converted to its physiologically acceptable quaternary ammonium salt by treatment with quaternary alkylating agents such as methyl iodide, dimethylsulfate or ethyl halide.

Photosynthetic compounds of general formula (I) can be readily obtained using starting materials which are already optically active.

The symmetry of HPI or the compound of formula (I) is usually used. However, the racemate of formula (I) obtained can be separated by its optical isomer, and chemical separation methods are usually used. For example, the partial geometric isomer mixture obtained by reacting the racemate of formula (I) with an optically active adjuvant can be separated by a suitable method. That is, racemates of general formula (I) with acidic groups (eg carboxyl groups) can be reacted with optically active bases, or racemates (I) with basic groups (eg amino groups) are optically active Can be reacted with an acid. Optically active bases include, but are not limited to, quinine, cinconidine, bursin, cinconine, hydroxyhydrindamin, morphine, 1-phenylethylamine, 1-naphthylethylamine, optically active amines such as quinidine or strikin, or lysine or arginine Basic amino acids, or amino acid esters. As optically active acids, (+) of tartaric acid, dibenzoyltinic acid, diacetyltinic acid, camphoric acid, β-campo-sulfonic acid, mandelic acid, malic acid, 2-phenylbutyl acid, dinitrodiphenic acid, lactic acid or quinic acid (+ ) And (-) types can be used. The resulting diastereomeric mixtures can be almost separated by selective crystallization or artificial selection. The separated diastereomeric isomers can in turn be separated into the desired optically active compounds of formula (I) by hydrolysis methods. The general formula (Ⅰ) compound has an antiparasitic effect on tapeworms and dystomies, and can be used as an insect repellent in the following tapeworms according to the host.

Ruminants: Moniezia, Stilsia, Abitellina, Tisanosoma, Tisaniezia, Taenian Insects, Koenurus Cerebraris and Echinoccosi.

2. ungulates: Anoflocepala.

3. Rodents: Hymonorepsis (especially H, Nana and H, Diminuta).

4. Birds: Davainea, Riley Tina and Hymonorepis.

5. Dogs and cats: Taenia (especially T, Heidatigena, T, Fish Pomis, T, Taenia Epomis, T. Ovia, T. Serialis, Servi and T. suticeptes). Depilidedium (particularly D, caninum), and echinococcus (particularly E. granulohydrogen and E, multyrokularis).

6. Humans: Taenia (especially T. Solium, T. Saginata and T. Serialis). Himezolepis (especially H. Nana and H. Diminuta), Drephanidotaenia, Diphylldium, Diplophilidum, Coenurus (especially C. Cerebrilis). Dipillobotium (especially D. Ratum) and echinococcus fossils (especially E. granulohydrogen and E. moltyrocactis).

Important reptiles to be remedied in medicine and veterinary medicine belong to the genus Cistosomida, especially cistosoma species (cystosoma mansony, cystosoma hamatobium and cystosoma japonicum). . In addition, passiola, dicrocoelium, clonokis, office torques, paragonimus, pararamptomum, and echinostoma species may also have an effect.

Compound (I) can be used to combat tapeworms, worms or larvae in hosts or intermediate media such as: humans, monkeys, or dogs or foxes, cats such as cats, horses, donkeys and donkeys. It can be used for most important livestock or wildlife, such as ungulates, deer such as roe deer or wild deer, ruminants such as chamois, rodents, goats, goats, ducks, birds, pigs and fish.

The habitats of parasites or larvae that can nourish are, for example, the gastrointestinal tract such as the stomach, intestines, intestines and bile ducts.

However, various other organs include the liver, kidneys, lungs, heart, lymphatic vessels, brain, spinal cord, testes, abdominal cavity, connective tissue, muscles, peritoneum, pleura, diaphragm, blood vessels, and the like.

Compound (I), for example, exerts excellent fighting ability against T. hidatigen and parasites of cystosoma in the vascular system, hymenorepis microma of the bile duct and liver.

Compound (I) can be used as is or mixed with a pharmaceutically acceptable inert carrier. Such carriers include capsules, solid diluents or fillers, sterile distilled water or various non-toxic organic solvents.

Dosage forms that may be used include tablets, dragees (which may contain the active substance in accumulated form), effervescent tablets, capsules, granules, suspensions, injectables, emulsifiers, suspensions, elticoses, syrups and ointments. have.

Such formulations may be prepared according to known methods, such as adding the active substance with an emulsifier or suspending agent to a solvent or a carrier.

Auxiliaries include water, non-toxic organic solvents (e.g. paraffin, alcohols such as glycerol or polyethylene glycol), vegetable oils (e.g. sesame oil), solid carriers such as millennium or synthetic inorganic powders (e.g. talc, fine silicic acid), sugars, emulsifiers ( For example, ionic or nonionic), suspending agents (eg methyl cellulose, polyvinyl pyrrolidine) or lubricants (eg magnesium stearate) can be used.

Tablets may also contain adjuvants such as sweeteners, sodium citrate, calcium carbonate, calcium phosphate, together with adducts such as starch, gelatin. Aqueous solutions or elixirs may contain a mate or colorant. Compound (I) may also be administered with little or no adjuvant as in capsules.

Oral administration of the active substance (I) is preferred, but may also be parenterally administered, especially subcutaneously.

In order to combat the growing tapeworms, the active ingredient is recommended to be administered orally or subcutaneously, 0.01-250, preferably 0.5-100mg per body weight per day. More active ingredients may be needed to combat growing dystomosis larvae or cystosomes.

When a relatively large amount of the active ingredient is administered, it may be divided into several small portions, for example, 200 mg instead of 1,000 mg may be administered five times. In the case of administration to animals, it may be administered with food, or a premixed food may be added to the food. The dosage may vary depending on the nature of the weight or route of administration as well as the type and its response to the drug, the nature of the formulation, the time of administration or the interval of administration. That is, in some cases an amount less than the minimum amount is sufficient, while in some cases the maximum amount is exceeded.

Depending on the mode of administration, the ratio of compound (I) to carrier or adjuvant used can vary considerably. For example, when administering compound (I) in tablets or dragees, about 0.01-2, 500 mg of active substance is used. -10, 0000 mg of adjuvant can be mixed, while 0.1-400 g of compound (I) per kg of carrier or adjuvant can be used when admixing compound (I) to feed. In preparing injections, 1 L liquid solution may contain about 0.5-100 g of compound (I) depending on the nature of the solvent used. Likewise, 1 liter syrup can dissolve or suspend 0.5-250 g of compound (I). Compound (I) may also be in admixture with other active substances. That is, to obtain a wide range of activities, for example, active substances active against nematodes, such as thiabendazole [2- (4-thiazolyl) benzimidazole] or piperazine (or piperazine derivatives such as N-methyl-piperazine) It may be advantageous to add.

It is also possible to administer a mixture of two or more compounds of general formula (I). The antiparasitic action of compound (I) is described in more detail in the following examples.

A. Pharmacological Examples

The following compounds (I) were tested.

The following compounds were used as comparative agents.

Quinacrine [2-methoxy-6-chloro-9-[(1-methyl-4-diethylaminobutyl) amino] -acridine

Nitrosamide [N- (2-chloro-4-nitrophenyl) -5-chlorosalicylamide

Dichlorophene (2, 2'-dihydroxy-5, 5'-dichlorodiphenylmethane).

Lucantone [1- (2-diethylaminoethylamino) -4-methylthioxanthone hydrochloride

Niridazole [1- (5-nitro-2-thiazolyl) -imidazolidine-2-silver]

Styvofen [Sodium antimony-bis- (pyrocatechol-2, 4-disulfonate)]

Example a

Hymenorepis nana, adult, larvae / mouse,

Hymenorepis microstomes, adult / mouse,

Hymenorfish Diminuta / Rat

Test animals infected with H. nana, H. microstoma or H. diminuta after larval infection or after parasites began to work were treated for 1-3 days and the active substance was orally or subcutaneously in aqueous suspension. Administered. The test animals were counted and the activity of the preparation was counted by counting the number of parasites remaining in the test animals and compared to the untreated animals to calculate the percentage of effect.

TABLE 1

Example b

Formia larvae (larva) / mice

Mice experimentally infected with theteaterian larvae larvae were treated for about 2-5 months after infection and the active substance was orally administered in an aqueous suspension. The activity level of the preparation was obtained by counting the number of live larvae and dead larvae in mice, and calculating the percentage of activity compared to the non-treated comparison animals.

TABLE 2

Example c

Dogs

Dogs that were experimentally or naturally infected with Tenia Haidatigen or Tenia Fishformis were treated after parasite activity and the active ingredient was orally administered with gelatin calcel. The degree of activity was determined by counting the number of parasites lost after treatment and the number of parasites remaining in the test animals. Table 3 was then obtained.

TABLE 3

Example d

Echinococcus multiroculus / dog

Dogs experimentally infected with Echinococcus multeroculus were treated 25-29 days after infection and the active ingredient was orally administered to the gelatin capsules in the pure state. Activity level was calculated in the same manner as in Example a) to obtain the following Table 4.

TABLE 4

Example e

Sistosoma Mansony / Mice

Mice experimentally infected with cystosoma mansoni were treated with parasites after active activity, and the active ingredient was orally administered in an aqueous suspension. Experimental animals were excised to count the number of living parasites and dead parasites to determine the effect of Table 5 below.

TABLE 5

을 의미한다.The following example illustrates the present invention in which [α] represents chloroform.

Means.

Example 1

50 ml of chloroform and 3.71 g of nitrobenzoyl chloride were added dropwise at 50 ° C. with 50 ml (±) -HPI 4.04 g of chloroform and 2.8 ml of triethylamine, and the reaction mixture was shaken with dilute hydrochloric acid and water after 1 hour. It was dried and evaporated to give (±) -2- (4-nitrobenzoyl) -HPI, and the melting point was 212-213 ° C when recrystallized from methanol. The following compounds were prepared in a similar manner from suitable carboxylic acid chlorides.

2-acetyl-HPI; Melting point 139 ℃

2-propionyl-HPI; 2-n-butyryl-HPI;

2-isobutyryl-HPI; Melting point 120 ° C;

2-n-valeryl-HPI;

2-isovaleryl-HPI; 2- (2-methylbutyryl) -HPI;

2-trimethylacetyl-HPI; Melting point 150 ° C .;

2-n-hexanoyl-HPI;

2- (2-methyl-n-valeryl) -HPI;

2- (3-methyl-n-valeryl) -HPI;

2- (4-methylvaleryl) -HPI;

2- (1-ethyl-n-butyryl) -HPI;

2- (2, 2-dimethyl-n-butyryl) -HPI;

2- (3, 3-dimethyl-n-butyryl) -HPI; Melting point 113 ° C .;

2-heptanoyl-HPI; Melting point 90-91 ° C .;

2- (2, 2-dimethyl valeryl) -HPl; Melting point 129 ° C .;

2-octanoyl-HPI; 2- (2-n-propyl-hexanoyl) -HPI;

2-decanoyl-HPI;

2- (2-n-butylhexanoyl) -HPI; Melting point 96 ℃

2-undecanoyl-HPI;

2-hexadecanoyl-HPI; Melting point 101-102 ° C .;

2-octadecanoyl-HPI;

2-trifluoroacetyl-HPI;

2-chloroacetyl-HPI;

2-dichloroacetyl-HPI; Melting Point 151-152 ℃

2-trichloroacetyl-HPI; Melting point 184-185 ℃

2- (3-chloropropionyl) -HPI;

2-tris- (chloromethyl) -acetyl-HPI; Melting point 133-135 ℃

2- (2-acetoxyacetyl) -HPI;

2- (2-ethoxyacetyl) -HPI; Melting point 135 ℃

2- (2-ethoxyacetyl) -HPI;

2-dimethylaminoacetyl-HPI;

2-dimethylaminoacetyl-HPI;

2-methyl-ethylaminoacetyl-HPI;

2- (2-dimethylamino-propionyl) -HPI;

2- (2-diethylamino-propionyl) -HPI;

2- (3-dimethylamino-propionyl) -HPI;

2- (3-diethylamino-propionyl) -HPI;

2- (2-dimethylamino-n-butyryl) -HPI;

2- (2-diethylamino-n-butyryl) -HPI;

2- (4-dimethylamino-n-butyryl) -HPI;

2- (4-diethylamino-n-butyryl) -HPI;

2- (2-dimethylamino-n-valeryl) -HPI;

2- (2-diethylamino-n-valeryl) -HPI;

2- (5-dimethylamino-n-valeryl) -HPI;

2- (5-diethylamino-n-valeryl) -HPI;

2- (2-dimethylamino-n-hexanoyl) -HPI;

2- (6-dimethylamino-n-hexanoyl) -HPI;

2- (6-diethylamino-n-hexanoyl) -HPI;

2- (2-phenylacetyl) -HPI; Melting point 123-124 ℃

2- (2-hydroxy-2-phenylacetyl) -HPI;

2- (2-acetoxy-2-phenylacetyl) -HPI; Melting point 101-102 ℃

2-phenoxyacetyl-HPI;

2- (4-fluorophenoxyacetyl) -HPI;

2- (3-chlorophenoxyacetyl) -HPI;

2- (4-chlorophenoxyacetyl) -HPI; Melting point 159-160 ℃

2- (3- (4-fluorophenoxy) propionyl) -HPI;

2- (3- (3-Chlorophenoxy) -propionyl) -HPI;

2- (3- (4-chlorophenoxy) -propionyl) -HPI;

2- (thienyl-2-mercaptoacetyl) -HPI; Melting point 89-90 ℃

2- (thienyl-3-mercaptoacetyl) -HPI;

2-chloronoyl-HPI;

2-methacryloyl-HPI;

2-vinylacetyl-HPI;

2-cinnamoyl-HPI; Melting point 152 ℃

2-phenylpropioyl-HPI; Melting point 155 ℃

2-phenoxycarbonyl-HPI; Melting point 136-137 ℃

2-ethoxysaryl-HPI; Melting point 126 ℃

2-cyclopropyl-carbonyl-HPI; Melting point 148 ℃

2- (2-acetoxycyclopropyl-carbonyl) -HPI;

2- (2-fluorocyclopropyl-carbonyl) -HPI;

2-cyclobutyl-carbonyl-HPI; Melting Point 154-155 ℃

2- (2-ketocyclobutyl-carbonyl) -HPI;

2- (3-ketocyclobutyl-carbonyl) -HPI;

2- (2-fluorocyclobutyl-carbonyl) -HPI;

2- (3-fluorocyclobutyl-carbonyl) -HPI;

2- (2-Chlorocyclobutyl-carbonyl) -HPI;

2- (3-Chlorocyclobutyl-carbonyl) -HPI;

2- (2-methylcyclobutyl-carbonyl) -HPI;

2- (3-methylcyclobutyl-carbonyl) -HPI;

2- (2, 2-difluorotocyclobutyl-carbonyl) -HPI;

2- (3, 3-difluorocyclobutyl-carbonyl) -HPI;

2- (1-acetoxycyclobutyl-carbonyl) -HPI;

2- (2-acetoxycyclobutyl-carbonyl) -HPI;

2- (3-acetoxycyclobutyl-carbonyl) -HPI;

2- (1-dimethylaminocyclobutyl-carbonyl) -HPI;

2- (2-dimethylaminocyclobutyl-carbonyl) -HPI;

2- (3-dimethylaminocyclobutyl-carbonyl) -HPI;

2- (2-methoxycarbonylcyclobutyl-carbonyl) -HPI;

2- (2-ethoxycarbonylcyclobutyl-carbonyl) -HPI;

2- (3-methoxycarbonylcyclobutyl-carbonyl) -HPI;

2- (3-ethoxycarbonylcyclobutyl-carbonyl) -HPI;

2-cyclophenyl-carbonyl-HPI; Melting point 127 ℃

2- (2-ketocyclopentyl-carbonyl) -HPI;

2- (3-ketocyclopentyl-carbonyl) -HPI;

2- (1-acetoxycyclopentyl-carbonyl) -HPI;

2- (2-acetoxycyclopentyl-carbonyl) -HPI;

2- (3-acetoxycyclopentyl-carbonyl) -HPI;

2- (2-fluorocyclopentyl-carbonyl) -HPI;

2- (3-fluorocyclopentyl-carbonyl) -HPI;

2- (2, 2-difluorocyclopentyl-carbonyl) -HPI;

2- (3, 3-difluorocyclopentyl-carbonyl) -HPI;

2- (2-chlorocyclopentyl-carbonyl) -HPI;

2- (3-chlorocyclopentyl-carbonyl) -HPI;

2- (2-methylcyclopentyl-carbonyl) -HPI;

2- (3-methylcyclopentyl-carbonyl) -HPI;

2- (1-dimethylaminocyclopentyl-carbonyl) -HPI;

2- (2-dimethylaminocyclopentyl-carbonyl) -HPI;

2- (3-dimethylaminocyclopentyl-carbonyl) -HPI;

2- (2-methoxycarbonylcyclopentyl-carbonyl) -HPI;

2- (2-ethoxycarbonylcyclopentyl-carbonyl) -HPI;

2- (3-methoxycarbonylcyclopentyl-carbonyl) -HPI;

2- (3-ethoxycarbonylcyclopentyl-carbonyl) -HPI;

2-cyclohexylcarbonyl-HPI; Melting point 136-138 ℃

2- (1-cyclohexenyl-carbonyl) -HPI;

2- (2-cyclohexenyl-carbonyl) -HPI;

2- (3-cyclohexenyl-carbonyl) -HPI; Melting point 126 ℃

2- (2-ketocyclohexyl-carbonyl) -HPI;

2- (3-ketocyclohexyl-carbonyl) -HPI;

2- (4-ketocyclohexyl-carbonyl) -HPI; Melting point 154 ℃

2- (1-acetoxycyclohexyl-carbonyl) -HPI;

2- (2-acetoxycyclohexyl-carbonyl) -HPI;

2- (3-acetoxycyclohexyl-carbonyl) -HPI;

2- (4-acetoxycyclohexyl-carbonyl) -HPI;

2- (1-formamidocyclohexyl-carbonyl) -HPI;

2- (2-formamidocyclohexyl-carbonyl) -HPI;

2- (3-formamidocyclohexyl-carbonyl) -HPI;

2- (4-formamidocyclohexyl-carbonyl) -HPI;

2- (1-dimethylaminocyclohexyl-carbonyl) -HPI;

2- (2-dimethylaminocyclohexyl-carbonyl) -HPI;

2- (3-dimethylaminocyclohexyl-carbonyl) -HPI;

2- (4-dimethylaminocyclohexyl-carbonyl) -HPI;

2- (2, 4-bis- (dimethylamino) -cyclohexyl-carbonyl) -HPI;

2- (3, 4-bis- (dimethylamino) -cyclohexyl-carbonyl) -HPI;

2- (3, 5-bis- (dimethylamino) -cyclohexyl-carbonyl) -HPI;

2- (1-diethylaminocyclohexyl-carbonyl) -HPI;

2- (2-Diethylaminocyclohexyl-carbonyl) -HPI;

2- (3-Diethylaminocyclohexyl-carbonyl) -HPI;

2- (4-Diethylaminocyclohexyl-carbonyl) -HPI;

2- (3-methylethylaminocyclohexyl-carbonyl) -HPI;

2- (4-Methylethylaminocyclohexyl-carbonyl) -HPI;

2- (2-fluorocyclohexyl-carbonyl) -HPI;

2- (3-fluorocyclohexyl-carbonyl) -HPI;

2- (4-fluorocyclohexyl-carbonyl) -HPI;

2- (2, 2-difluorocyclohexyl-carbonyl) -HPI;

2- (3, 3-difluorocyclohexyl-carbonyl) -HPI;

2- (4, 4-difluorocyclohexyl-carbonyl) -HPI;

2- (2-Chlorocyclohexyl-carbonyl) -HPI;

2- (3-Chlorocyclohexyl-carbonyl) -HPI;

2- (4-Chlorocyclohexyl-carbonyl) -HPI;

2- (2-bromocyclohexyl-carbonyl) -HPI;

2- (3-bromocyclohexyl-carbonyl) -HPI;

2- (4-bromocyclohexyl-carbonyl) -HPI;

2- (2-methylcyclohexyl-carbonyl) -HPI;

2- (3-methylcyclohexyl-carbonyl) -HPI;

2- (4-methylcyclohexyl-carbonyl) -HPI;

2- (2-methoxycarbonylcyclohexyl-carbonyl) -HPI;

2- (3-methoxycarbonylcyclohexyl-carbonyl) -HPI;

2- (4-methoxycarbonylcyclohexyl-carbonyl) -HPI;

2- (2-ethoxycarbonylcyclohexyl-carbonyl) -HPI;

2- (3-ethoxycarbonylcyclohexyl-carbonyl) -HPI;

2- (4-ethoxycarbonylcyclohexyl-carbonyl) -HPI;

2-cycloheptylcarbonyl-HPI; Melting point 91 ℃

2- (4-dimethylaminocycloheptyl-carbonyl) -HPI;

2- (4-Diethylaminocycloheptyl-carbonyl) -HPI;

2- (4-fluorocycloheptyl-carbonyl) -HPI;

2- (4-Chlorocycloheptyl-carbonyl) -HPI;

2-cyclooctylcarbonyl-HPI; Melting point 109 ℃

2-cyclonoylcarbonyl-HPI;

2-cyclodecylcarbonyl-HPI;

2-cycloundecylcarbonyl-HPI; Melting point 150-151 ℃

2-cyclododecylcatebonyl-HPI;

2-bicyclo (2, 2, 1) heptyl-2-carbonyl-HPI;

2-bacyclo (2, 2, 2) -octyl-2-carbonyl-HPI;

2- (adammantyl-carbonyl) -HPI; Melting point 159-160 ℃

2- (2-methylbenzoyl) -HPI;

2- (3-methylbenzoyl) -HPI; Melting point 124 ℃

2- (4-methylbenzoyl) -HPI; Melting point 183-184 ℃

2- (4-ethylbenzoyl) -HPI;

2- (4-n-procklebenzoyl) -HPI;

2- (4-isopropylbenzoyl) -HPI;

2- (4-tert-butylbenzoyl) -HPI; Melting Point 198 ℃

2- (4-phenylbenzoyl) -HPI;

2- (3, 4-dimethylbenzoyl) -HPI;

2- (3, 5-dimethylbenzoyl) -HPI;

2- (3, 4-diethylbenzoyl) -HPI;

2- (3, 5-diethylbenzoyl) -HPI;

2- (2-fluorobenzoyl) -HPI; Melting point 129 ℃

2- (3-fluorobenzoyl) -HPI; Melting Point 164-166 ℃

2- (4-fluorobenzoyl) -HPI; Melting Point 181-182 ℃

2- (2-chlorobenzoyl) -HPI;

2- (3-chlorobenzoyl) -HPI; Melting Point 181-182 ℃

2- (4-chlorobenzoyl) -HPI; Melting Point 214-215 ° C

2- (2-bromobenzoyl) -HPI;

2- (3-bromobenzoyl) -HPI;

2- (4-bromobenzoyl) -HPI; 2- (2-iodinebenzoyl) -HPI;

2- (3-iodinebenzoyl) -HPI; 2- (4-iodinebenzoyl) -HPI;

2- (2, 3-difluorobenzoyl) -HPI;

2- (2, 4-difluorobenzoyl) -HPI;

2- (2, 5-difluorobenzoyl) -HPI;

2- (2, 6-difluorobenzoyl) -HPI;

2- (3, 4-difluorobenzoyl) -HPI;

2- (3, 5-difluorobenzoyl) -HPI;

2- (3, 4-dichlorobenzoyl) -HPI;

2- (3, 5-dichlorobenzoyl) -HPI; Melting Point 165-166 ℃

2- (3, 4-dibromobenzoyl) -HPI;

2- (3, 5-dibromobenzoyl) -HPI;

2- (3, 4, 5-trifluorobenzoyl) -HPI;

2- (2, 3, 4, 5, 6-pentafluorobenzoyl) -HPI; Melting point 156 ℃

2- (2-hydroxybenzoyl) -HPI;

2- (3-hydroxybenzoyl) -HPI; Melting point 153 ℃

2- (4-hydroxybenzoyl) -HPI; Melting point 243-245 ℃

2- (3, 4-dihydroxybenzoyl) -HPI;

2- (3, 5-dihydroxybenzoyl) -HPI; Melting Point 250-254 ° C (Decomposition)

2- (3, 4, 5-trihydroxybenzoyl) -HPI;

2- (3-methoxybenzoyl) -HPI;

2- (4-methoxybenzoyl) -HPI; Melting point 204-205 ℃

2- (3-acetoxybenzoyl) -HPI;

2- (4-acetoxybenzoyl) -HPI;

2- (3-trifluoroacetoxybenzoyl) -HPI;

2- (4-trifluoroacetoxybenzoyl) -HPI;

2- (3, 4-dimethoxybenzoyl) -HPI;

2- (3, 5-dimethoxybenzoyl) -HPI;

2- (3, 4, 5-trimethoxybenzoyl) -HPI;

2- (4-phenoxybenzoyl) -HPI;

2- (2-dimethylaminobenzoyl) -HPI;

2- (3-dimethylaminobenzoyl) -HPI;

2- (4-dimethylaminobenzoyl) -HPI; Melting point 225-226 ℃

2- (2-diethylaminobenzoyl) -HPI;

2- (3-diethylaminobenzoyl) -HPI;

2- (4-diethylaminobenzoyl) -HPI;

2- (4-methylethylaminobenzoyl) -HPI;

2- (3, 4-bis- (dimethylamino) -benzoyl) -HPI;

2- (3, 5-bis- (dimethylamino) -benzoyl) -HPI;

2- (2-formamidobenzoyl) -HPI;

2- (3-formamidobenzoyl) -HPI; Melting point 176 ℃

2- (4-formamidobenzoyl) -HPI; Melting point 207-208 ℃

2- (2-acetamidobenzoyl) -HPI;

2- (3-acetamidobenzoyl) -HPI;

2- (4-acetamidobenzoyl) -HPI; Melting point 247-248 ℃

2- (2-propionamidebenzoyl) -HPI;

2- (2-propionamidebenzoyl) -HPI;

2- (3-propionamidebenzoyl) -HPI;

2- (4-propionamidebenzoyl) -HPI;

2- (3-n-butylamidebenzoyl) -HPI;

2- (4-n-butylamidebenzoyl) -HPI;

2- (3, 4-bis- (formamido) -benzoyl) -HPI;

2- (3, 5-bis- (formamido) -benzoyl) -HPI

2- (3-isobutylamidebenzoyl) -HPI

2- (4-isobutylamidebenzoyl) -HPI

2- (2-pentanoylamidebenzoyl) -HPI

2- (3-pentanoylamidebenzoyl) -HPI

2- (4-pentanoylamidebenzoyl) -HPI

2- (2-hexanoylamidebenzoyl) -HPI

2- (3-hexanoylamidebenzoyl) -HPI

2- (4-hexanoylamidebenzoyl) -HPI

2- (2-octanoylamidebenzoyl) -HPI

2- (3-octanoylamidebenzoyl) -HPI

2- (4-octanoylamidebenzoyl) -HPI

2- (2-Oleoylamidebenzoyl) -HPI

2- (3-Oleoylamidebenzoyl) -HPI

2- (4-Oleoylamidebenzoyl) -HPI

2- (2-methylthiobenzoyl) -HPI

2- (3-methylthiobenzoyl) -HPI

2- (4-methylthiobenzoyl) -HPI fusion 195 ° C

2- (3-ethylthiobenzoyl) -HPI

2- (4-ethylthiobenzoyl) -HPI

2- (3, 4-bis- (methylthio) -benzoyl) -HPI

2- (3, 5-bis- (methylthio) -benzoyl) -HPI

2- (3, 4, 5-tris- (methylthio-benzoyl) -HPI

2- (4-phenylthiobenzyl) -HPI

2- (2-nitrobenzoyl) -HPI; Melting Point 188-189 ℃

2- (3-nitrobenzoyl) -HPI; Melting point 172 ℃

2- (3, 4-dinitrobenzoyl) -HPI; Melting point 219 ℃

2- (3, 5-dinitrobenzoyl) -HPI; Melting point 251-252 ℃

2- (2-trifluoromethylbenzoyl) -HPI

2- (3-trifluoromethylbenzoyl) -HPI; Melting point 148-149 ℃

2- (4-trifluoromethylbenzoyl) -HPI

2- (2-cyanobenzoyl) -HPI

2- (3-cyanobenzoyl) -HPI

2- (4-cyanobenzoyl) -HPI; Melting Point 214-215 ° C

2- (2-methoxycarbonylbenzoyl) -HPI

2- (3-methoxycarbonylbenzoyl) -HPI

2- (4-methoxycarbonylbenzoyl) -HPI; Melting point 178 ℃

2- (2-ethoxycarbonylbenzoyl) -HPI

2- (3-ethoxycarbonylbenzoyl) -HPI

2- (4-ethoxycarbonylbenzoyl) -HPI

2- (3, 4-bis- (methoxycarbonyl) -benzoyl) -HPI

2- (3, 5-bis- (methoxycarbonyl) -benzoyl) -HPI

2- (2-azidobenzoyl) -HPI

2- (3-azidobenzoyl) -HPI

2- (4-azidobenzoyl) -HPI

2- (2-methoxysulfonylbenzoyl) -HPI

2- (3-methoxysulfonylbenzoyl) -HPI

2- (4-methoxysulfonylbenzoyl) -HPI

2- (pyryl-3-carbonyl) -HPI; Melting point 132-133 ℃

2- (thienyl-3-carbonyl) -HPI; Melting point; 142-143 ℃

2- (3-fluorothienyl-2-carbonyl) -HPI

2- (4-fluorothienyl-2-carbonyl) -HPI

2- (5-fluorothienyl-2-carbonyl) -HPI

2- (3-nitrothienyl-2-carbonyl) -HPI

2- (4-nitrothienyl-2-carbonyl) -HPI

2- (5-nitrothienyl-2-carbonyl) -HPI melting point 172-173 ° C

2- (3-dimethylaminothienyl-2-carbonyl) -HPI

2- (4-dimethylaminothienyl-2-carbonyl) -HPI

2- (3-formamidethienyl-2-carbonyl) -HPI

2- (4-formamidethienyl-2-carbonyl) -HPI

2- (3-Methyl-thienyl-2-carbonyl) -HPI

2- (4-Methyl-thienyl-2-carbonyl) -HPI

2- (5-methyl-thienyl-2-carbonyl) -HPI melting point 134-136 ° C.

2- (2-Methyl-thienyl-3-carbonyl) -HPI

2- (4-Methyl-thienyl-3-carbonyl) -HPI

2- (5-Methyl-thienyl-3-carbonyl) -HPI

2- (duryl-2-carbonyl) -HPI 120 ° C

2- (furyl-3-carbonyl) -HPI

2- (3-fluorofuryl-2-carbonyl) -HPI

2- (4-fluoropuryl-2-carbonyl) -HPI

2- (5-Pluoropuryl-2-carbonyl) -HPI

2- (5-chlorofuryl-2-carbonyl) -HPI

2- (3-Methyl-thienyl-2-carbonyl) -HPI

2- (4-Methyl-thienyl-2-carbonyl) -HPI

2- (5-methyl-thienyl-2-carbonyl-HPI melting point 134-136 ° C.

2- (2-Methyl-thienyl-3-carbonyl) -HPI

2- (4-Methyl-thienyl-3-carbonyl) -HPI

2- (5-Methyl-thienyl-3-carbonyl) -HPI

2- (furyl-2-carbonyl) -HPI melting point 120 ° C

2- (furyl-3-carbonyl) -HPI

2- (3-fluorofuryl-2-carbonyl) -HPI

2- (4-fluoropuryl-2-carbonyl) -HPI

2- (5-fluoropuryl-2-carbonyl) -HPI

2- (5-chlorofuryl-2-carbonyl) -HPI

2- (5-bromofuryl-2-carbonyl) -HPI melting point 209 ° C

2- (5-nitrofuryl-2-carbonyl) -HPI melting point 182 ° C

2- (indolyl-2-carbonyl) -HPI

2- (indolyl-3-carbonyl) -HPI

2- (indolyl-4-carbonyl) -HPI

2- (indolyl-5-carbonyl) -HPI melting point 235 ° C

2- (indolyl-6-carbonyl) -HPI

2- (indolyl-7-carbonyl) -HPI

2- (pyrazoryl-3-carbonyl) -HPI

2- (pyrazoryl-4-carbonyl) -HPI

2- (5-methyl-pyrazolyl-3-carbonyl) -HPI melting point 201 ° C.

2- (4-Methyl-pyrazolyl-3-carbonyl) -HPI

2- (4-Methyl-imidazolyl-2-carbonyl) -HPI

2- (5-Methyl-imidazolyl-2-carbonyl) -HPI

2- (2-Methyl-imidazolyl-4-carbonyl) -HPI

2- (5-Methyl-imidazolyl-4-carbonyl) -HPI

2- (imidazolyl-2-carbonyl) -HPI

2- (imidazolyl-4-carbonyl) -HPI

2- (thiazolyl-2-carbonyl) -HPI

2- (4-Methyl-thiazolyl-2-carbonyl) -HPI

2- (5-Methyl-thiazolyl-2-carbonyl) -HPI

2- (thiazolyl-4-carbonyl) -HPI melting point 154 ° C.

2- (2-Methyl-thiazolyl-4-carbonyl) -HPI

2- (5-Methyl-thiazolyl-4-carbonyl) -HPI

2- (thiazolyl-5-carbonyl) -HPI

2- (2-Methyl-thiazolyl-5-carbonyl) -HPI

2- (4-Methyl-thiazolyl-5-carbonyl) -HPI

2- (5-nitrothiazolyl-2-carbonyl) -HPI

2- (2,4-dimethyl-thiazolyl-5-carbonyl) -HPI Melting Point 162-163 ° C

2- (benzthiazolyl-2-carbonyl) -HPI

2- (benzthiazolyl-4-carbonyl) -HPI

2- (benzthiazolyl-5-carbonyl) -HPI

2- (isothiazolyl-3-carbonyl) -HPI

2- (4-Methyl-isothiazolyl-3-carbonyl) -HPI

2- (5-Methyl-isothiazolyl-3-carbonyl) -HPI

2- (isothiazolyl-4-carbonyl) -HPI

2- (3-Methyl-isothiazolyl-4-carbonyl) -HPI

2- (5-Methyl-isothiazolyl-4-carbonyl) -HPI

2- (isothiazolyl-5-carbonyl) -HPI

2- (3-Methyl-isothiazolyl-5-carbonyl) -HPI

2- (4-Methyl-isothiazolyl-5-carbonyl) -HPI

2- (oxazolyl-2-carbonyl) -HPI

2- (4-Methyl-oxazolyl-2-carbonyl) -HPI

2- (5-Methyl-oxazolyl-2-carbonyl) -HPI

2- (oxazolyl-4-carbonyl) -HPI

2- (2-Methyl-oxazolyl-4-carbonyl) -HPI

2- (5-Methyl-oxazolyl-4-carbonyl) -HPI

2- (oxazolyl-5-carbonyl) -HPI

2- (2-Methyl-oxazolyl-5-carbonyl) -HPI

2- (4-Methyl-oxazolyl-5-carbonyl) -HPI

2- (isoxazolyl-3-carbonyl) -HPI

2- (4-Methyl-isoxazolyl-3-carbonyl) -HPI

2- (5-methyl-isoxazolyl-3-carbonyl) -HPI; Melting Point 173-174 ℃

2- (isoxazolyl-4-carbonyl) -HPI

2- (3-ethyl-isoxazolyl-4-carbonyl) -HPI

2- (5-Methyl-isoxazolyl-4-carbonyl) -HPI

2- (isoxazolyl-5-carbonyl) -HPI

2- (3-Methyl-isoxazolyl-5-carbonyl) -HPI

2- (4-Methyl-isoxazolyl-5-carbonyl) -HPI

2-picolinoyl-HPI hydrogen bromide; Melting point 163 ℃

2- (3-fluoropicolinoyl) -HPI

2- (4-fluoropicolinoyl) -HPI

2- (5-fluoropicolinoyl) -HPI

2- (6-fluoropicolinoyl) -HPI

2- (3-diethylaminopicolinoyl) -HPI

2- (4-diethylaminopicolinoyl) -HPI

2- (5-Diethylaminopicolinoyl) -HPI

2- (6-Diethylaminopicolinoyl) -HPI

2- (3-formaminopicolinoyl) -HPI

2- (4-formaminopicolinoyl) -HPI

2- (5-formaminopicolinoyl) -HPI

2- (6-formaminopicolinoyl) -HPI

2-nicotinoyl-HPI melting point 172 ° C

2- (2-Pluoronicotinoyl) -HPI

2- (4-fluoronicotinoyl) -HPI

2- (5-fluoronicotinoyl) -HPI

2- (6-fluoronicotinoyl) -HPI

2- (2-chloronicotinoyl) -HPI

2- (4-chloronicotinoyl) -HPI melting point 158 ° C

2- (5-chloronicotinoyl) -HPI

2- (6-chloronicotinoyl) -HPI

2- (2-hydroxynicotinoyl) -HPI

2- (4-hydroxynicotinoyl) -HPI

2- (5-hydroxynicotinoyl) -HPI

2- (6-hydroxynicotinoyl) -HPI

2- (2-dimethylaminonicotinoyl) -HPI

2- (4-dimethylaminonicotinoyl) -HPI

2- (5-dimethylaminonicotinoyl) -HPI

2- (6-dimethylaminonicotinoyl) -HPI

2- (2-formamidonicotinoyl) -HPI

2- (4-formamidonicotinoyl) -HPI

2- (5-formamidonicotinoyl) -HPI

2- (6-formamidonicotinoyl) -HPI

2- (2-acetamidonicotinoyl) -HPI

2- (4-acetamidonicotinoyl) -HPI

2- (5-acetamidonicotinoyl) -HPI

2- (6-acetamidonicotinoyl) -HPI

2-isonicotinoyl-HPI melting point 140-141 ° C

2- (2,6-dichloroisonicotinoyl) -HPI Melting Point 207-208 ° C

2- (quinolyl-2-carbonyl) -HPI melting point 198-200 ° C

2- (quinolyl-3-carbonyl) -HPI

2- (quinolyl-4-carbonyl) -HPI

2- (quinolyl-5-carbonyl) -HPI

2- (quinolyl-6-carbonyl) -HPI

2- (quinolyl-7-carbonyl) -HPI

2- (quinolyl-8-carbonyl) -HPI

2- (isoquinolyl) -1-carbonyl) -HPI melting point 157 ° C

2- (isoquinolyl-3-carbonyl) -HPI

2- (pyridazinyl-3-carbonyl) -HPI

2- (pyridazinyl-4-carbonyl) -HPI

2- (pyrimidinyl-2-carbonyl) -HPI

2- (pyrimidinyl-4-carbonyl) -HPI

2- (pyrimidinyl-5-carbonyl) -HPI

2- (pyrazinyl-2-carbonyl) -HPI melting point 153-154 ° C

2- (purinyl-2-carbonyl) -HPI

2- (purinyl-2-carbonyl) -HPI

2-Naridicinyl-HPI (ie 2- (1-ethyl-7-methyl-1, 8-napridin-4-one-3-carbonyl) -HPI

2- (dioxanyl-2-carbonyl) -HPI

2- (4-methyl-piperazinyl-1-carbonyl) -HPI; Hydrogen Chloride Melting Point 290 ℃

2- (dihydrofuryl-2-carbonyl) -HPI

2- (tetrahydrofuryl-2-carbonyl) -HPI

2- (tetrahydrofuryl-3-carbonyl) -HPI

2- (1-methyl-1, 2, 5, 6-tetrahydropyridyl-3-carbonyl) -HPI; Hydrogen Chloride Melting Point 211 ℃

2- (1-Methyl-1, 4, 5, 6-tetrahydropyridyl-3-carbonyl) -HPI

2- (1-methylpiperidyl-2-carbonyl) -HPI

2- (1-methylpiperidyl-3-carbonyl) -HPI

2- (1-methylpiperidyl-4-carbonyl) -HPI

2- (1-ethylpiperidyl-2-carbonyl) -HPI

2- (1-ethylpiperidyl-3-carbonyl) -HPI

2- (1-ethylpiperidyl-4-carbonyl) -HPI

2- (1-benzylpiperidyl-2-carbonyl) -HPI

2- (1-benzylpiperidyl-3-carbonyl) -HPI

2- (1-benzylpiperidyl-4-carbonyl) -HPI

2- (1-formylferridyl-3-carbonyl) -HPI

2- (1-formylferridyl-4-carbonyl) -HPI melting point 160 캜

2- (1-acetylpiperidyl-2-carbonyl) -HPI

2- (1-acetylpiperidyl-3-carbonyl) -HPI

2- (1-acetylpiperidyl-4-carbonyl) -HPI

2- (1-hexanoylpiperidyl-2-carbonyl) -HPI

2- (1-hexanoylpiperidyl-3-carbonyl) -HPI

2- (1-hexanoylpiperidyl-4-carbonyl) -HPI

2- (1-octanoylpiperidyl-2-carbonyl) -HPI

2- (1-octanoylpiperidyl-3-carbonyl) -HPI

2- (1-octanoylpiperidyl-4-carbonyl) -HPI

2- (1-Oleoylpiperidyl-2-carbonyl) -HPI

2- (1-Oleoylpiperidyl-3-carbonyl) -HPI

2- (1-Oleoylpiperidyl-4-carbonyl) -HPI

2- (1-methoxyacetyl) -piperidyl-2-carbonyl) -HPI

2- (1-methoxyacetyl) -piperidyl-3-carbonyl) -HPI

2- (1-methoxyacetyl) -piperidyl-4-carbonyl) -HPI

2- (1-ethoxyacetyl) -piperidyl-2-carbonyl) -HPI

2- (1-ethoxyacetyl) -piperidyl-3-carbonyl) -HPI

2- (1-ethoxyacetyl) -piperidyl-4-carbonyl) -HPI

2- (tetrahydropyranyl-2-carbonyl) -HPI

2- (tetrahydropyranyl-3-carbonyl) -HPI

2- (tetrahydropyranyl-4-carbonyl) -HPI melting point 172 ° C

2- (Chlomon-2-carbonyl) -HPI Melting Point

2- (tetrahydrothiopyranyl-2-carbonyl) -HPI

2- (tetrahydrothiopyranyl-3-carbonyl) -HPI

2- (tetrahydrothiopyridyl-4-carbonyl) -HPI melting point 168 ° C

2- (1, 2, 3-thiadiazoryl-4-carbonyl) -HPI

2- (2, 1, 3-benzothiadiazolyl-5-carbonyl) -HPI melting point 144 캜

Example 2

1 ml of phosphorus trichloride was added dropwise to a solution containing 6.1 g of HPI and 5.5. G of 5-chromosalicylic acid in 50 ml of chlorobenzene at 140 ° C. (bath temperature), and the reaction mixture was boiled and evaporated. Chromatography with chloroform and recrystallization with isopropanol gave 2- (5-chloro-2-hydroxybenzoyl) -HPI having a melting point of 180 °.

Example 3

6.75 g of HPI 10.1 g isonicotinic acid and 5.5 g of silicon tetrachloride were boiled in 150 ml of pyridine for 1 hour, and the reaction mixture was poured into ice, extracted with chloroform and washed with water. The chloroform solution was dried over anhydrous sodium sulfate and recrystallized with ethanol to give 2- (isonicotinoyl) -HPI having a melting point of 140-141 ° C.

Example 4

6.1 g of HPI and 1.4 g of formic acid were heated in 100 ml of toluene for 5 hours to distill off the resulting water, cool down and recrystallize with ethanol to give 2-formyl-HPI at 206 ° C.

Example 5

4.04 g and cyclohexane-1, 2-trans-dicarboxylic anhydride 3.4 were each dissolved in 25 ml of methylene chloride at 20 ° C. and mixed together. The reaction mixture was left to stand and then evaporated and recrystallized from ethyl acetate / petroleum ether to give 2- (2-trans-carboxy-cyclohexylcarbonyl) -HPI having a melting point of 208-210 ° C. Cyclohexane-1, 2-cis-dicarboxylic acid anhydride was boiled in dioxane for 6 hours in the same manner to obtain 2- (2-cis-carboxyhexylcarbonyl) -HPI having a melting point of 194-196 占 폚.

In the same manner, cyclobutane-1, 2-dicarboxylic acid anhydride, cyclopentane-1, 2-dicarboxylic acid anhydride, cycloheptan-1, 2-dicarboxylic anhydride, phthalic anhydride and succinic anhydride Trans-Carboxycyclopentyl-Carbonyl-HPI

2- (2-trans-carboxycycloheptyl-carbonyl) -HPI;

2- (2-cis-carboxycyclobutyl-carbonyl) -HPI;

2- (2-cis-carboxycyclopentyl-carbonyl) -HPI;

2- (2-cis-carboxycycloheptyl-carbonyl) -HPI;

2- (2-carboxybenzoyl) -HPI;

2- (3-carboxypropionyl) -HPI; was obtained.

Example 6

The following compounds were obtained in the same manner as in Example 1 from chlorides corresponding to the (+)-and (-)-isomers of HPI.

(+)-2-acetyl-HPI

(-)-2-acetyl-HPI

(+)-2-propionyl-HPI

(-)-2-propionylHPI

(+)-2-isobutyryl-HPI

(-)-2-isobutyryl-HPI

(+)-2-trimethylacetyl-HPI

(-)-2-trimethylacetyl-HPI

(+)-(3, 3-dimethyl-n-butyryl) -HPI

(-)-2- (3, 3-dimethyl-n-butyryl) -HPI

(+)-2-heptanoyl-HPI

(-)-2-heptanoyl-HPI

(+)-2- (thienyl-2-mercaptoacetyl) -HPI

(-)-2- (thienyl-2-mercaptoacetyl) -HPI

(+)-2-cyclopropyl-carbonyl-HPI

(-)-2-cyclopropyl-carbonyl-HPI

(±) -2-cyclobutyl-carbonyl-HPI

(±) -2-cyclopentyl-carbonyl-HPI

(+)-2-cyclohexyl-carbonyl-HPI melting point 108-110 ° C. [α] = + 145.2 °

(-)-2-cyclohexyl-carbonyl-HPI melting point 107-108 ° C. [α] =-146.9 °

(±) -2- (4-formamidecyclohexyl-carbonyl) -HPI

(±) -2-cycloheptyl-carbonyl-HPI

(±) -2-cyclooctyl-carbonyl-HPI

(+)-2- (4-methylbenzoyl) -HPI melting point 180-181 ° C. [α] = + 29.2 °

(-)-2- (4-methylbenzoyl) -HPI Melting Point 181-182 ° C [α] =-28.5 °

(+)-2- (4-3bo-butylbenzoyl) -HPI Melting Point 181-182 ° C [α] = + 21.5 °

(-)-2- (4-tert-butylbenzoyl) -HPI Melting point 168-169 ° C [α] =-20.5 °

(+)-2- (2-fluorobenzoyl) -HPI melting point 155-156 ° C. [α] = + 49.1 °

(-)-2- (2-fluorobenzoyl) -HPI Melting point 159-161 ° C. [α] =-49.9 °

(+)-2- (3-fluorobenzoyl) -HPI melting point 156-158 ° C [α] = -40.2 °

(-)-2- (3-fluorobenzoyl) -HPI Melting point 156 ° C. [α] =-41.6 °

(+)-2- (4-fluorobenzoyl) -HPI melting point 200-201 ° [α] = + 33.5 °

(-)-2- (4-fluorobenzoyl) -HPI Melting Point 202-203 ° C. [α] =-32.6 °

(±) -2- (3-chlorobenzoyl) -HPI

(+)-2- (4-chlorobenzoyl) -HPI melting point 231-232 ° C [α] = + 20.4 °

(-)-2- (4-chlorobenzoyl) -HPI Melting point 233-234 ° C. [α] =-20.7 °

(±) -2- (3-hydroxybenzoyl) -HPI

(±) -2- (4-hydroxybenzoyl) -HPI

(+)-2- (4-methoxybenzoyl) -HPI melting point 215 ° C. [α] = + 19.8 °

(-)-2- (4-methoxybenzoyl) -HPI Melting Point 216 ° C [α] =-18.7 °

(±) -2- (3-dimethylaminobenzoyl) -HPI

(±) -2- (4-dimethylaminobenzoyl) -HPI

(±) -2- (4-diethylaminobenzoyl) -PHI

(±) -2- (2-formamidebenzoyl) -HPI

(±) -2- (3-formamidebenzoyl) -HPI

(+)-2- (4-formamidebenzoyl) -HPI melting point 193 ° C [α] = + 8.6 °

(-)-2- (4-formamidobenzoyl) -HPI melting point 193 ° C. [α] =-8.4 °

(±) -2- (2-acetamidobenzoyl) -HPI

(±) -2- (3-acetamidebenzoyl) -HPI

(±) -2- (4-acetamidebenzoyl) -HPI

(±) -2- (2-nitrobenzoyl) -HPI

)-염기로부터(±) -2- (3-nitrobenzoyl) -HPI melting point 139 ° C .; [α] = ± 2.9 ° (

) -From base

(+)-2- (4-nitrobenzoyl) -PHI melting point 223-224 ° C. [α] = + 18.5 °

(-)-2- (4-nitrobenzoyl) -PHI melting point 223-224 ° C. [α] = -21.4 °

(±) -2- (thienyl-2-carbonyl) -HPI

(±) -2- (thienyl-3-carbonyl) -HPI

(±) -2- (5-methyl-thienyl-2-carbonyl) -HPI

(±) -2- (furyl-2-carbonyl) -HPI

(±) -2- picolinoyl-HPI

(+)-2-nicotinoyl-HPI melting point 148 ° C. [α] = + 25.5 °

(-)-2-nicotinoyl-HPI melting point 156 ° C. [α] =-28.4 °

(±) -2-isonicotinoyl-HPI

(±) -2-nicotinoyl-HPI-1'-N-oxide

(±) -2- (tetrahydropyranyl-4-carbonyl) -HPI

(±) -2- (tetrahydrothiopyranyl-4-carbonyl) -HPI

(±) -2- (N-formylpiperidyl-4-carbonyl) -HPI

Compounds, such as these, can be obtained.

Example 7

3.8 g of 3-trifluoromethyl-benzoyl fluoride was added to 50 ml of chloroform, which was added dropwise to 50 ml of chloroform in an amount of 4.04 g of HPI and 2.8 ml of triethylamine. Dry over sodium sulfate, evaporate and recrystallize with ethanol to give 2- (3-trifluoromethylbenzoyl) -HPI having a melting point of 148-149 ° C.

Example 8

HPI and P-nitrobenzoylbromide were treated in the chloroform as in Example 1 in the presence of triethylamine to give 2- (4-nitrobenzoyl) -HPI having a melting point of 212-213 ° C after 2 hours.

Example 9

HPI, P-nitrobenzoyl and iodide in chloroform in the presence of triethylamine were treated as in Example 1 to give 2- (4-nitrobenzoyl) -HPI having a melting point of 212-213 ° C after 2 hours at 40 ° C. .

Example 10

N- (1, 2, 3, 4-tetrahydroiso) obtained by reducing 1-cyano-2- (4-fluorobenzoyl) -1,2-dihydroisoquinoline on Raney nickel at 100 ° C and 250 atmospheres N- (2-chloroacetyl-1, 2, 3, 4- which can be obtained by reacting quinolinyl-1-methyl) -4-fluorobenzamide with chloroacetyl chloride in chloroform in the presence of triethylamine. To 8.5 g of tetrahydro isoquinolinyl-1-methyl) -4-fluorobenzamide, 12 ml of a 20% butyldium hexane solution in 300 ml of anhydrous tetrahydrofuran was added dropwise at 20 DEG C under nitrogen stream. The reaction mixture was stirred at 20 ° C. for 2 hours and boiled for another 12 hours. After adding water, the solvent was removed and the residue was poured into chloroform, the chloroform solution was shaken with water, dried, evaporated and recrystallized with methanol to obtain 2- (4-fluorobenzoyl) -HPI having a melting point of 181-182 ° C. Likewise melting point 202-203 from 8.5 g of (+)-N- (2-chloroacetyl-1, 2, 3, 4-tetrahydro isoquinolinyl-1-methyl) -4-fluorobenzamide and butylrium (-)-2- (4-fluorobenzoyl) -HPI was obtained, which was ° C and [α] = -32.6 ° C. In the same way N- (2-bromoacetyl-1, 2, 3, 4-tetrahydroisoquinolinyl-1-methyl) -4-methylbenzamide or N- (2-iodoacetyl-1, 2 , 3, 4-tetrahydroisoquinolinyl-1-methyl) -4-methylbenzamide or N- (2-p-toluenesulfonyloxyacetyl-1, 2, 3, 4-tetrahydroisoquinolinyl 2- (4-methylenezoyl) -HPI having a melting point of 183-184 占 폚 was obtained from -1-methyl) -4-methylbenzamide and butylrium.

In the same way, N- (2-chloroacetyl-1, 2, 3, 4-tetrahydroisoquinolinyl-1-methyl) -cyclohexyl-carboxide and 2-butyric acid having a melting point of 136-138 ° C Cyclohexyl-carbonyl-HPI was obtained.

Example 11

15 g of a nickel-aluminum mixture (1: 1) was introduced into 200 ml of 20% sodium hydroxide in 5 minutes with slight stirring and held at 80 ° C. for 45 minutes. After stopping, the supernatant was inclined and the needles were washed four times with water and 1,000 ml of 1% (-)-tin acid solution, and then adjusted to pH5 by adding 1N sodium hydroxide solution. The mixture was shaken several times, heated to 80 ° C. for 90 minutes, the supernatant was decanted and the solid was washed several times with water and methanol. 2- (4-fluorobenzoyl) obtained by dehydrogenating (±) -na (+)-2- (4-fluorobenzoyl) -HPI with (±) -tartrate-rannickel catalyst thus obtained with sulfur 0.322 mg of 4-oxo-2, 3, 6, 7-tetrahydro-4H-pyrazino- [2, 1-a] isoquinoline was added to a solution in 40 ml of methanol, and hydrogenated at atmospheric pressure and room temperature.

The catalyst was filtered off and the solvent was evaporated to afford (-)-2- (4-fluorobenzoyl) -HPI with an optical purity of 23% and a melting point of 190-193 ° C. with [α] = 7.5 °.

Melting point 122-127 with 20% optical purity from 2-cyclohexyl-carbonyl-4-oxo-2, 3, 6, 7-tetrahydro-4H-pyrazino- [2, 1-a] isoquinoline in the same manner (-)-2-cyclohexyl-carbonyl-HPI was obtained which was ° C. and [α] = -29.3 °.

Example 12

2- (4-fluorobenzoyl) -4-oxo-2, 3, 6, 7-tetrahydro-4H-pyrazino [2, 1- in the same manner as in Example 11 in 40 ml of methanol in the presence of 300 mg of Ranickel. a] 322 mg of isoquinolines were hydrogenated to obtain 2- (4-fluorobenzoyl) -HPI racemate having a melting point of 181-182 ° C.

In the same manner, 2-cyclohexylcarbonyl-4-oxo-2, 3, 6, 7-tetrahydro-4H-pyrazino [2, 1-a] isoquinoline has a melting point of 136-138 ° C. Neil-HPI was obtained.

Example 13

67.7 g of 2- (4-nitrobenzoyl) -HPI in 1,500 ml of methanol in the presence of 12 g of 5% palladium charcoal at 20 ° C. atmospheric pressure were hydrogenated, the catalyst was filtered off, the filtrate was evaporated and the residue was recrystallized from ethanol to give a melting point. 2- (4-aminobenzoyl) -HPI was obtained at 212-213 ° C. The melting point of the hydrochloride was 165-166 ° C. (decomposition), the melting point of the sulfate was 234-235 ° C. and the isethionate melting point was 233-234 ° C.

The following compounds were obtained by hydrogenation of the corresponding nitro compounds in the same manner.

2- (2-amino-acetyl-HPI

2- (3-amino-propionyl) -HPI

2- (2-amino-n-butyryl) -HPI

2- (2-amino-n-butyryl) -HPI

2- (2-amino-n-valeryl) -HPI

2- (5-amino-n-valeryl) -HPI

2- (3-aminophenoxyacetyl) -HPI

2- (4-aminophenoxyacetyl) -HPI

2- (2-Aminocyclopropyl-carbonyl) -HPI

2- (1-Aminocyclobutyl-carbonyl) -HPI

2- (2-Aminocyclobutyl-carbonyl) -HPI

2- (3-Aminocyclobutyl-carbonyl) -HPI

2- (1-aminocyclopentyl-carbonyl) -HPI

2- (2-Aminocyclopentyl-carbonyl) -HPI

2- (3-Aminocyclopentyl-carbonyl) -HPI

2- (1-Aminocyclohexyl-carbonyl) -HPI

2- (2-Aminocyclohexyl-carbonyl) -HPI

2- (3-Aminocyclohexyl-carbonyl) -HPI

Cis-2- (4-aminocyclohexyl-carbonyl) -HPI

Amorphous: Infrared (IR) 3, 500, 3, 300 and 1, 645 cm ^-1

Trans-2- (4-aminocyclohexyl-carbonyl) HPI; Melting point 284 ℃

2- (4-Aminocycloheptyl-carbonyl) -HPI

2- (2-aminobenzoyl) -HPI hydrogen bromide: melting point 279-280 ° C

2- (3-aminobenzoyl) -HPI: Melting point 161-162 ° C

(+)-2- (3-aminobenzoyl) -HPI: Melting point 164-165 deg.

[α] = + 35.9 ° (from (-)-nitrosomer)

(-)-2- (3-aminobenzoyl) -HPI: Melting point 164-165 ° C

[α] = 36.5 ° (from (+)-nitrosomer)

(+)-2- (4-aminobenzoyl) -HPI: Melting point 231-232 ° C

[α] = + 23.1 ° hydrogen bromide: melting point 193 ° C. (decomposition) isethionate melting point 200-210 °: [α] = + 16.0

(-)-2- (4-aminobenzoyl) -HPI: Melting point 231-232 ° C

[α] = 23.0 ° hydrogen bromide: melting point 205 ° C. (decomposition) isethionate: melting point 200-210 ° C. [α] =-16.3 °

2- (3,4-diaminobenzoyl) -HPI: Melting point 143 ° C.

2- (3,5-diaminobenzoyl) -HPI: Melting point 235-236 ° C.

2- (2-chloro-4-amino-benzoyl) -HPI; Melting point 145 ℃

Hydrogen Chloride: 181-182 ℃

2- (2-Chloro-5-amino-benzoyl) -HPI

2- (3-Chloro-4-amino-benzoyl) -HPI

2- (3-Chloro-5-amino-benzoyl) -HPI

2- (2-amino-3-chlorobenzoyl) -HPI

2- (2-amino-4-chlorobenzoyl) -HPI

2- (2-amino-5-chlorobenzoyl) -HPI

2- (3-amino-4-chlorobenzoyl) -HPI: hydrogen bromide melting point 208-210 ° C.

2- (3-amino-thienyl-2-carbonyl) -HPI

2- (4-amino-thienyl-2-carbonyl) -HPI

2- (4-Amino-tetrahydrothiopyranyl-4-carbonyl) -HPI Melting Point 157-158 ° C .:

2- (4-aminonicotinoyl) -HPI

2- (5-aminonicotinoyl) -HPI

Example 14

2.4 g of acetyl chloride was added to 100 ml of chloroform, and 9.6 g of chloroform 300 ml 2- (4-aminobenzoyl) -HPI and 3.1 g of triethylamine were added thereto, and the reaction mixture was left at room temperature for 2 hours. 2.4 g of acetyl chloride and 3.1 g of triethylamine were added thereto, and the mixture was boiled for 3 hours, and washed with dilute hydrochloric acid and water. The solvent was evaporated and recrystallized with acetone to give 2- (4-acetylaminobenzoyl) -HPI having a melting point of 247-248 ° C.

In a similar manner the following compounds were obtained using suitable acylating agents:

2-acetamidoacetyl-HPI

2- (1-acetamidocyclohexyl-carbonyl) -HPI

2- (2-acetamidocyclohexyl-carbonyl) -HPI

2- (3-acetamidocyclohexyl-carbonyl) -HPI

2- (4-acetamidocyclohexyl-carbonyl) -HPI

2- (4-propionamidocyclohexyl-carbonyl) -HPI

2- (4-pentanoylaminocyclohexyl-carbonyl) -HPI

2- (4-hexanoylaminocyclohexyl-carbonyl) -HPI

2- (4-octanoylaminocyclohexyl-carbonyl) -HPI

2- (4-Oleoylaminocyclohexyl-carbonyl) -HPI

2- (2-sulfaminoacetyl-HPI (with chlorosulfonic acid)

2- (4-Sulfaminocyclohexyl-carbonyl) -HPI

2- (3-Sulfaminobenzoyl) -HPI

2- (4-Sulfaminobenzoyl) -HPI

2- (1-sulfo-piperidyl-4-carbonyl) -HPI

Example 15

A solution of 3.5 g of 2- [4-methyl-nitrosamino-benzoyl] -HPI prepared by nitrating 2- (4-methylaminobenzoyl) -HPI in 5 ml of glacial acetic acid was added to zinc powder in 5 ml of water with vigorous stirring. 2.7 g was added slowly to the mixture and stirred for 2 hours at 20 ° C., then heated to 80 ° C. and filtered when hot.

The residue was washed with 5% hydrochloric acid, the combined filtrates were alkaline, extracted with chloroform, the extract was washed with water, neutralized and evaporated to afford 2- [4- (1-methylhydrazino) -benzoyl] -HPI.

In a similar manner the following compounds were prepared.

2- [2- (1-Methylhydrazino) -benzoyl] -HPI:

2- [3- (1-Methylhydrazino) -benzoyl] -HPI:

2- [4- (1-ethylhydrazino) -benzoyl] -HPI:

Example 16

0.8 ml of aqueous 6N-sodium hydroxide solution was added with 8 ml of 30% hydrogen peroxide to 5 ml of 2- (4-cyanobenzoyl) -HPI in 20 ml of ethanol, and heated to extract oxygen and the temperature was heated to 40-50 ° C. for 1 hour. The reaction mixture was then cooled and diluted with 5 ml of water to give 2- (4-carboxamidobenzoyl) -HPI.

2- (3-carboxamidobenzoyl) -HPI was prepared from 2- (3-cyanobenzoyl) -HPI in a similar manner.

Example 17

A mixture containing 8 g of 2- (4-methoxycarbonyl benzoyl) -HPI in 500 ml of 10% aqueous sodium hydroxide solution was stirred at 20 ° C. for 12 hours, the insolubles were filtered, and the filtrate was acidified with hydrochloric acid and extracted with chloroform. The residue was purified by chromatography on silica gel, eluting with chloroform and methanol to give 2- (4-carboxybenzoyl) -HPI having a melting point of 251 占 폚.

Alkali saponification in a similar manner yields the following compounds:

2- (2-carboxycyclopropyl-carbonyl) -HPI

2- (2-carboxycyclobutyl-carbonyl) -HPI

2- (3-carboxycyclobutyl-carbonyl) -HPI

2- (2-carboxycyclopentyl-carbonyl) -HPI

2- (3-carboxycyclopentyl-carbonyl) -HPI

Trans-2- (2-carboxycyclohexyl-carbonyl) -HPI

Melting point 208-210 ℃

Cis-2- (2-carboxycyclohexyl-carbonyl) -HPI

Melting Point 194-196 ℃

2- (3-carboxycyclohexyl-carbonyl) -HPI

2- (4-carboxycyclohexyl-carbonyl) -HPI

2- (2-carboxybenzoyl) -HPI

2- (3-carboxybenzoyl-HPI

2- (3, 2-dicarboxy-benzoyl) -HPI

2- (3, 5-dicarboxy-benzoyl) -HPI

Example 18

A solution of 32 g of a 10: 1 mixture of methanol and water in 32 g 2- (4-hydroxybenzoyl) -HPI was mixed with an excess of etheric diazomethane solution until light yellow remained and the reaction mixture was evaporated to give a residue. Recovered to ether, washed with dilute aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and evaporated to give 2- (4-methoxybenzoyl) -HPI having a melting point of 204-205 占 폚.

Example 19

7.5 g of boron tribromide was added dropwise to a solution of 5.4 g of 2- (4-methoxybenzoyl) -HPI in 100 ml of methylene chloride at -5-10 ° C, and the reaction mixture was stirred at 20 ° C for 1 hour and poured into ice. The organic layer was separated and the aqueous layer was shaken several times with methylene chloride, the organic layers combined, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from ethanol to give 2- (4-hydroxybenzoyl) -HPI having a melting point of 243-245 ° C.

Example 20

3.22 g of 2- (4-hydroxybenzoyl) -HPI, 1.02 g of acetic anhydride and 100 ml of pyridine are boiled for 3 hours, immediately poured over ice, extracted with ether, washed with water and dried over anhydrous sodium sulfate. Benzoyl) -HPI was obtained.

Example 21

A mixture of 4.8 g of 2- (4-aminobenzoyl) -HPI and 1.5 g of 33% formaldehyde solution in 200 ml of methanol was hydrogenated in the presence of 5% palladium charcoal. The catalyst was filtered off, the solvent was evaporated and the residue was purified by chromatography on silica gel, eluting with chloroform to give 2- (4-methylaminobenzoyl) -HPI having a melting point of 220 ° C.

Example 22

In a similar manner to Example 21, 2- (4-dimethylaminobenzoyl) -HPI having a melting point of 225-226 ° C. was obtained from 4.8 g of 2- (4-aminobenzoyl) -HPI and 4 g of 33% formaldehyde solution.

Example 23

3.2 g of 2- (4-aminobenzoyl) -HPI was added to 100 ml of dioxane, followed by dehumidification for 2 hours, mixed with 2.5 g of dimethyl sulfate, and stirred at 100 ° C. for 15 hours. After cooling, 5 g of potassium hydroxide (1.4 g) was added thereto, followed by extraction with chloroform and evaporation to obtain 2- (4-dimethylaminobenzoyl) -HPI having a melting point of 225-226 ° C.

Example 24

10.4 g of 2- (4-trifluoroacetamidobenzoyl) -HPI obtained by reacting 2- (4-aminobenzoyl) -HPI with trifluoroacetic anhydride and triethylamine in iodine in 300 ml of anhydrous acetone It was heated to boiling with 34.2 g of methyl, thereto was added powdered sodium hydroxide 13.4, then boiled for 5 minutes and evaporated to dryness. The residue was mixed with water, stirred at 20 ° C. for 2 hours, extracted with chloroform, washed with water and evaporated to give 2- (4-methylaminobenzoyl) -HPI having a melting point of 220 ° C.

If methyl iodide is not removed prior to hydrolysis, 2- (4-dimethylaminobenzoyl) -HPI with a melting point of 225-226 ° C. is obtained.

Example 25

In a similar manner to Example 19, 2- (4-mercaptobenzoyl) -HPI was obtained from 2- (4-methylmercaptobenzoyl) -HPI and borontribromide. 2- (2-mercaptobenzoyl) -HPI and 2- (3-mercaptobenzoyl) -HPI were prepared in a similar manner.

Example 26

a) 1.15 g of sodium brohydride was added dropwise to 100 ml of ethanol in 6.5 g of 2- (4-oxocyclohexyl-carbonyl) -HPI at 0 ° C, stirred at 20 ° C for 12 hours, and poured into ice to give an isomeric mixture. 2- (4-hydroxycyclohexyl-carbonyl) -HPI was obtained.

b) 24 ml of 0.5M solution containing potassium tris- (sec-butyl) -borohydride in tetrahydrofuran was dissolved in anhydrous tetrahydrofuran 35 ml 2- (4-oxocyclohexyl-carbonyl) under nitrogen stream at -70 ° C. To this solution was added 3.25 g of HP, and the reaction mixture was mixed with 35 ml of water, warmed to 20 DEG C, and recovered with chloroform. Purification using chloroform on silica gel afforded cis-2- (4-hydroxycyclohexyl-carbonyl) -HPI with a melting point of 162-163 ° C.

Example 27

6.5 g of 2- (4-oxocyclohexyl-carbonyl) -HPI was added to 100 ml of methanol, and the mixture was hydrogenated at 50 ° C. and 100 atm to saturate in the presence of 2 g of nickel nickel. The catalyst was filtered off and the solvent was evaporated to afford 2- (4-hydroxycyclohexyl-carbonyl) -HPI in the form of an isomer mixture.

Example 28

3.16 g of 2- (4-oxocyclohexyl-carbonyl) -HPI were hydrogenated in 100 ml of methanol for 10 hours and saturated with ammonia in the presence of 1 g of Ranickel at 100C at 10 ° C. The catalyst was filtered off and the solvent was evaporated to dissolve the residue in ethanol. After adding bromic acid to ethanol, the obtained product was crystallized with ether to obtain trans-2- (4-aminocyclohexylcarbonyl) -HPI-bromate having a melting point of 285 ° C. Sodium hydroxide was added to the filtrate, extracted with chloroform, and evaporated to afford cis-2- (4-aminocyclohexylcarbonyl) -HPI.

Example 29

3.1 g of 2- (4-oxyminocyclohexyl-carbonyl) -HPI having a melting point of 194 ° C. prepared from 2- (4-oxocyclohexyl-carbonyl) -HPI and hydroxylamine was prepared at room temperature, in the presence of 5 g of rannickel. Hydrogenation and evaporation until saturated in 100 ml of ethanol at 5 atmospheres yielded 2- (4-aminocyclohexyl-carbonyl) -HPI in the form of an isomer mixture.

Example 30

A solution of 5.5 g of 2-isonicotinoyl-HPI and 6.3 g of 3-chloroperbenzoic acid (50%) was added to methylene chloride overnight at 20 ° C, ammonia was introduced until saturated, and then filtered by suction and methylene chloride. Washed.

The filtrate was evaporated and recrystallized from ethanol to give 2-isonicotinoyl-HPI-1′-N-oxide having a melting point of 250 ° C.

In a similar manner, 2-nicotinoyl-HPI-1′-N-oxide having a melting point of 178 ° C. was obtained from 2-nicotinoyl-HPI.

From the dialkylamino compounds mentioned in Example 1 the corresponding N-oxides, for example 2- (4-dimethylaminobenzoyl) -HPI-N-oxide, can be obtained.

Example 31

3.2 g of 2- (4-dimethylaminobenzoyl) -HPI and 5 g of methyl iodide were heated to 75 ° C. overnight in 600 ml of acetonitrile.

The solvent was evaporated and the resulting mixture was purified by elution with chloroform and methanol on silica gel and recrystallized with ethanol to give methoxide of 2- (4-dimethylaminobenzoyl) -HPI having a melting point of 215-216 ° C.

Example 32

2.1 g of 1-amino-cyclohexane-1-carboxylic acid was mixed with 6.3 g of trifluoroacetic anhydride, and 2 ml of HPI and 2.3 g of triethylamine were added to 20 ml of methylene chloride at 0 ° C., and warmed at 30 ° C., and after 1 hour The reaction mixture was poured into water, the organic layer was separated, washed with aqueous sodium hydroxide solution and water, dried, evaporated and recrystallized with benzene to give 2- (1-aminocyclohexyl-1-carbonyl) -HPI having a melting point of 146 ° C. In a similar manner the following compounds were obtained.

2-methylaminoacetyl-HPI

2-ethylaminoacetyl-HPI

2- (2-methylamino-propionyl) -HPI

2- (2-ethylamino-propionyl) -HPI

2- (3-Methylamino-propionyl) -HPI

2- (3-ethylamino-propionyl) -HPI

2- (2-methylamino-n-butyryl) -HPI

2- (4-methylamino-n-butyryl) -HPI

2- (4-ethylamino-n-butyryl) -HPI

2- (2-methylamino-n-valeryl) HPI

2- (5-methylamino-n-valeryl) -HPI

2- (1-methylaminocyclobutyl-carbonyl) -HPI

2- (2-Methylaminocyclobutyl-carbonyl) -HPI

2- (3-Methylaminocyclobutyl-carbonyl) -HPI

2- (1-ethylaminocyclobutyl-carbonyl) -HPI

2- (2-ethylaminocyclobutyl-carbonyl) -HPI

2- (3-ethylaminocyclobutyl-carbonyl) -HPI

2- (1-methylaminocyclopentyl-carbonyl) -HPI

2- (2-methylaminocyclopentyl-carbonyl) -HPI

2- (3-Methylaminocyclopentyl-carbonyl) -HPI

2- (1-ethylaminocyclopentyl-carbonyl) -HPI

2- (2-ethylaminocyclopentyl-carbonyl) -HPI

2- (3-ethylaminocyclopentyl-carbonyl) -HPI

2- (2,4-Diaminocyclohexyl-carbonyl) -HPI

2- (3,4-Diaminocyclohexyl-carbonyl) -HPI

2- (3, 5-Diaminocyclohexyl-carbonyl) -HPI

2- (1-Methylaminocyclohexyl-carbonyl) -HPI

2- (2-Methylaminocyclohexyl-carbonyl) -HPI

2- (3-Methylaminocyclohexyl-carbonyl) -HPI

2- (4-Methylaminocyclohexyl-carbonyl) -HPI

2- (1-ethylaminocyclohexyl-carbonyl) -HPI

2- (2-ethylaminocyclohexyl-carbonyl) -HPI

2- (3-ethylaminocyclohexyl-carbonyl) -HPI

2- (4-ethylaminocyclohexyl-carbonyl) -HPI

2-2, 4-bis- (methylamino) -cyclohexyl-carbonyl-HPI

2-3, 4-bis- (methylamino) -cyclohexyl-carbonyl-HPI

2-3, 5-bis- (methylamino) -cyclohexyl-carbonyl-HPI

2-2, 4-bis- (ethylamino) -cyclohexyl-carbonyl-HPI

2-3, 4-bis- (ethylamino) -cyclohexyl-carbonyl-HPI

2-3, 5-bis- (ethylamino) -cyclohexyl-carbonyl-HPI

2-4-methylaminocycloheptyl-carbonyl) -HPI

2- (4-Ethylaminocycloheptyl-carbonyl) -HPI

2- (2-methylaminobenzoyl) -HPI

2- (3-Meeaminobenzoyl-HPI

2- (4-methylaminobenzoyl) -HPI melting point 220 ° C

2- (2-ethylaminobenzoyl) -HPI

2- (3-ethylaminobenzoyl) -HPI

2- (4-ethylaminobenzoyl) -HPI

2- [3, 4-bis- (methylamino) -benzoyl] -HPI

2- [3, 5-bis- (methylamino) -benzoyl] -HPI

2- [3, 4-bis- (ethylamino) -benzoyl] -HPI

2- [3, 5-bis- (ethylamino) -benzoyl] -HPI

2- (3-aminopicolinoyl) -HPI

2- (4-aminopicolinoyl) -HPI

2- (5-aminopicolinoyl) -HPI

2- (6-aminopicolinoyl) -HPI

2- (3-methylaminopicolinoyl) -HPI

2- (4-Methylaminopicolinoyl) -HPI

2- (5-methylaminopicolinoyl) -HPI

2- (6-methylaminopicolinoyl) -HPI

2- (2-aminonicotinoyl) -HPI

2- (4-aminonicotinoyl) -HPI

2- (5-aminonicotinoyl) -HPI

2- (6-aminonicotinoyl) -HPI

2- (2-methylaminonicotinoyl) -HPI

2- (4-methylaminonicotinoyl) -HPI

2- (5-methylaminonicotinoyl) -HPI

2- (6-methylaminonicotinoyl) -HPI

2- (benzoimidazolyl-2-carbonyl) -HPI

2- (pyrrolinyl-2-carbonyl) -HPI

2- (pyrrolidinyl-2-carbonyl) -HPI

2- (pyrrolidinyl-3-carbonyl) -HPI

2- (1, 2, 3, 4-tetrahydropyridyl-1-carbonyl) -HPI

2- (1, 2, 3, 4-tetrahydropyridyl-2-carbonyl) -HPI

2- (piperidyl-1-carbonyl) -HPI

2- (piperidyl-2-carbonyl) -HPI

2- (piperidyl-3-carbonyl) -HPI

2- (piperidyl-4-carbonyl) -HPI monohydrate

Melting point 146-147 ℃

2- (1, 2, 3, 4-tetrahydroquinolyl-3-carbonyl) -HPI

2- (1, 2, 3, 4-tetrahydroquinolyl-4-carbonyl) -HPI

2- (1, 2, 3, 4-tetrahydroquinolyl-1-carbonyl) -HPI

2- (1, 2, 3, 4-tetrahydroisoquinolyl-3-carbonyl) -HPI

2- (1, 2, 3, 4-tetrahydroisoquinolyl-4-carbonyl) -HPI

If the organic phase is not washed with an aqueous sodium hydroxide solution, a trifluoroacetyl compound 2- (1-trifluoroacetamidocyclohexyl-carbonyl) -HPI is obtained.

Example 33

"Lloyd anhydride" of 4-amino-tetrahydrothiopyran-4-carboxylic acid in 300 ml of chloroform (1,3-dioxo-2-oxa-8-thiaspiro, obtainable with diacids and phosgene [4, 5] 4.04 g of HPI and 1.5 g of acetic acid were added to the suspension containing 4.2 g of decane) and the reaction mixture was boiled for 24 hours. The reaction mixture was cooled, filtered and the filtrate was washed with dilute aqueous sodium hydroxide solution and water, evaporated, and then recrystallized with ethyl acetate, ether and petroleum ether to recrystallize 2- (4-amino-tetrahydrothiopyran-4- with a melting point of 157-158 ° C. Carbonyl) -HPI was obtained.

Example 34

Into 50 ml of methylene chloride, 3.26 g of 2- (4-oxocyclohexyl-carbonyl) -HPI, 0.2 ml of water and 3.2 g of sulfitetetrafluoride were shaken for 24 hours at 30 ° C. in an autoclave and the reaction mixture was diluted. Poured over sodium sulfate and evaporated to afford 2- (4,4-difluorocyclohexyl-carbonyl) -HPI.

Example 35

3.4 g of 2- (4-mercaptobenzoyl) -HPI were heated with 40 ml of nitric acid (d = 1.2) in a water bath and the reaction mixture was evaporated after the first vigorous reaction ceased, resulting in 2- (4-sulfobenzoyl) -HPI. Got. In a similar manner the corresponding mercapto compound was oxidized to give 2- (2-sulfobenzoyl) -HPI and 2- (3-sulfobenzoyl) -HPI.

Example 36

In a similar manner as in Example 17, 8 g of 2- (4-acetoxybenzoyl) -HPI was saponified in the presence of 10% aqueous sodium hydroxide solution to give 2- (4-hydroxybenzoyl) -HPI having a melting point of 243-245 ° C.

In a similar manner, the appropriate compounds were saponified to afford the following compounds.

2- (2-hydroxy-acetyl) -HPI

2- (2-hydroxycyclopropyl-carbonyl) -HPI

2- (1-hydroxycyclobutyl-carbonyl) -HPI

2- (2-hydroxycyclobutyl-carbonyl) -HPI

2- (3-hydroxycyclobutyl-carbonyl) -HPI

2- (1-hydroxycyclopentyl-carbonyl) -HPI

2- (2-hydroxycyclopentyl-carbonyl) -HPI

2- (3-hydroxycyclopentyl-carbonyl) -HPI

2- (1-hydroxycyclohexyl-carbonyl) -HPI

2- (2-hydroxycyclohexyl-carbonyl) -HPI

2- (3-hydroxycyclohexyl-carbonyl) -HPI

2- (4-hydroxycyclohexyl-carbonyl) -HPI

(+)-2- (4-hydroxycyclohexyl-carbonyl) -HPI

(-)-2- (4-hydroxycyclohexyl-carbonyl) -HPI

2- (2,4-Dihydroxycyclohexyl-carbonyl) -HPI

2- (3, 4-cis-dihydroxycyclohexyl-carbonyl) -HPI

Hydrate: melting point 100-102 ℃

2- (3, 5-Dihydroxycyclohexyl-carbonyl-)-HPI

2- (3, 4, 5-trihydroxycyclohexyl-carbonyl) -HPI

Example 37

2- (4-benzyloxycarbonylaminobenzoyl) -HPI was prepared from HPI and 4- (benzyloxy-carbonylamino) -benzoyl chloride in a similar manner as in Example 1. The following compounds were similarly prepared with suitably substituted acid halides.

2- (1-methoxyacet amidocyclopentyl-carbonyl) -HPI

2- (1-tert-butoxycarbonylaminocyclopentyl-carbonyl) -HPI

2- (4-benzyloxycarbonylaminocyclohexyl-carbonyl) -HPI

2-4- (3, 5-dimethoxybenzyloxycarbonyl) -aminocyclohexyl-carbonyl-HPI

2- (2-methoxyacetamidebenzoyl) -HPI

2- (2-tert-butoxycarbonylaminobenzoyl) -HPI

2- (2-benzyloxycarbonylaminobenzoyl) -HPI

2-2- (3, 5-dimethoxybenzyloxycarbonyl) -aminobenzoyl-HPI

2- (3-methoxyacetamidobenzoyl) -HPI

2- (3-tert-butoxycarbonylaminobenzoyl) -HPI

2- (3-benzyloxycarbonylaminobenzoyl) -HPI

2-3- (3,5-dimethoxybenzyloxycarbonyl) -aminobenzoyl-HPI

2- (4-methoxyacetamidebenzoyl) -HPI Melting Point 172 ° C

2- (4-tert-butoxycarbonylaminobenzoyl) -HPI

2-4- (3, 5-dimethoxybenzyloxycarbonyl) -aminobenzoyl) -HPI

2- (l-tert-butoxycarbonyl-piperidyl-3-carbonyl) -HPI

2- (1-benzyloxycarbonyl-piperidyl-3-carbonyl) -HPI

2-1- (3, 5-dimethoxybenzyloxycarbonyl) -piperidyl-3-carbonyl-HPI

2- (1-benzyloxycarbonyl-piperidyl-4-carbonyl) -HPI

Example 38

4.5 g of 2- (1-benzyloxycarbonyl-piperidyl-3-carbonyl) -HPI was hydrogenated in 100 ml of 80% dioxane aqueous solution and 1 ml of acetic acid in the presence of 300 mg of palladium, and then the catalyst was filtered and the filtrate was evaporated. The residue was then taken up in chloroform, washed with aqueous sodium carbonate solution and water and then evaporated to afford 2- (piperidyl-3-carbonyl) -HPI. The following compounds were prepared by hydrolyzing the appropriate benzyloxycarbonylaminoacyl derivatives in a similar manner.

Trans-2- (4-aminocyclohexyl-carbonyl) -HPI bromate: Melting point 284 ° C

2- (2-aminobenzoyl) -HPI bromate: melting point 279-280 ° C

2- (3-aminobenzoyl) -HPI: Melting point 161-162 ° C

2- (4-aminobenzoyl) -HPI: Melting point 212-213 ° C

2- (piperidyl-4-carbonyl) -HPI monoamideate: melting point 146-147 ° C

Example 39

A solution containing 4.3 g of 2- (1-tert-butyloxycarbonyl-piperidyl-3-carbonyl) -HPI in 80 ml of 98% formic acid was allowed to stand at 20 ° C. for 5 hours, evaporated, and the residue was chloroform and an aqueous sodium carbonate solution. And washed with water and then evaporated to afford 2- (piperidyl-3-carbonyl) -HPI.

Example 40

A solution of 2- [1- (3,5-dimethoxybenzyloxycarbonyl) -piperidyl-3-carbonyl] -HPI was added to 100 ml of 80% aqueous dioxane solution in 5.1 g for 2 hours using high pressure mercury or the like. The reaction mixture was mixed with hydrochloric acid, washed with ether, alkaline with an aqueous sodium hydroxide solution, extracted with chloroform, and the extract was evaporated to give 2- (piperidyl-3-carbonyl) -HPI.

Example 41

6.4 g of 2- (4-aminobenzoyl) -HPI, 2.7 g of salicyaldehyde and 100 mg of P-toluenesulfochloride were boiled in 150 ml of toluene for 12 hours to remove the water formed and the reaction mixture was evaporated. Shaking and recrystallization with benzene and petroleum ether gave 2- (4-0-hydroxybenzylideneamino-benzoyl) -HPI having a melting point of 196-197 ° C.

In a similar manner benzaldehyde was used to obtain 2- (4-benzylideneamino-benzoyl) -HPI.

Example 42

3 g of 2- (4-benzylideneamino-benzoyl) -HPI was added to 50 ml of methanol, hydrogenated at 1 atmosphere and 20 ° C for 3 hours in the presence of 1 g of platinum, and the catalyst was filtered and evaporated. -Benzylamino-benzoyl) -HPI was obtained.

In a similar manner the appropriate Schiffbases were hydrogenated to afford the following compounds:

2- (3-benzylamino-cyclopentyl-carbonyl) -HPI

2- (4-Benzylamino-cyclohexyl-carbonyl) -HPI

2- (3-benzylamino-benzoyl) -HPI

2- [3- (2-hydroxybenzoyl) -aminocyclopentyl-carbonyl-HPI

2-4- (2-hydroxybenzoyl) -aminocyclohexyl-carbonyl-HPI

2-3- (2-hydroxybenzoyl) -aminobenzoyl-HPI

2-4- (2-hydroxybenzoyl) -aminobenzoyl-HPI melting point 201-202 ° C

2- [3- (2-hydroxy-3-methoxybenzoyl) -aminocyclopentyl-carbonyl] -HPI

2-4- (2-hydroxy-3-methoxybenzyl) -aminocyclohexyl-carbonyl] -HPI

2- [3- (2-hydroxy-3-methoxybenzyl) -aminobenzoyl] -HPI

2- [4- (2-hydroxy-3-methoxybenzyl) -aminobenzoyl] -HPI

2- (3-carboxymethylaminocyclopentyl-carbonyl) -HPI

2- (4-carboxymethylaminobenzoyl) -HPI

2- (3-carboxymethylaminobenzoyl) -HPI

2- (4-carboxymethylaminobenzoyl) -HPI

Instead of platinum, it is also possible to hydrogenate with nickel. Dioxane is used as the solvent and the reaction is carried out at 45 DEG C, 1-5 atm.

Example 43

In a similar manner as in Example 38, 2- (4-benzylideneamino-benzoyl) -HPI was hydrogenated in the presence of palladium to give 2- (4-aminobenzoyl) -HPI having a melting point of 212-213 ° C.

Example 44

A diazonium solution was prepared from 3.21 g of 2- (4-aminobenzoyl) -HPI, 5 ml of 6N-hydrochloric acid, and 0.7 g of sodium nitrite, and the solution was added to a solution containing 15 ml of 1 N salicylic acid in 15 ml of 2N-sodium hydroxide solution at 5-10 ° C. 4 ml of water was introduced while being careful to make this alkaline. After 30 minutes, the obtained product was precipitated with hydrochloric acid, filtered, washed with water and a small amount of ethanol and dried to give an orange-yellow powder of 2-4- (3-carboxy-4-hydroxyphenylazo) at a melting point of 241-244 ° C. Benzoyl] -HPI was obtained. In a similar manner the following compounds are obtained using anisole and dimitaniline.

2- [4- (4-methoxyphenylazo-benzoyl] -HPI and 2- [4- (4-dimethylaminophenylazo) -benzoyl] -HPI,

Example 45

300 ml of a 3.7 N sodium bisulfite solution was heated with cinnamilaldehyde at 90 ° C. for 30 minutes, and 11.7 g of 2- (4-aminobenzoyl) -HPI was added to 1 liter of dioxane, and the reaction mixture was heated to 90 ° C. After heating and cooling for 12 hours, the mixture was extracted with chloroform, the aqueous layer was concentrated, ethanol was added to precipitate the desired product, and 2- [4- (1,3-disulfo-3-phenylpropylamino) having a melting point of 221-222 DEG C (decomposition) was obtained. Disodium salt of) -benzoyl] -HPI was obtained.

Example 46

In a similar manner to Example 24, 2- (4-allylamino-benzoyl) -HPI was obtained from 2- (4-aminobenzoyl) -HPI and allyliodide:

In a similar manner the following compounds were obtained.

2- (3-allylaminocyclopentyl-carbonyl) -HPI:

2- (4-allylaminocyclohexyl-carbonyl) -HPI:

2- (3-allylaminobenzoyl) -HPI:

Example 47

In a similar manner to Example 5, the following compounds were obtained from suitable amino compounds and succinic anhydrides, maleic anhydride or phthalic anhydride:

2- (4-succinylamino-benzoyl) -HPI:

2- (4-Malaynoylamino-benzoyl) -HPI:

2- (4-phthaloylamino-benzoyl) -HPI:

2- (1-Succinyl-piperidinyl-4-carbonyl) -HPI:

2- (1-phthaloyl-piperidyl-4-carbonyl) -HPI:

Example 48

4.8 g of 2- (3-cyclohexyl-1-carbonyl) -HPI and 4 g of osmium tetraoxide were stirred overnight at 20 ° C. in 60 ml of pyridine, and a solution of 7 g of sodium bisulfite was added to 100 ml of water and 85 ml of pyridine. It was stirred for 30 minutes, extracted with methylene chloride and evaporated to dryness to obtain 2- (3,4-cis-dihydroxycyclohexyl-1-carbonyl) -HPI hydrate having a melting point of 100-102 ° C.

[49]

3.1 g of 2- (3-cyclohexyl-1-carbonyl) -HPI was hydrogenated in 100 m of methanol at 20 ° C. at atmospheric pressure in the presence of 300 mg of platinum oxide, and the reaction mixture was filtered to evaporate the filtrate to evaporate the melting point. 2-cyclohexylcarbonyl-HPI was obtained at 136-138 ° C.

Example 50

A solution containing 3.3 g of 2- (tetrahydrothiopyran-4-carbonyl) -HPI and 1.05 ml of 30% aqueous hydrogen peroxide solution in 20 ml of acetic acid was left at 20 ° C. overnight, evaporated, and recovered with chloroform and water. 2- (tetrahydrothiopyran-4-carbonyl) -HPI-S-dioxide was obtained at 175-180 ° C.

Example 51

3.3 g of 2- (tetrahydrothiopyran-4-carbonyl) -HPI and 2.5 ml of 30% hydrogen peroxide were heated in 60 ml of acetic acid at 60 ° C. for 2 hours, evaporated, recovered with chloroform and water, and recrystallized from ethanol to give a melting point 253-. 2- (tetrahydrothiopyran-4-carbonyl) -HPI-S at 255 ° C. S.-dioxide was obtained.

Example 52

35 ml of 0.5 M solution with potassium tri-sec-butylborohydride in tetrahydrofuran was added to 50 ml of anhydrous tetrahydrofuran under nitrogen gas at -70 ° C. in 2- (4-oxocyclohexyl-carbonyl) -HPI 4.9 The solution was slowly added to the solution, and after 3 hours, the reaction mixture was mixed with 50 ml of water, warmed to room temperature, acidified with hydrochloric acid, and extracted with chloroform. This chloroform extract was purified by chromatography (silica gel / chloroform), and the recrystallized isopofane with / diethyl ether to obtain a melting point of 162-163 ° C cis-2- (4-hydroxycyclohexyl-carbonyl) -HPI. The active substance of formula (I) can be treated according to the known method described in the literature to obtain a pharmaceutical adjustment as shown in the following examples.

Example 53

Tablets for tapeworms

a) A tablet containing 500 mg of 2-cyclohexylcarbonyl-HPI as the active substance was prepared from a powder mixture of 5 kg 2-cyclohexylcarbonyl-HPI, 3 kg lactose, 1.8 kg corn starch and 0.2 kg magnesium stearate.

b) The mixtures described in Example 53) can also be used for the preparation of tablets containing 50 mg, 250 mg of 2-cyclohexylcarbonyl-HPI and 1, 000 kg.

Tablets containing 250 mg and 5 mg 2-cyclohexylcarbonyl-HPI as the active substance are recommended for use as a medicament, but all such tablets can be used as veterinary medicine.

Example 54

Tablets for removing tapeworms and schistosomiasis

Effervescent tablet

Authoritarian

Example 55

Dragee for human tapeworm

Dragee coating consists of talc, saccharose, titanium dioxide, calcium carbonate, polyvinyl pyrrolidone, methylcellulose, glycerol, magnesium oxide and lacquer, which contains 500 mg of 2-cyclohexylcarbonyl HPI as active ingredient Can also be used for one party.

Example 56

Human tapeworm syrup

This syrup is obtained from a suspension consisting of the following components:

The mixture is mixed with colorants and flavorings and brought to 100 l with distilled water.

Example 57

Capsule for controlling tapeworm and schistosomiasis in humans and animals

An appropriately sized capsule is filled with 5,000 mg of 2-cyclohexylcarbonyl-HPI, 250 mg of talc and 150 mg of magnesium stearate. In the same manner, a capsule containing 1,000 mg of 2-cyclohexylcarbonyl-HPI and 10,000 mg is produced.

Example 58

Human and Animal Injections

A 15 mg ampoule for subcutaneous administration into an emulsion or a homemade suspension is filled with a solution containing 6 ml of water and 500 mg of propylene glycol 4 ml 2-cyclohexylcarbonyl-HPI together with the solubilizer, heat sterilized and then a preservative. Similarly, ampoules containing 100 mg of 2-cyclohexylcarbonyl-HPI (for small animals) and 1,000 mg of 2-cyclohexylcarbonyl-HPI (for large animals) are also produced.

Example 59

Pellet

A powder mixture is prepared from an equivalent amount of 2-cyclohexylcarbonyl-HPI with lactose and sodium carboxy methylcellulose and treated by known methods to produce uniform granules with an average particle size of 1.5 mm.

Example 60

Animal premixes adapted to be mixed with feed as a carrier to obtain feed with added agent:

a) 25% premix suitable for large animals;

25 kg of 2-cyclohexylcarbonyl-HPI are mixed with 75 kg of fine bran or lactose obtained by milling wheat.

b) 5% premix suitable for small animals;

5 kg 2-cyclohexylcarbonyl-HPI is treated as in Example 60 a).

c) Examples of using premixes prepared according to Example 60 a) to control the moniezia type in the bovine of bovine animals Premixes prepared in Example 60 a) to make a suitable medicated feed. Mix 1 kg with conventional feed concentrate 9.

400 g of this feed containing 10,000 mg of 2-cyclohexylcarbonyl-HPI is administered to control Monygia infection in mature livestock.

Instead of 2-cyclohexylcarbonyl-HPI, other active substances of formula (I) or physiologically acceptable salts thereof can be used for the production of pharmaceutical compositions in a manner similar to that described in Examples 53-60.

Claims (1)

As described in the text, 4-oxo-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino [2, 1-a] isoquinoline is reacted with the following inban (II) compound or Then, the compound of formula (III) is cyclized with a cyclizing agent in the state where HX is separated, or the compound of formula (IV) is reduced to form 2-acyl-4-oxo-hexahydro-4H of the following formula (I). A process for preparing pyrazino [2, 1-a] isoquinoline derivatives.

In the above formula, COR is an acyl group having up to 26 carbon atoms, and when R is a phenyl group, this group is substituted. X is a fluorine, chlorine, bromine or iodine atom or methylsulfonyloxy or an arylsulfonyloxy group having 6-10 carbon atoms.