CA1334967C - Pharmacologically active compounds, methods for the preparation thereof and compositions containing the same - Google Patents

Pharmacologically active compounds, methods for the preparation thereof and compositions containing the same

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Publication number
CA1334967C
CA1334967C CA 552987 CA552987A CA1334967C CA 1334967 C CA1334967 C CA 1334967C CA 552987 CA552987 CA 552987 CA 552987 A CA552987 A CA 552987A CA 1334967 C CA1334967 C CA 1334967C
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CA
Canada
Prior art keywords
dihydroxy
c1
cyano
nitrophenyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA 552987
Other languages
French (fr)
Inventor
Reijo Backstrom
Kalevi Heinola
Erkki Honkanen
Seppo Kaakkola
Pekka Kairisalo
Inge-Britt Linden
Pekka Mannisto
Erkki Nissinen
Pentti Pohto
Aino Pippuri
Jarmo Pystynen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orion-Yhtyma Oy
Original Assignee
Orion-Yhtyma Oy
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Filing date
Publication date
Family has litigation
Priority to FI864875 priority Critical
Priority to FI864875A priority patent/FI864875A0/en
Priority to GB878712437A priority patent/GB8712437D0/en
Priority to GB8712437 priority
Application filed by Orion-Yhtyma Oy filed Critical Orion-Yhtyma Oy
Application granted granted Critical
Publication of CA1334967C publication Critical patent/CA1334967C/en
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26158050&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA1334967(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Anticipated expiration legal-status Critical
Application status is Expired - Lifetime legal-status Critical

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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07C205/00Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/20Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/21Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C205/22Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring having one nitro groups bound to the ring
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    • C07C205/21Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C205/23Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring having two nitro groups bound to the ring
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    • C07C205/36Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
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    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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    • C07C45/67Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C45/68Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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    • C07D319/101,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/141,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/24[b,e]-condensed with two six-membered rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Disclosed and claimed are pharmacologically active catechol derivatives of formula (I):

(I) or a salt thereof, in which R1 and R2 independently represent hydrogen, optionally substituted acyl or aroyl, lower alkylcarbamoyl, X represents an electronegative substituent such as halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents alkyl substituted by lower alkoxy lower alkoxy, carboxy lower alkyl, thio or pyrrole group, or a group selected from:

(A) or wherein R4 represents cyano or acyl and R5 represents cyano, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, hydroxyalkyl, carboxyalkyl, one of the following optionally substituted groups: carbamoyl, aroyl or heteroaroyl, or R4 and R5 form together a five to seven membered, optionally substituted cycloalkanone ring;

(B) (CH2)m-COR

wherein m is 2-7 and R represents hydroxy, alkyl, carboxyalkyl, optionally substituted alkene, alkoxy or optionally substituted amino;

(C)

Description

The present invention relates to some members of a broad family of catechol derivatives that are active as catechol-0-methyltransferase (COMT) inhibitors and useful as such in the treatment of depression, heart failure and for hypertension.

The catechol derivatives of the broad family referred to hereinabove are of general formula:

~1~
RzO ~ R3 X

and the salts thereof, which are new and in which R1 and R2 independently represents hydrogen, alkyl, optionally substituted acyl or aroyl, lower alkylsulfonyl or alkylcarbamoyl or taken together form a lower alkylidene or cycloalkylidene group, X represent an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde carboxyl, lower alkylsulfonyl, sulfonamide or trifluoromethyl and R3 represents hydrogen, halogen, substituted alkyl, hydroxy alkyl, nitro, cyano, optionally substituted amino, trifluoromethyl, lower alkylsulfonyl, sulfonamide, aldehyde, alkyl or aralkylidene carbonyl or carboxyl group, or a group selected from:

(A) -CH=C-R5 or -CH2-CH-R5 wherein R4 represents hydrogen, alkyl, amino, cyano, carboxyl or acyl and R5 represents hydrogen, amino, cyano, carboxyl, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, hydroxyalkyl, carboxyalkyl one of the following optionally substituted groups: carboxamido, carbomoyl aroyl or ~J

-~ 2 -heteroaroyl, or R4 and R5 form together a five to sevent membered, optionally substituted cycloalkanone ring:

(B) -(CO)n(CH2)m-COR

wherein n is 0-l, m is 0-7 and R represents alkyl, hydroxy, carboxyalkyl, optionally substituted alkene, alkoxy or substituted amino;

1 o /R8 (C) -CON ~
Rg wherein R8 and Rg independently represent hydrogen or one of the following optionally substituted groups: alkyl, alkenyl, alkynyl, cycloalkyl and aralkyl, or R8 and Rg taken together form an optionally substituted piperidyl group: and (D) -NH-CO-Rlo wherein Rlo comprises a substituted alkyl group.

As aforesaid, the present invention as claimed hereinafter is catechol however restricted to some members of the broad family of derivatives defined hereinabove. More particularly, the invention relates as claimed hereinafter is restricted to the catechol derivatives of formula (I'):

R20~ R3 ( I ~ ) '~
~" ..~ ~

: :., .. : . . - .

and to their salts, wherein Rl and R2 independently represents hydrogen, optionally substituted acyl or aroyl, lower alkylcarbamoyl; X represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde, and trifluoromethyl; and R3 represents alkyl substituted by lower alkoxy lower alkoxy, carboxy lower alkyl, thio or pyrrole groùp, or a group selected from:

(A) -CH=C-R5 or -CH2-CH-R

wherein R4 represents cyano or acyl and R5 represents cyano, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, hydroxyalkyl, carboxyalkyl or one of the following optionally substituted groups: carbamoyl, aroyl or heteroaroyl, or R4 and R5 form together a five to seven membered, optionally substituted cycloalkanone ring;

(B) (CH2)m-COR

wherein m is 2-7 and R represents hydroxy, alkyl, carboxyalkyl, optionally substituted alkene, alkoxy or optionally substituted amino;

(C) -CON
Rg wherein R8 represents hydrogen and Rg represents~an optionally substituted adamantyl group.

The term "alkyl" as employed herein either alone or as part of another group includes both straight and branched chain ~. ~ i radicals of up to 18 carbon atoms, preferably 1 to 8 carbon atoms, most preferably 1 to 4 carbon atoms. The term "lower alkyl" as employed herein by itself or as part of another group includes both straight and branched chain radicals of 1 to 7, preferably 1 to 4, most preferably 1 or 2 carbon atoms. Specific examples for the alkyl and lower alkyl residues, respectively, are methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, pentyl, hexyl, octyl, decyl and dodecyl including the various branched chain isomers thereof.

The term "alkenyl" and alkynyl designate a hydrocarbon residue as defined above with respect to the term "alkyl"
including at least one carbon to carbon double bond and carbon to carbon tripe bend, respectively. The alkenyl and alkynyl residues may contain up to 12, preferably 1 to 8, most preferably 1 to 4 carbon atoms.

The term "acyl" as employed herein by itself or as part of another group refers to an alkylcarbonyl or alkenylcarbonyl group, the alkyl and alkenyl groups being defined above.

The term "aroyl" as used herein by itself or as part of another group refers to an arylcarbonyl group, the aryl group being a monocyclic or bicyclic group containing from 6 to 10 carbon atoms in the ring portion. Specific examples for aryl groups are phenyl, naphtyl and the like.

The term "lower alkylidene" refers to a chain containing from 2 to 8, preferably 2 to 4 carbon atoms. In a similar way the term "cycloalkylidene" refers to a cyclic hydrocarbon group containing 3 to 8, preferably 5 to 7 carbon atoms.

,~

. .

! ` _ 5 _ The term "cycloalkyl" includes saturated cyclic hydrocarbon groups containing 3 to 8, preferably 5 to 7 carbon atoms.
Specific examples are the cyclopentyl, cyclohexyl, cycloheptyl and adamantyl groups.

The term "aralkyl" as employed herein refers to alkyl groups as defined above having an aryl substituen`t. A specific example is the benxyl group.

The term "alkoxy" as employed herein by itself or as part of another group includes an alkyl residue as defined above linked to an oxygen atom.

The term "halogen" as used herein refers to chlorine, bromine, fluorine or iodine, chlorine and bromine being preferred.

The term "optionally substituted" as used herein in connection with various residues refers to halogen substituents, such as fluorine, chlorine, bromine, iodine or trifluoromethyl groups, alkoxy, aryl, alkyl-aryl, halogen-aryl, cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino, alkanoylamino arylcarbonylamino, nitro cyano, thiol, or alkylthio substituents.
The "optionally substituted" groups may contain 1 to 3, preferably 1 or 2, most preferably 1 of the above mentioned substituents.

The term "heteroaroyl" or "heteroaryl" or "heteroalkyl" as employed herein refers to monocyclic or bicyclic group containing 1 to 3, preferably 1 ot 2 heteroatoms N and/or 0 and/or S. Specifific examples are morfolinyl, piperidyl, piperidinyl piperazinyl, pyridyl, pyrrolyl, quinolinyl and .
~,.

.

quinolyl.

The compounds of formula (I') may be used to make pharmaceutical compositions which are also claimed hereinafter.

The present invention as claimed hereinafter also relates to a method for preparing the compounds of formula (I'), which method comprises one or more of the followings steps.
An aldehyde of formula (II):

R10 ~ ~

- 2 ~ C~O

X (II) wherein R1, R2 and X are as defined above, may be condensed in the presence of a base or acid catalyst with a compound of formula (III):

2 5 (III) having an active methyl or methylene group and wherein R4 and R5 are as defined above, thereby giving the compounds of formula (I'a):

1 ~ R4 ~ (I'a) X

r2 ~
~,' .. ... . . .

1 33~967 wherein R4 and R5 are as defined above and wherefrom the double bond optionally may be reduced to a single bond.

The compounds of formula (II) are valuable intermediates for preparing most of the compounds of the broad family of formula (I), including, of course, those of formula (I') according to the invention.

The compounds of formula (II) wherein X is a cyano group can be prepared from the same compound of formula (II) wherein X
is halogen, preferably bromine, by allowing these compounds to react with cuprous cyanide in a polar, aprotic solvent, such as pyridine, N-methylpyrrolidone or N,N-dialkylform-amide at elevated temperature (100-200 C).
Alternatively, the compounds of formula (II) wherein Z is a 5-cyano group, can be prepared by formylation o 2,3-dihydroxybenzonitrile with hexamethylenetetramine.

The compounds of formula (I') wherein R3 is substituted alkyl group (B) i.e. (CH2)m-COR, can be prepared by Friedel-Craft's reaction from a compound of formula (VI):

R2 ~ (VI) wherein Rl and R2 are as defined above, by allowing the compound of the formula (VI) to react in the presence of aluminium chloride either with a cyclic acid anhydride of formula (VII):

~ ~, ~ , .: .... :.. .. . . . . . .. . .. .

- ~ - 1 3 3 4 9 6 7 co\
( C~2 ~ m ~ CO (VII) wherein m is 2-7 or alternatively with a dicarboxylic acid ester chloride of formula (VIII):

( 2)m-1 (VIII) wherein m is 2-7 and R is as defined above and Hal is a halogen atom, to give the compounds of formula (IX):

RlOj~
R20Wc- ( CH2 ) m- 1 COR ( IX ) whose aromatic ring is subsequently substituted with a group X to give a compound of formula (I'c):

1 ~
2~ O ~ CO-(CH2)m-1 COR
(I'c) wherein R, Rl, R2 and X are as defined above, which corresponds to a compound of formula (I') wherein R3 is -Co-(cH2)m-coR.

The carbonyl group(s) of the compounds of formula (I'c) can be reduced to methylene group(s) by conventional methods (Clemmensen and Wolff-Kischner reduction) to give the corresponding compound of formula (I'd):

B~

............... . .. .... ...

!'` g RlO j~\
2 ~ ( 2)m-l X (I'd) The compounds of formula (I') according to the invention wherein R3 is the substituted carbamido group (C) -CON , can be prepared by reacting an activated benzoic Rg acid derivative of formula (X):

R10~
2 ~ coY (x) ZO X

wherein R1, R2 and X are as defined above and Y comprises halogen or some other activated group with an amine of formula (XI):

- HN (XI) Rg wherein R8 and Rg are as defined above to give a compound of formula (I'e):

::. - . .. ... .

R2O ~ O ~ CON\
~ Rg (I'e) X

wherein R1, R2, X, R8 and Rg are as defined above which corresponds to the requested compound of formula (I').

It is known that in Parkinson's disease, the dopaminergic neurones, primarily the nigrostriatal neurones, are damaged, causing dopamine deficiency in the cerebral basal ganglia.
This deficiency can be compensated by levodopa which is converted to dopamine in the central nervous system under the influence of DDC.

It is also known that today, levodopa treatment is almost invariably supplemented with a peripheral DDC inhibitor to inhibit too early dopamine formation and thereby to increase the cerebral levodopa concentration and to decrease the peripheral side effects of dopamine.

It is further known that catechol-0-methyltransferase (COMT) catalyzes the transfer of the methyl group from S-adenosyl-~i ~ lOa -t 334967 L- methionine to a number of compounds with catechol structures. This enzyme is important in the extraneuronal inactivation of catecholamines and drugs with catechol structures. COMT is one of the most important enzymes involved in the metabolism of catecholamines. It is present in most tissuesr both in the periphery and the central nervous system. The highest activities are found in the liver, intestine and kidney. COMT probably is present in soluble and membrane bound forms. The exact character of the two forms has not been established.

Therefore, COMT like monoamine oxidase (MAO), is a major enzyme participating in the amine metabolism. COMT
metabolizes levodopa and converts it to 3-0-methyldopa (3-OMD) which readily penetrates the blood-brain barrier via an active transport system. Alone, COMT is therapeutically ineffective and detrimental when competing with levodopa as

3-OMD is accumulated in tissues because of its long half-life (ca. 15 h) as compared to levodopa (ca. 1 h). In other words, the high activity of COMT clearly correlates with the poor efficacy of levodopa despite the presence of peripheral DDC inhibitor.

COMT inhibitors are known, which inhibit the metabolism of endogenous amines (dopamine, noradrenaline, adrenaline) in the brain. The COMT inhibitors decrease decomposition of these compounds and thus may be useful in the treatment of depression.

In addition, by inhibiting peripheral COMT effectively, COMT
inhibitors direct the metabolic route of levodopa towards decarboxylation, forming thereby more dopamine which is important in the treatment of hypertension and heart failure.

.~
~`

:: ,.. .,.. ... . . , .. . -. ..

- 10b -The present invention is based on the observation that the compounds of formula (I) as defined hereinabove, including those of formula (I') that are new and claimed hereinafter, are extremely effective, specific and non toxic COMT
inhibitors. This, of course, opens up new, previously unknown possibilities in treatment of depression and heart failure as well as hypertension.

The compounds of formula (I) including those of formula (I') as claimed inhibit formation of 3-OMD and thus decrease the adverse effects of long-term use of levodopa. Furthermore, they make it possible to reduce the levodopa doses. In practise, it has been shown that the dose of levodopa can be reduced by half or to one-third of the dose of levodopa can be reduced by half or to one-third of the dose used without COMT inhibitor. Since dosage of levodopa is individual, it is difficult to give any absolute dosage, but daily doses as low as 25-50 mg have been considered sufficient to start with.
A preliminary clinical trial on n-butyl gallate, a known COMT inhibitor, showed patients with Parkinson's disease clearly to benefit of n-butyl gallate. The study was, however, discontinued because of the too high toxicity of n-butyl gallate.

The following description will give some examples ofpreparation of compounds of formula (I), including of course, some compounds of formula (I') according to the invention.

The COMT inhibitory efficacy of the compounds of formulae (I) and (I') that were so prepared, was tested using the following experimental procedures.

~' v ~" , , .. . , . , .. : . ... . -.- .. .. - . -.

~ ~349~7 Determination of COMT activity in vitro The in vitro activity of COMT was determined in enzyme preparations isolated from the brain and liver of female Han:WIST rats, weight ca. 100 g. The rats were killed by carbon dioxide, and the tissues were removed and stored at -80C until determination of enzyme activity.

The enzyme prepafation was prepared by homogenizing the tissues in 10 mM phosphate buffer, pH 7.4, (1:10 weight g/ml) which contained 0.5 mM dithiotreitol. The homogenate was centrifuged 15000 x G for 20 min. The supernatant was recentrifuged 100000 x G for 60 min. All procedures were done at +4C. The supernatant of the last centrifugation (100000 x G) was used to determine the activity of soluble COMT enzyme.

Determination of IC50 was performed by measuring the COMT
activity in several drug concentrations of the reaction mixture which contained the enzyme preparation, 0.4 mM
dihydroxybenzoic acid (substrate), S mM magnesium chloride, O.2 mM S-adenosyl-L-methionine and COMT inhibitor in 0.1 M
phosphate buffer, pH 7.4. No COMT inhibitor was added to the control. The mixture was incubated for 30 min at 37C
whereafter the reaction was stopped by perchloric acid and the precipitated proteins were removed by centrifugation (4000 x G for 10 min). The activity of the enzyme was measured by determining the concentration of 3-methoxy-

4-hydroxybenzoic acid formed from the substrate of COMT
(dihydroxybenzoic acid) by HPLC using an electrochemical detector. Chromatography was performed by injecting 20 ul of the sample in a 4.6 mm x 150 mm Spherisorb ODS*column (particle size 5 um). The reaction products were eluted from the column with 20 % methanol containing 0.1 M phosphate, 20 mM citric acid and 0.15 mM EDTA, pH 3.2, at a flow rate of 1.5 ml/min. The electrochemical detector was set to 0.9 V
against an Ag/AgCl electrode. The concentration of the reaction product, 3-methoxy-4-hydroxybenzoic acid, was compared with the control samples and the samples containing * trade mark - 12 l 334967 COMT inhibitor. The IC50 value is the concentration which causes a 50 % decrease in COMT activity.

Effect of COMT inhibitors in vivo Male Han:WIST rats, weight 200 - 250 g, were used in the experiment. The control group was given 50 mg/kg carbidopa 30 min before levodopa (50 mg/kg). The test group was also given carbidopa 50 mg/kg 30 min before levodopa + COMT
inhibitor. The drugs were administered orally.

Sampling About 0.5 ml of blood was drawn from the tail artery. The sample was allowed to coagulate in ice. Thereafter the sample was centrifuged and serum separated. Serum was stored at -80 oC until determination of concentrations of levodopa and its metabolite 3-OMD.

Determination of levodopa and 3-OMD serum concentrations To serum (e.g. 100 ul), an equal volume of 0.4 M perchloric acid, 0.1 % sodium sulphate, 0.01 % EDTA, which contained dihydroxybenzylamine as internal standard, were added. The sample was mixed and kept in ice, whereafter the proteins were removed by centrifugation (4000 x G for 10 min.) and the concentrations of levodopa and 3-OMD were determined by HPLC
using an electrochemical detector. The compounds were separated in a 4.6 mm x 150 mm Ultrasphere ODS*column in an eluent containing 4 ~ acetonitrile, 0.1 M phosphate buffer, 20 mM citric acid, 0.15 mM EDTA, 2 mM octylsulphonic acid and 0.2 % tetrahydropholan, pH 2.8. The flow rate was 2 ml/min.
The electrochemical detector was set to +0.8 V against an Ag/AgCl electrode. The concentrations of the test compounds were determined by comparing the heights of the pea~s with that of the internal standard. The ratio was used to calculate the serum concentrations of levodopa and 3-oMD in control rats and those given COMT inhibitor.
. .
~ ~ * trade mark _ t 33~9~7 Resul ts The best COMT inhibitors used in the canposition accor~ling to the invention were more than thousan~ times more potent in vitro than the most potent known reference compound U-0521 (Table I). Also the orally administered COMT inhi~itors were shown to inhibit the formation of serum 3 - OMD significantly more than U-0521 (Table II). The reference compound U-0521 furthermore penetrated the blood-brain barrier and inhibited the thyrosine hydroxylase activity thereby blocking the bio-synthe~is of vitally important catecholamines. In contrast the compounds of:fonmul~ ~I) are'COM~.specific and they do not significantly penetrate the blood-brain barrier.

Results in vitro 2 ~

Example E~1 2 R3 COMT--INHIBITION

compound (IC50(nM3 ~ CH2 ) P~

7g H H 5-NO2 CH ~ H ~ OH 3 ~ O~H3 11 H ~ 5-NO2 CH=CH-C ~ OCH3 t ~34967 Example Rl 2 R3 8 H H 5-NO2 CHsCH-C~ 6 6 H H 5--NO2 CH=C -- C--CH3 12 CH3 o 130 CH3 ( CH2 ) 2C H 5--NO2 No2 18 /CN
S H H 5--NO2 CH~C \ 20 CN

27 H H 5--NO2 CH2CH2CH2CH2CN--CH2C=CH 20 - 16 H H 5--NO2 CH~C -- ICH -- CH3 23 113 H H 5--NO2 Cl 25 Example Rl R2 3 28 H H S--NO2 C 2CH2CH2CH2CONH ~)27 26 H H ' S - NO2 CH2CH2CH2CH2CNH--CH\ 33 O O
12 8CH3CH2 C CH3CH2C 5--NOz 2 6 0 O O
127CH3 C CH3 C No2 No2 .

131 ~ CH3 ) 3C--C H 5--NO2 No2 220 54 H H 5--Cl CONH ~) 400 67 CH3CO CH3CO 6--N02 Co--~j3 CO C> 750 16 ~ 49i~;7' .

~CH3 U--0521 H H 5--H COCE~ 6000 T~BL~: 2 In vivo results 3-OMD concentration % of control Oral dose Compound 1 h 5 h 3 mg/kg Example 110 - 97 - 80 4.3 mg/kg Example 127 - 67 - 76 4.7 mg/kg Example 128 - 70 - 77 4.3 mg/kg Example 131 - 92 - 83 4.1 mg/*g Example 130 - 98 - 92 30 mg/kg Example 19 - 99 - 76 30 mg/kg Example 111 - 100 - 65 30 mg/kg Example 5 - 96 - 89 30 mg/kg Example 6 . - 84 - 49 30 mg/kg Example 11 - 63 - 26 30 mg/kg Example 8 - 58 - 34 100 mg/kg Example 24 - 86 - 41 100 mg/kg U-0521 - 34 - 14 The results indicate that the compounds of formula ~I) that were tested are even more than thousand times more potent in vitro (Table 1) than the reference coumpound tU-05211. The orally administered new compounds inhibit COMT also in vivo significantly better than the reference compound, which is reflected as decreased serum 3-OMD concentration (Table 23.
The reference compound U-0~21 furthermore penetrates the blood-brain barrier and nonspecifically inhibits thyrosine hydroxylase which is essential for the biosynthesis of catecholamines.

17 l 3 3 4 9 6 7 Fig. 1 shows the 3-OMD secum concentrations for the new compound (e.g. according to example 51 and for the control compound which does not contain COMT inhibitor. The experimental design is the same as for the in vivo experiments above. Fig. 2 shows the levodopa serum concentrations after the same treatments. These figures show that the compounds of formula (I) increase the bioavailability of levodopa and decrease the level of the harmful metabolite 3-OMD. The change observed in serum is re1ected in the brain concentrations of 3-oMD and levodopa.

Specificity of COMT inhibition The compounds of f~n~ (I) are sper~ific~lly CoMr inhibitors and not inhibitors of other essential enzymes. This was shown in in vitro experiments which were performed as described above.

.C50 Compound COMT TH DBH DDC MAO-A MAO-B

Example 87 3 38.000 >S0.000 ~50.000 >50.000 >50.000 Example 11 5 18.000 >50.000 >50.000 >50.000 >50.00~
Example 8 6 21.000 >50.000 >~0.000 >50.000 >50.000 Example 6 12 50.000 >50.000 >50.000 >50.000 >50.000 ~xample 110 12 14.000 >50.000 >50.000 >50.000 >50.000 Example 19 16 17.500 >50.000 >~0.000 >50.000 >50.000 Example 5 20 21.000 >50.000 >50.000 >50.000 >50.000 Example 111 24 50.000 >50.000 >50.000 >50.000 >50.000 U-0521 6000 24.000 >50.000 >50.000 >50.000 >50.000 TH c Thyrosine hydroxylase, DsH = Dopamine-~-hydroxylase MAO-A and -B = Monoamine oxidase- A and -B.

The COMT inhibitors of ~ormula (I) are extremely specific. They inhibit COMT effectively at low concentra-tions, while inhibition of other enzymes involved in the meta~olism of catecholamines requires a 1000-10000 times ~1 ~ 334967 higher concentration. The difference between ~he inhibition of TH and COMT in the reference compound U-0521 is only 4-fold.

IC50 is the concentration which inhibits 50 % of the enzyme activity.

Toxicity The ~oMT inhibitors of formula (I) are non-toxic. For instance, the LDSo of 3-(3,4-dihydroxy-5-nitrophenyl)-1-(3,4,5-trimethoxy-phenyl)prop-2-en-1-one (Example 11) given as an oral ~uspension to rats, was over 2500 mg/kg.

Example 1 ~ 3349~7 3-Nitro-5-[2-(4-pyridyl)vinyl] catechol A solution containing 2.0 q ~0.011 mole) of 3,4-dihydroxy-

5-nitrobenzaldehyde and 2.23 g (0.024 mole~ of 4-picoline in 9.0 ml of acetic anhydride was refluxed for 1 h. About 15 ml of isopropanol was then added and the solution was cooled to 0C where upon the diacetyl-derivative of the desired product crystallized. After filtration the product was suspended in 100 ml of 0.5 N hydrochloric acid and refluxed for 1.5 h.
After cooling the precipitate was filtered, washed with water and acetone and dried. Yield 1.89 g (67 %), m.p. above 350C.

Example 2 3-Nitro-5-t2-(4-quinolyl)vinyll catechol The same procedure described in Example 1 was repeated u~ing 2.0 g ~0.011 mole) of 3,4-dihydroxy-5-nitrobenzaldehyde and 3.44 g (0.024 mole) of 4-quinaldine. Yield 1.7 g (50 %), m.p.
250~C (decomp.).

Example 3 4-Hydroxy-3-methoxy-5-nitrocinnamic acid A sol~tion of 1.0 g of 5-nitrovanillin and 4.0 g of malonic acid in 10 ml of pyridlne was heated for 50 h at 80C. The reaction mixture was dlluted with water, acidified with hydrochloric acid, filtered, washed with water and dried.
Yield 0.44 g (36 ~). The 1H-NMR spectrum was in accordance with the structure alleged.

Example 4 3,4-Dihydroxy-5,~tdinitrostyrene A solution containing 3.66 g (0.02 mole) of 3,4-dlhydroxy-~ 20 l 334967 5-nitrobenzaldehyde, 3.66 g (0.06 mole) of nitromethane and 3.31 g of ammonium acetate in 10 ml of abs. ethanol was refluxed for 6 h. water was added to the reaction mixture.
The mixture was acidified with hydrochloric acid and extracted with ~ethylene chloride. The methylene chloride extract was washed with water and the ~olvent was evaporated in ~acuo. The residue was crystallized from isopropanol, yield 1.9 g (40 %3, m.p. 258-260C.

Example 5 3,4-Dihydroxy-S-nitro-~,~-dicyanostyrene The same procedure described in Example 4 was repeated using 3.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 3.0 g of malonodinitrile. The product was crystallized from methanol-water, yield 1.9 g (50 %), m.p. 20S-209C.

Example 6 4-t3,4-Dihydroxy-5-nitrophenyl~-3-methylbut-3-en-2-one A solution containing 0.5 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 2.0 ml of butanone was saturat~d with gaseous hydrogen chloride. After standing over night ether was added to the sol~tion and it was filtered. The product was crystallized from isopropanol, yield 0.2 g (30 ~), m.p.
139-141C.

Example 7 3-(3,4-Dihydroxy-5-nitrobenzylidene~-2,4-pentanedione A solution containing 1.83 g of 3,4-dihydroxy-5-nitro-benzaldehyde and 1.00 g of 2,4-pentanedione in 10 ml of tetrahydrofuran was saturated with gaseous hydrogen chloride.
After standing over night at ~C the product was filtered and washed with ether. Yield 1.2 g (50 %), m.p. 175-178C.

~ 21 ` ~ 1 334967 Example 8 3-(3,4-Dihydroxy-S-nitrophenyl)-l-phenylprop-2-en-1-one A solution containing 0.55 g of 3,'4-dihydroxy-S-nitro-benzaldehyde and 0.36 g of acetophenone in 10 ml of methanol was saturated with gaseo~s hydrogen chloride. After standing over night at 5C the product was filtered and washed with methanol. Yield 0:55 g (68 %), m.p. 192-195C.

Example 9 3-(3,4-Dihydroxy-S-nitrophenyl)-1-(4-methoxyphenyl)-prop-2-en-l-one The procedure described in Example 8 was repeated using 1.8 g of 3,4-dihydroxy-5-nitrobenzaldehyde and l.S g of 4'-methoxy-acetophenone in 20 ml of tetrahydrofuran. Yield 1.88 g (60 %), m.p. 222-228aC.

~xample 10 3-(3,4-Dihydroxy-5-nitrophenyl)-1-(3,4-dimethoxyphenyl)prop-2-en-1-one The procedure described in Example 8 was repeated u~ing 1.8 g of 3.4-dihydroxy-S-nitrobenzaldehyde and 1.8 g of 3',4'-di-methoxyacetophenone in 20 ml of methanol. Yield 1.7 g (50 %), m.p. 206-208~C.

Example 11 3-(3,4-Dihydroxy-S-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one The procedure described in Example 8 was repeated using O.SS
g of 3,4-dihydroxy-S-nitrobenzaldehyde and 0.63 g of 3',4',5'-trimethoxyacetophenone. Yield 0.50 g (44 %), m.p.
213-216C.

` ` ~ 1 334967 Example 12 3-(3,4-Dihydroxy-5-nitrophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one The procedure described in Example 8 was repeated using 1.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.74 g of 2'-hydr-oxyacetophenone. Yield 0.2 g (12 %), m.p. 231-234C.

Example 13 3-(3,4-Diacetoxy-5-nitrophenyl)-1-phenylprop-2-en-1-one A solution containing 1.0 g of the product obtained in Example 8 in 5.0 ml of acetic anhydride was refluxed for 2 h.
After cooling the product was filtered and washed with ether.
Yield 0.73 g ~68 %), m.p. 183-185C.

Example 14 3-(3,4-Dibenzoyloxy-S-nitrophenyl)-l-phenylprop-2-en-l-one 1.0 g of the product obtained in Example 8 and 2.0 ml of benzoylchloride were dissolved in 5 ml of tetrahydrofuran.
Tetrahydrofuran was distilled off to a great extend and the residue was refluxed for 2 h. After cooling ether was added to the mixture and the product was filtered and triturated with ethylmethylketone. Yield 0.50 g (29 %), m.p. 206-210~C.
.
Example 15 3-(3-Pivaloyloxy-4-hydroxy-5-nitrophenyl)-1-phenyl-prop-2-en-1-one 1.0 g of the product obtained in Example 8 was dissolved in 5 ml of tetrahydrofuran, 4.7 ml of pivaloyl chloride was added and the mixture was refluxed for 16 h. The solvent was evaporated in vacuo and the residue was purified in a silicagel column by using toluene-acetic acid-dioxane ` `` 1 334967 -(18:1:1) mixture as an eluent. The product was crystallized from ether, m.p. 148-150C.

Example 16 4-(3,4-Dihydroxy-5-nitrophenyl)-3-methylbut-3-e~n-2-ol 1.8 g of the product obtained in Example 6 was dissolved in 20 ml of lN NaOH solution and 4.0 g of sodium borohydride in small amount of water was added. The mixture was stirred over night at room temperature, acidified with hydrochloric acid and extracted with ether. The solvent was evaporated in vacuo and the residue purified in a silica gel column by using toluene-acetic acid dioxane (18:1:1). The product was crystallized from dichloromethane petroleum ether. Yield 0.80 g (44 %~, m.p. 102-104C.
., Example 17 7-(3,4-Dihydroxy-5-nitrobenzylidene)-8-ketononanoic acid The procedure described in Example 9 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.72 g of 8-ketononanoic acid. Yield 1.85 g (55 %), yellow viscous oil.

Example 18 4'-Hydroxy-3'-methoxy-5'-nitroacetophenone ~o a solution containing 40 ml of nitric acid (d~1.41) and 40 ml of water was gradually added while cooling (below 7C) and stirring 25.0 g of 4'-hydroxy-3'-methoxyacetophenone. After stirring for 0.5 h at 0C the product was filtered, washed first with diluted nitric acid (1:1) and then with water.
Yield 24.0 g (75 %). The 1H-NMR-spectrum of the product was in accordance with the structure alleged.

` ~ _ 24 Example 19 3'4'-Dihydroxy-5'-nitroacetophenone A solution containing 19.9 g of the product obtained in Example 18 in 200 ml of acetic acid and 200 ml of ~8 %
hydrobromic acid was refluxed for 5 h. 500 ml of a saturated solution of sodium sulfate was added to the reaction mixture and the same was let stand overnight at 5C. The solution was extracted with ether. The ether phase was washed with 2~0 ml of water, dried and the solvent evaporated in vacuo. The residue was crystallized from isopropanol. Yield 10.2 g (S5 %), m.p~ 155-159C.

Example 20 1-(3,4-Dihydroxy-5-nitrophenyl)-3-(4-dimethylaminophenyl~-prop-2-en-1-one A solution containing 0.5 g of the product obtained ~n Example 19 and 0.38 of 4-dimethylamino~enzaldehyde in 5 ml of methanol was saturated with gaseous hydrogen chloride. The solution was refluxed for 1 h. After cooling the product was filtered and washed with methanol. Yield 0.26 g ~7 decomp. on heating.

Example 21 (int~n~i~te~

5-(4-Benzyloxy-3-methoxyphenyl~-2,4-pentadienoic acid To a solution containing 260 g of 4-benzyloxy-3-methoxy-benzaldehyde and 200 ml of ethyl crotonate in 1200 ml of N-methylpyrrolidone was qradually added while stirring and cooling at 0C 149.6 g of potassium tert.-butoxide. The solution was stirred for 0.5 h after which 200ml of 10 ~
NaOH-solution was added and stirred for 0.5 h more at 0C.
The reaction mixture was added to a mixture of hydrochloric acid and ice. The semisolid product was separated and used without purification to the next step.

~ ~ ~ 25 Example 22 5-(4-Hydroxy-3-methoxyphenyl)pentanoic acid The raw product obtained in Example 21 was dissolved in 500 ml of N,N-dimethylformamide and 22 g of 10 % palladium on charcoal catalyst was added. The mixture was hydrogenated at 60C and normal pressure until the theoretical amount (3 mole~ of hydrogen was consumed. After filtering the solvent was evaporated in vacuo to a great extent and the residue was dissolved in 1 1 of dichloromethane and washed with 2 l of water. The product was extracted with l.S 1 of saturated NaHCO3-solution. After acidification of the aqueous phase with hydrochloric acid the product was extracted with 1 1 of dichloromethane. The solvent was distilled off in vacuo and the semisol~d residue (180 g) was used to the next ~tep.

Example 23 5-~4-Hydroxy-3-methoxy-5-nitrophenyl)pentanoic acid The above product (180 g) was dissolved in 1 1 of dichloromethane and 820 ml of 1 molar HNO3-dichloromethane solution was added gradually while stirring and cooling (0-5C). The solution was stirred for 10 min more at 0C
after which water was added. The organic phase was separated and washed with water. The solvent was evaporated in vacuo and the semisolid residue was used as such to the next step.

Example 24 5-(3,4-Dihydroxy-5-nitrophenyl)pentanoic acid The above product obtained in Example 23 was dissolved in a mixture containing 500 ml of acetic acid and 500 ml of 48 %
hydrobromic acid and refluxed for 4 h. 1 1 of saturated Na2SO4-solution was added to the reaction mixture and the solution was allowed to stand over night at 5C. The product crystallized was filtered and washed with 50 % acetic acid.

~ ' 26 ` _ ~334967 This product was recrystallized from ethyl acetate Yield 32 g (16 %), m.p 135-138~C

Example 25 1-senzyl-4- [5-(3,4-dihydroxy-5-nitrophenyl)pentanoyl3 piperazine hydrochloride A solution containing 3.0 g of the product obtained in Example 24 in 18 ml of thionyl chloride was refluxed for 10 min. The excess of thionyl chloride was evaporated in vacuo and the acid chloride formed was dissolved in Z0 ml of dichloromethane. To this solution 2.1 g of 1-benzylpiperazine in 20 ml of dichloromethane was added with stirring and stirred ~or 0.5 h more. Ether was added to the reaction mixture and the crystals were filtered. Yield 3.55 g ~73 %), m.p. 85-89C.

Example 26 N-Isopropyl-5-(3,4-dihydroxy-5-nitrophenyl)pentanoic amide A solution containing O.S g of the product obtained in Example 24 in 2.5 ml of thionyl chloride was refluxed for 10 min. The excess of thionyl chloride was evaporated in vacuo and the residue dissolved in 25 ml of dichloromethane. To this solution Q.47 g of isopropylamine was added and the mixture was stirred for 1 h at 20C. Dichloromethane phase was washed with 1 N hydrochloric acid and evaporated in vacuo. The residue was crystalLized from toluene. Yield 0.44 g (75 %), m.p. 113-115C.

Example 27 N-Methyl -N-propargyl-5-(3,4-dihydroxy-5-nitrophenyl)-pentanoic amide The procedure described in Example 26 was repeated using 0.5 g of methyl propargylamine instead of isopropylamine.

:

-~ ` ~ 27 ~ ~ 9 ~ ~

Yield 0.5 g (83 %), m.p. 133-135C.

Example 28 N-(1-Adamantyl)-5-(3,4-dihydroxy-5-nitrophenyl)-pentanoic amide The procedure described in Example 26 was repeated using 1.5 g of 1-aminoadamantane instead of isopropylamine. Yield 0.61 g (80 %), m.p. 157-160C.

Example 29 Tetradecyl-5-(3,4-dihydroxy-5-nitrophenyl)pentanoate The procedure described in Example 26 was repeated using 1.26 g of l-tetradecanol instead of isopropylamine. The reaction mixture was washed with water and the solvent evaporated in vacuo. Yield 0.44 g (50 %), m.p. 46-47C.

Example 30 Tetradecyl 5-(3,4-diacetoxy-5-nitrophenyl)pentanoate A solution containing 0.1 g of the product obtained in Example 29 in 2 ml of acetic anhydride was refluxed for 20 min. The solvent was evaporated in vacuo and the residue crystallized from petroleum ether (b.p. 40C1, m.p. 52-54C.

Example 31 Tetradecyl 5-(4-hydroxy-3-pivaloyloxy-5-nitrophenyl)-pentanoate The procedure described in Example 30 was repeated using 2 ml of pivaloyl chloride instead of acetic anhydride. The product was a viscous oil.

Example 32 5-(3,4-Dimethoxy-5-chlorophenyl)-2,4-pentadienoic acid To a solution containing 10.0 g of dimethoxy-5-chloro-benzaldehyde and 8.3 ml of ethyl crotonate in 65 ml of N-methylpyrrolidone 6.7 g of potassium tert.-butoxide was added with stirring. The solution was stirred for 0.5 h more at 20C and the solution was poured then to a mixture of ice and hydrochloric acid and extracted with ether. The ether extract was washed with water and extracted then with NaHCO3-solution. The aqueous phase was acidified with hydrochloric acid and the semisolid product was separated and washed with water. Yield 7.3 g (55 ~).

Example 33 5-(3,5-Dimethoxy-5-chlorophenyl)pentanoic acid A solution containing 6.2 g of the above product o~tained in Example 32 was dissolved in a mixture of 30 ml of acetic acid and 3 ml of conc. hydrochloric acid. Palladium on charcoal catalyst (10 % Pd) was added and the mixture was hydrogenated at normal pressure and room temperature. After filteration the solvents were evaporated in vacuo. Yield 3.2 g (55 %), a viscous oil.

Example 34 5-(3,4-Dihydroxy-5-chlorophenyl)pentanoic acid A solution containing 3.2 g of the above product in 8 ml of acetic acid and 10 ml of 48 % hydrobromic acid was refluxed for 3 h. A saturated solution of Na2SO4 in water was added to the reaction mixture. The crystallized product was filtered, washed with water and recrystallized from toluene, m.p.
99-101 C .

~ ~ 29 Example 35 5-(3,4-Dimethoxy-6-chlorophenyl)-2,4-pentadienoic acid To a solution containing 10.0 q 3,4 dimethoxy-6-chloro-benzaldehyde and 8 ml of ethyl crotonate in 60 ml of N-methylpyrrolidone 6.0 g of potassium tert.-butoxide was added while stirring . The solution was stirred for 0.5 h more at 20C and poured then to a mix~ure of ice and hydrochloric acid. The solution was extracted with ether. The ether solution was washed with water and extracted with 2.5 N
NaO~-solution. The aqueous phase was acidified with hydrochloric acid and the semisolid product was separated.
Yield 10.8 g (81 %).

Example 36 5-(3,4-Dihydroxy-6-chlorophenyl)-2,4-pentadienoic acid To a solution containing 0.54 g of the product obtained in Example 35 in 6 ml dichloromethane 6 ml of 1 molar boron tribromide-dichloromethane solution was added and stirred for 24 h at 20C. The solvent was evaporated in vacuo and 2 N
hydrochloric acid was added to the residue. The product was filtered and washed with water. Recrystallization from isopropanol-water yielded 0.22 g (46 %) of the product desired, m.p. 203-206C.

~xample 37 3-(3,4-Dihydroxy-S-nitrophenyl)-1-(4-methylphenyl)-prop-2-en-1-one A solution containing 5.4g g of 3,4-dihydroxy-5-nitrobenz-aldehyde and 5.37 g of 4'-methylacetophenone in 5~ ml of tetrahydrofuran was added a catalytic amount of gaseous hydrogen chloride and refluxed for 4.5 h. The solvent was evaporated in vacuo and the residue crystallized from ether-petroleum-ether, yield 1.85 g (21 %), m.p. 184-186C.

~ 4 9 6 7 Example 38 (intermediate) 5-(3,~-Dimethoxyphenyl)-5-ketopentanoic acid A solution containing 36 g of veratrole and 30 g glutaric anhydride in 120 ml of nitrobenzene was gradually added while stirring and cooling at 0C to a mixture of 72 g of anhydrous aluminium chloride and 240 ml of nitrobenzene. The mixture was stirred for 1 h at 0C and then for 18 h at 20C. Ice and hydrochloric acid were added to the reaction mixture.
Nitrobenzene layer was separated and to this ethyl acetate was added whereupon the product crystallized. After filtering the crystals were washed with ethyl acetate. Yield 42.3 g ~64 %) Example 39 (intermediate) 5-(3,4-Dimethoxyphenyl)pentanoic acid A mixture containing 37.6 g of the product obtained in Example 38 and 64 g of zinc turnings (treated w5th a solutlon of HgC12), 55 ml of toluene and 22U ml of conc. hydrochloric acid was refluxed for 1 h. Toluene phase was separated and evaporated in vacuo. The residue was crystallized from toluene-petroleum ether, yield ll.S g (32 %).

Example 40 5-(3,4-Dimethoxy-6-nitrophenyl)pentanoic acid l5.Q g of product described in Example 39 was gradually added to 75 ml of nitric acid (d-1.41) at 20~C. The mixture was stirred for 20 min more. Ice-water was added and solution was extracted with dichloromethane The solvent was evaporated in vacuo yielding 14.0 g (79 %) of the desired product.

Example ~1 5-(3,4-Dihydroxy-~-nitrophenyl3pentanoic acid A solution containing 42.0 g of the product obtained in Example 40 in 100 ml of acetic acid and 150 ml of 48 %
hydrobromic acid was refluxed for 10 h. 1 l of saturated Na2SO4-solution was added to the reaction mixture and extracted with ether~ The solvent was evaporated in vacuo and the residue crystallized from ethyl acetate-petroleum ether.
Yield 7.9 g (19 %), m.p. 111-114C.

Example 42 3-(3,4-Dimesyloxy-S-nitrophenyl)-l-phenylprop-2-en-1-one A solution containing 2.0 g of product described in Example 2 and 5 ml of mesyl chloride in 20 ml of N-methylpyrrolidone was heated for 1.5 h at 100C. After cooling water was added and the solution was extracted with ether. The solvent was evaporated in vacuo and the residue was crystallized from l-propanol. Yield 0.14 g, m.p. 181-184C.

Example 43 N-~ ntyl)-3,4-diacetoxy-5-nitrobenzamide A solution containing 0.85 g of 3,4-diacetoxy-5-nitrobenzoic acid and 0.32 ml of thionyl chloride and a catalytic amount of N,N-dimethylformamide ;n 10 ml of toluene was heated for 1 h at 80C. The solvent was evaporated in vacuo and the residue was dissolved in 5 ml of dichloromethane and added to a mixture containing 0.56 g of 1-aminoadamantane hydro-chlor;de and 0.94 ml of triethylamine in 10 ml of dichloro-methane and stirred for 15 min at 0C and then 15 min at 20C. Water was added to the reaction mixture and dichloro-methane phase was separated. The solvent was evaporated in vacuo yielding yellow viscous oil 1.2 g (100 ~.

Example 44 N-(1-A~ ntyl)-3 t 4-dihydroxy-5-nitrobenzamide ` ~ 32 ` "-- 1 334967 A ~olution containing 1.2 g of the product obtained in Example 43 and a catalytic amount of sulfuric acid in 10 ml of methanol was refluxed for 3 h. 20 ml of water was added and on cooling 0.8S g (89.5 %) of the desired product was crystallized, m.p. 207-208C.

Example 45 4-Cyclohexylcarbonyl-1-(3,4-diacetoxy-S-nitrobenzoyl)-piperidine The procedure described in Example 43 was repeated using 0.58 g of cyclohexylcarbonylpiperidine and 0.38 ml 2,6-lutidine instead of 1-amino~ ntane hydrochloride and triethylamine respectively. Yield 1.2 g (87 %), a viscous yellow oil.

Example 46 4-Cyclohexylcarbonyl-1-(3,4-dihydroxy-5-nitrobenzoyl)-piperidine The procedure described in Example 44 was repeated using 1.2 g of the product obtained in Example 45. Yield 0.5 ~ (S0 %), m.p. 155-165C.

Example 47 N-Benzyl-3,4-diacetoxy-5-nitrobenzamide 0.75 g of 3,4-diacetoxy-5-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43.
It was dissolved in 5 ml of dichloromethane and added to a solution containig 0.27 ml of benzylamine and 0.5 ml of 2,6-lutidine in 7 ml of dichloromethane. Yield 0.95 g (96 %), a viscous oil.

Example 48 N-Benzyl-3,4-dihydroxy-S-nitrobenzamide ~ 33 1 3~967 . ~ .

The procedure described in Example 44 was repeated using 0.95 g of the product obtained in Example 47. Yield 0.5 g (68 ~), m.p. 185-189C.

Example 49 N-~l-Adamantyl)-3,4-cyclohexylidenedioxy-6-nitrobenzamide 2 g of 3,4-cyclohexylidenedioxy-6-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was added to a solution containing 1.1 g of 1-aminoadamantane and 1.1 ml of triethylamine in lS ml of dichloromethane. Yield 2.9 g (98 %), a viscous oil.

Example 50 N-(l-Adamantyl)-3,4-dihydroxy-6-nitrobenzamide A solution containing O.S g of the product obtained in Example 49 and 0.09 ml of methanesulfonic acid in 8 ml of 98 % formic acid was heated for 15 min at 60C. The solvent was evaporated in vacuo and water was added to the residue. Yield 0.35 g (88 %), m.p. 250-255c.

Example 51 N-(4-Morpholinoethyl)-3,4-cyclohexylidenedioxy-6-nitrobenzamide 2.0 g of 3,4-cyclohexylidenedioxy-6-nitrobenzoic acid was converted into the corresponding acid chloride like described in Example 43. It was added to a solution containing 0.9 ml of 4-(2-aminoethyl)morpholine and 1.1 ml of triethylamine in 15 ml of dichloromethane. Yield 2.5 g (89 %), a viscous oil.

Example 52 N-(4-Morpholine ethyl)-3,4-dihydroxy-6-nitrobenzamide hydromesylate The procedure described in Example S0 was repeated using 1.95 g of the product obtained in Example 51. Yield 0.8 g (40 %~, a viscous oil. The H-NMR-spectrum was in accordance with the alleged structure.

Example 53 N-tl-Adamantyl)-3,4-diacetoxy-5-chlorobenzamide 0.7 g of 3,4-diacetoxy-5-chlorobenzoic acid was converted to the corresponding acid chloride and the procedure described in Example 43 was repeated. Yield 1.0 g (95 %), a viscous oil .

Example 54 N-(1-Adamantyl)-3,4-dihydroxy-~-chlorobenzamide The product of Example 53 was deacetylated like described in Example 44. Yield 0.6 g (78 %), m.p. 244-247C.

Example 55 N~ ntyl)-3,4-cyclohexylidenedioxy-6-chlorobenzamide 0.8 g of 3,4-cyclohexylidenedioxy-6-chlorobenzoic acid was converted to the corresponding acid chloride and the procedure described in Example 43 was repeated. Yield 1.0 g (83 %~, viscous oil.

Example 56 N-(l-Adamantyl)-3,4-dihydroxy-6-chlorobenzam;de 1.0 g of the product obtained in Example 55 was treated with methanesulfonic acid in formic acid as described in Example 50. Yield 0.65 g (81 %), m.p. 225-230C.

-~ 35 l 334967 ~ .

Example 57 N~ Adamantyl)-3,4-diacetoxy-5-cyanobenzamide 0.6 g of 3,4-diacetoxy-5-cyanobenzoic acid was converted to the corresponding acid chloride and the procedure described in Example 43 was repeated. Yield 0 75 g (88 %), viscous oil.

Example 58 N~ A~ ~ntyl)-3,4-dihydroxy-5-cyanobenzamide 0.75 g of the a~ove product was deacetylated as described in Example 44. Yield 0.5 g (89 ~), m.p. 253-255C.

Example 59 l-Butyl 3,4-dihydroxy-5-cyanobenzoate A ~olution containing 0.5 g of 3,4-dihydroxy-5-cyanobenzoic acid in 10 ml of l-butanol was saturated with gaseous hydrogen chloride at 0C. The solution was then heated for 3 h at 100C. The ~oLvent was evaporated in vacuo and dichloromethane was added to the residue. The formed crystals were filtered. Yield 0.19 g (30 %), m.p. 135-140C.

Example 60 ~-t2-Methylpiperidyl~-3,4-dimethoxy-6-cyanopropionanilide A mixture containing 2.68 g of ~-chloro-3,4-dimethoxy-6-cyanopropionanilide, 1.5 g of 2-methylpiperidine, 1.4 g of CaO and a catalytic amount of potassium iodide in 15 ml of toluene was heated for 18 h at 100C The solution was filtered, washed with water and evaporated in vacuo The residue was treated with petroleum ether and filtered. Yield 2.79 g (84 %~, m p 126-127C.

Example 61 ~ Adamantylamino)-3,4-dimethoxy-6-cyanopropionanilide A mixture containing 3.0 g of ~-chloro-3,4-dimethoxy-6-cyanopropionanilide, 2.3 g of 1-aminoadamantane hydrochlo-ride, 4.6 g of potassium carbonate and a catalytic amount of potassium iodide in 15 ml of toluene was heated while stirring for 6 h at 100C. The solution was filtered and the solvent evaporated in vacuo. Water was added to the residue and the product was filtered. Yield 3.4 g (74 %), m.p.
137-140C.

Example 62 1-(3,4-Cyclohexylidenedioxy-6-nitrobenzoyl)-4-cyclohexyl-carbonylpiperidine 0.5 g of 3,4-cyclohexylidenedioxy-6-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was added to a solution containing 0.35 g of 4-cyclohexylcarbonylpiperidine and 0.2 g of triethylamine in 30 ml of d~chloromethane. Yield 0.7 g (85 %), m.p. 2~0C.

Example 63 1-(3,~-Dihydroxy-6-nitrobenzyl)-4-cyclohexylcarbonyl piperidine 0.48 g of the above product was treated with methanesulfonic acid in formic acid as described in Example 50. Yield 0.3 g ~75 %), m.p. 240C.
.

Example 64 1-(3,4-Cyclohexylidenedioxy-6-nitrobenzoyl3-4-(1-piperidyl)-piperidine The procedure described in Example 62 was repeated using 0.3 `t~ 37 ` ~ 1 334967 f of 4-(1-piperidyl)piperidine instead of 4-cyclohexyl-carbonylpiperidine. Yield 0.57 g (74 %), m.p. 200C.

Example 65 Cyclohexyl-4- 1-(3,4-cyclohexylidenedioxy-6-nitro-benzoyl)piperidyl carbinol To a solution containing 0.5 g of the product obtained in Example 62 and 1.1 ml of lN NaOH in 20 ml of methanol 0.1 g of sodium borohydride was added at room temperature. The solution was acidified with acetic acid and extracted with dichloromethane. The solvent was removed in reduced pre~sure and the residue treated with petroleum ether. Yield 0.45 g (90 %), m.p. 155C.

Example 66 1-(3,4-Dihydroxy-6-nitrobenzoyl)-4-(1-piperidyl)piperidine hydromesylate 0.3 g of the product obtained in Example 64 was treated with methanesulfonic acid in formic acid as described in Example 50. Yield 0.26 g (84 %), m.p. 290C.

Example 67 1-(3,4-Diacetoxy-6-nitrobenzoyl)-4-cyclohexylcarbonyl-piperidine 0.5 g of the product obtained in Example 63 was heated in 10 ml of acetic anhydride for 1 h at 40C. Ice-water was added and the product was filtered. Yield 0.5 g (87 %), m.p.
160-165C.

Example 68 N-Methyl-N-propargyl-3,4-cyclohexylidenedioxy-6-nitrobenzamide ' 38 ~ 33~9~7 0.5 g of 3,4-cyclohexylidenedioxy-6-nitrobenzoic acid was converted to the corresponding acid chloride and added to a solution containing 0.12 g methylpropargylamine and 0.18 g of triethylamine in 20 ml of dichloromethane. Yield 0.3 g (S0 %), m.p. 50-55C.

Example 69 1-(3,4-Dimethoxy-6-nitrobenzoyl)-4-cyclohexylcarbonyl piperidine 10.3 g of 3,4-dimethoxy-6-nitrobenzoic acid was converted to the corresponding ac~d chloride as described in Example 43.
It was added to a solution containing 8.83 g of 4-cyclohexylcarbonylpiperidine and 4.58 g of triethylamine i~
300 ml of dichloromethane. Yield 16.4 g (90 %), m.p.
120-125C.

Example 70 1-(3,4-Dihydroxy-6-nitrobenzoyl)-4-cyclohexylcarbonyl-piperidine A solution containing 0.81 g of the above compound in 12 ml of 1 molar BBr3-CH2Cl2 was stirred over night at 20C. Water was added and the product was filtered. Yield 0.5 g ~67 %), m.p. 240C.

Example 71 Cyclohexyl-4- 1-(3,4-dimethoxy-6-nitrobenzoyl)piperidyl carbinol 2.03 g of the product obtained in Example 69 was reduced with sodium borohydride as described in Excample 65. Yield 1.89 g (93 %)~ m.p. 145-150C.

~ ; 39 ~ 1 3 3 4 9 67 Example 72 3-(3-Ethoxycarbonylmethylcarbamoyloxy-4-hydroxy-5-nitro-phenyl)-l-phenylprop-2-en-1-one 1.5 g of ethyl isocyanatoacetate was added to a solution containing 0.54 g of the product obtained in Example 8 in 10 ml of tetrahydrofuran and the solution was stirred for 3 days at 20C. The solvent was evaporated in reduced pressure and the raw product was purified in a silica gel column using toluene-dioxane-acetic acid (8:1:1) as an eluent.
Crystallization from acetone-petroleum ether yielded 0.13 g (17 %) of the desired product desired, m.p 155-158C.

Example 73 3-(3,4-Methylenedioxy-6-nitrophenyl)-1-phenylprop-2-en-1-one The procedure described in Example 8 was repeated by using l.9S g of 6-nitropiperonal and 2.10 g of 3',4',5'-tr~methoxy-acetophenone in 30 ml of methanol. Yield 0.88 ~24 %), m.p.
157-159C.

Example 74 3-(4-Hydroxy-3-methoxy-5-nitrophenyl)-1-(3,4,5-trimethoxy-phenyl)prop-2-en-1-one The procedure described in Example 8 was repeated by using 2.0 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde and 2.1 g of 3',4',5'-trimethoxyacetophenone. Yield 2.2 g (57 %~, m.p.
123-125C.

Example 75 3-t3,4-Dihydroxy-S-nitrophenyl)-1-~2-carboxyphenyl)prOp-2-en-1-one The procedure described in Example 8 was repeated using 1.83 ~ 40 ` ~ ~ 1 334967 -g of 3,4-dihydroxy-S-nitrobenzaldehyde and 1.64 g of 2'-carboxyacetophenone. Yield 0.36 g (11 %), m.p. 178-180C.

Example 76 3-(3,4-Dihydroxy-5-nitrophenyl3-1-t4-nitrophenyl)-prop-2-en-1-one The procedure described in Example 8 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.65 g of 4'-nitroacetophenone. Yield 1.25 g (38 %), m.p. 255-256C.

Example 77 3-(3-methoxy-4-hydroxy-5-trifluoromethylphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one The procedure described in Example 8 was repeated using 2.2 g of 3-methoxy-4-hydroxy-5-trifluoromethylbenzaldehyde and 2.1 g of 3',4',5'-trimethoxyacetophenone. Yield 2.6 g (61 %), m.p. 190-192C.

Example 78 4-(3,4-Dimethoxy-5-methylsulfonylphenyl)-3-methyl-but-3-en-2-one The procedure described in Example 8 was repeated using 2.44 g of 3,4-dimethoxy-5-methylsulfonylbenzaldehyde and 1.0 g of 2-butanone. Yield 2.0 q (63 ~), viscous oil.

Example 79 2, 5-Bi s- t3~4-dihydroxy-5-nitrobenzylidene)cyclopentanone~

The procedure described in Example 8 was repeated using 5.0 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.0 g of cyclopentanone. Yield 4.4 g (78 %), m.p. 300C (decomp.).

` 41 Example 80 1-Phenyl-3-(3-stearoyloxy-4-hydroxy-5-nitrophenyl3-prop-2-en-1-one A solution containing 2.0 g of the product obtained in Example 8 and 10.0 g of stearoyl chloride in 10 ml of dioxane was stirred and heated for 18 h at 90C. After cooling petroleum ether was added and the product was filtered.
Recrystallization from dichloromethane-petroleum ether yielded 0.64 g (17 %) of the desired product desired, m.p.
112-118C.

Example 81 Ethyl 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylate The procedure desc~ibed in Example 4 was repeated u~ing 1.0 g of 3,4-dihydroxy-S-nitrobenzaldehyde, 0.9 g of ethyl cyanoacetate and 0.15 g of ammonium acetate in 10 ml of ethanol. Yield 0.8~ g (57 ~), m.p. 205-210C.

Example 82 Methyl 3-(3,4-dihydroxy-5-nitrobenzylidine)-4-ketopentanoate A solution containing 1.83 g of 3,4-dihydroxy-5-nitro-benzaldehyde and 1.1 g of levulinic acid in 10 ml of methanol was saturated with gaseous hydrogen chloride. The mixture was refluxed for 20 h after which water was added and the solution was extracted with ether. The solvent was evaporated in reduced pressure and the residue crystallized from ether-petroleum ether. Yield 0.54 g (20 %), m.p. 142-150C.

Example 83 3,4-Dihydroxy-S-nitrobenzylmalonitrile l.S g of sodium borohydride was added to a suspension ` ~ 42 ~ 1 334967 -containing 3.7 g of the product obtained in Example 5 in 10 ml of water at room temperature. The solution was stirred for 2 h more, acidified with hydrochloric acid and extracted with ether. The solvent was evaporated in vacuo and the residue crystallized from methanol-isopropanol. Yield 1.1 g (30 ~), m.p. 211-215C.

~xample 84 Ethyl 3,4-dihydroxy-5-nitrobenzylcyanoacetate The procedure described in Excample 83 was repeated using 2.78 g of the product obtained in Example 81. Yield 0.98 g (35 %), yellow viscous oil.

Example 85 l-Phenyl-3-(3-methoxy-4-hydroxy-5-trifluoromethylphenyl) prop-2-en-1-one The procedure described in Example 8 was repeated using 1.7 g of 3-methoxy-4-hydroxy-5-trifluoromethylbenzaldehyde and 1.0 g of acetophenone. Yield 1.1 g (45 %), m.p. 166-168C.

Exa~ple 86 l-Phenyl-3-(3,4-dihydroxy-~-trifluoromethylphenyl3-prop-2-en-1-one To a solution containing 0.32 g of the above product obtained in Example 8~ in 10 ml of dichloromethane 3 ml of 1 molar BBr3-CH2C12 was added. The mixture was stirred for 20 min at room temperature, acidified with 10 ml 2 N hydrochloric acid and extracted with dichloromethane. The solvent was evaporated in reduced pressure and the residue crystallized from acetone-dichloromethane. Yield 0.07 g (23 %), m.p.
1 96-201C.

~ ; 43 9 ~ ~

Example 87 3,4-Dihydroxy-5-sulfonamidobenzaldehyde A solution containing 1.89 g of 2,3-dihydroxybenzene-sulfonamide and 1.4 g of hexamethylenetetramine in 20 ml of trifluoroacetic acid was refluxed for 2 h. The solvent was evaporated in vacuo, water was added to the residue and the product was filteted. Yield 0.78 g (35 ~).

Example 88 2-Methoxy-6-trifluoromethylphenol A solution containing 160 ml of 1.6 molar butyllithium in hexane, 300 ml of tetrahydrofuran and 40 ml of N,N,N',N'-tetramethylethylenediamine was cooled to -78C and 43.3 g of 3-tri~luoromethylanisole was added with stirring under nitrogen atmosphere. The solution was allowed to warm up to room temperature and cooled then again to -78C after which 35 ml of trimethyl borate was added. The solution was warmed up to 20C and SO ml of conc. ammonia solution was added. The solvents were evaporatéd in reduced pressure and to the residue 60 ml of 98-100 % formic acid followed with 2S ml of 35 % hydrogen peroxide were added. The solution was extracted with ether-petroleum ether (1 : 1). The organic pha~e was separated and the product was extracted with 2.5 N
NaOH-solution. The aqueous phase was acidified with hydrochloric acid and the product was extracted in dichloromethane. The solvent was removed for the most part in vacuo after which petroleum ether was added. The crystalline product was filtered, yield 8.5 g (18 %), m.p. 51-53C.

Example 89 4-Hydroxy-3-methoxy-5-trifluoromethylbenzaldehyde A solution containing 1.9 g of 2-methoxy-6-trifluoromethyl-phenol and 1.4 g of hexamethylenetetramine in 20 ml of ~ 44 trifluoroacetic acid was refluxed for 1 h. The solvent was removed in reduced pressure, 50 ml of 1 N hydrochloric acid was added to the residue and the solution was extracted with dichloromethane. Most part of the solvent was evaporated in vacuo and petroleum ether was added, whereupon the product crystallized. Yield 0.7 g (32 %), m.p. 151-152C.

Example 90 3,4-Dimethoxy-5-cyanobenzaldehyde A mixture containing 2.5 g of 3,4-dimethoxy-5-bromobenz-aldehyde and 1.0 g of cuprous cyanide in N-methylpyrrolidone was refluxed for 2 h. Water was added and the solut~on was extracted with dichloromethane. The solvent was evaporated in vacuo. Yield 1.55 g (81 %), m.p. 109-112~C.

Example 91 3,4-Dihydroxy-S-cyanobenzaldehyde A solution containing 0.96 g of the above product in 15 ml of 1 molar ssr3-cH2cl2-solutiOn was stirred for 4 h at room temperature under nitrogen. 15 ml of 1 N hydrochl~ric acid was added and the dichloromethane phase was separated. The solvent was evaporated in vacuo. Yield 0.61 g (75 %), m.p.
210-215C.

Example 92 1,2-Dimethoxy-3-methylsulfonylbenzene ~o a solution containing 3.68 g of 2,3-dimethoxythioanisole in 50 ml of dichloromethane 3.6 g of 3-chloroperoxybenzoic acid was added with stirring. Stirring was continued for 18 h more at room temperature. 30 ml of 1 N NaOH-solution was added, dichloromethane phase was separated and the solvent evaporated in vacuo. Yield 4.51 g ~91 ~, a viscous oil.

4~
`-- 1 33 4967 Example 93 3,4-Dimethoxy-5-methylsulfonylbenzaldehyde The procedure described in Example 80 was repeated using 2.16 g of 2,3-dimethoxy-3-methylsulfonylbenzene and 1.4 g of hexamethylenetetramine. Yield 0.97 g (45 %), a viscous oil.

Example 94 3,4-Dihydroxy-5-methylsulfonylbenzaldehyde A solution containing O.S g of the above product and S ~1 of 48 % hydrobromic acid in 5 ml of acetic acid was refluxed for 8 h. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated ~n vacuo. Yield 0.3 g (68 ~), a viscous oil.

Example 9S

3,4-Dihydroxy-5-cyanobenzaldehyde A solution containing 1.35 g of 2,3-dihydroxybenzonitrile and 1.4 g of hexamethylene tetramine in 20 ml of trifluoroacetic acid was refluxed for l.S h. Water was added and the product was filtered. Yield 0.9 g (SS %), m.p. 211-215C.

Example 96 3-(3,4-Dihydroxy-5-trifluoromethylphenyl)-1-phenylprop-2-en-1-one The procedure described in Example 8 was repeated using 2.06 g of 3,4-dihydroxy-S-trifluoromethylbenzaldehyde and 1.20 g of acetophenone. Yield 2.19 g ~71 %), m.p. 196-210~C.

't~ 46 ~ ~ 1 33 4 9 6 7 Example 97 3,4-Dihydroxy-5-trifluoromethylbenzaldehyde A solution containing 2.2 g of 4-hydroxy-3-methoxy-5-trifluoromethylbenzaldehyde in 65 mi of 1 molar ~sr3 in dichloromethane was stirred for 2 h at room temperature.
Hydrochloric acid was added and the organic phase was separated. The solvent was evaporated in vacuo. Yield 1.4 g (68 %), m.p. 188-192C.

Example 98 2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl3acrylamide A solution containing 1.3 g of 3,4-dihydroxy-5-nitro-benzaldehyde, 0.73 g of cyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. The solvent was evaporated in vacuo and the residue was recrystallized water-DMF. Yield 0.8~ g (48 %), m.p. 296-298C.

Example 99 N,N-Dimethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenz-aldehyde, 1.2 g of N,N-dimethylcyanoacetamide and catalytic amount of piperidine acetate in 40 ml of dry ethanol was refluxed over night. Yield 1.1 g ~40 %), m.p. 183-185C.

Example 100 N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acryla-mide The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of N,N-~ 47 diethylcyanoacetamide. Yield 2.23 g (73 %~, m~p. 153-156C.

Example 101 N-Isopropyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.3 g of N-isopropylcyanoacetamide. Yield 1.46 g (50 %~, m.p.
243-245C.

Example 102 N'-Methyl-N''-/2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acryl/
piperazine The procedure described in Example 99 was repeated using 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.7 g of N'-methyl-Nn-cyanoacetylpiperazine. Yield 2.16 g (65 ~), m.p.
265~C (decomp.).

Example 103 3-(3,4-Dihydroxy-5-trifluoromethylbenzylidene)-2,4-penta-nedione The procedure described in Example 7 was repeated using 2.06 g of 3,4-dihydroxy-5-trifluoromethyl-benzaldehyde and 1.00 g of 2,4-pentanedione. Yield 1.39 g (45 %), m.p.
198-205C.

Example 104 3,4-Dihydroxy-5-nitrobenzylalcohol To a solution containing-6.0 g of sodium borohydride in S0 ml of water 9.15 g of 3,4-dihydroxy-S-nitrobenzaldehyde was gradually added with stirring at room temperature. The mixture was stirred for 1 h more after which it was acidified ` ' 48 ` 1334967 with hydrochloric acid. The solution was filtered to remove tarry impurities and extracted 4 times with ether. The ether extract was dried over anhydrous sodium sulfate, filtered and concentrated to a volyme of about 100 ml.

The crystalline solid was filtered. Yield 6.0 g (65 %), m.p.
lQ0C ~decomp.).

Example 105 3,4-Dihydroxy-5-nitrobenzyl-2-methoxyethylether A solution of 1.0 g of 3,4-dihydroxy-5-nitrobenzylalcohol in 5.0 ml of 2-methoxyethanol was refluxed for 1 h. The solvent was evaporated in vacuo and the residue was triturated with isopropanol. Yield 0.4 g (30 ~), m.p. 154-157C.

Example 106 3,4-Dihydroxy-S-nitrobenzylthioacetic acid A solution containing 1.0 g of 3,4-dihydroxy-5-nitro~enzyl-alcohol in 5.0 g of thioglycolic acid was stirred for 1.5 h at 120C. 25 ml of water was added and product was filtered and washed w~th water. Yield 0.25 g (19 %), m.p. 91-93C.

Example 107 2-(3,4-Dihydroxy-5-nitrobenzyl)pyrrole A solution containing 1.0 g of 3,4-dihydroxy-5-nitrobenzyl-alcohol and 5.0 ml of pyrrole in 3.0 ml of dioxane was heated for 5 h at 100C. Water was added and the solution was extracted with dichloromethane. The solvent was evaporated and the residue was puri~ied in a silicagel column using toluene-acetic acid-dioxane (18:1:1) mixture as an eluent.
Yield 0.42 g (33 %), m.p. 115-118C.

~ ~ ~ 49 `~ 1 33 49 67 Example 108 2-Cyano-3-(3,4-dihydroxy-S-nitrophenyl)propanol To a solution containing 0.85 g of ethyl 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylate (Example 81) in 70 ml of dry ethanol 0.3 g of sodium borohydride was gradually added. The solution was stirred for O.S h at room temperature, acidified with hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated yielding 0.55 g (75 %) of yellow crystals, m.p. 149-152C.

Example 109 3-Nitrocatechol To a solution containing 2.5 g of catechol in 125 ml of ether 1.0 ml of conc. nitric acid (d~1.52) was gradually added. The solution was stirred over night at room temperature and washed with water. The solvent was evaporated and the re~idue was treated with boiling petroleum ether (b.p. 60-80C). The insoluble 4-nitrocatechol was filtered and the filtrate concentrated in vacuo. After cool~ng the 3-nitrocatechol wa~
filtered. Yield 0.85 g (24 %), m.p. 82-8SC.

Example 110 3,5-Dinitrocatechol To a solution containing 50.0 g of catechol diacetate in 2S0 ml of acetic acid 125 ml of nitric acid (d~1.42) was gradually added at 50C. The solution was stirred for 1.5 h more at 50C and poured then to crushed ice. The product was filtered, washed with water and dissolved in 500 ml o methanol containing 1.0 ml of conc. sulfuric acid. The solution was refluxed for 2.5 h. Methanol was distilled off to a ~reat extend and 100 ml of water was added. The remaining methanol was evaporated in vacuo whereupon the product was crystallized. Yield 20.9 g (40.4 %), m.p.
168-170C.
-` ~` so Example 111 3,4-Dihydroxy-5-nitro~enzaldehyde A solution containing 8.0 kg of 5-nitrovanillin and 8.7 kg of acetic acid in 35 kg of conc. hydrobromic acid was refluxed for 20 h. 0.6 kg of charcoal was added and the mixture was filtered. 32 kg of water was added with stirring and the solution was cOOled to -10C and stirring was continued for 2 h more. The crystalline product was iltered and washed with water. Yield 5.66 kg (80 %), m.p. 135-137C.

Example 112 3,4-Dihydroxy-5-nitrobenzonitrile A solution containing 0.92 g of 3,4-dihydroxy-5-nitrobenz-aldehyde and 0.49 g of hydroxylamine hydrochloride in 5.0 ml of formic acid was refluxed for 1 h. 50 ml of water was added and the product was filtered and washed with water. Yield 0.3 g (33 %), m.p; 175-178C.

Example 113 4-Chloro-6-nitrocatechol A mixture containing 1.0 g of 4-chloro-3-methoxy-6-nitrophenol in 20 ml of conc. hydrobromic acid was refluxed for 2 h. After cooling the product was filtered and washed with water. Yield 0.6 g (65 ~), m.p. 108-lllaC.

Example 114 4,5-Dihydroxyisophtalaldehyde To a suspension containing 1.8 g of 4-hydroxy-5-methoxy-isophtalaldehyde in 20 ml of dichloromethane was added 35 ml of 1 molar Psr3 in dichloromethane. The mixture was allowed to stand over night at room temperature and poured the to ice-water. Dichloromethane was evaporated in vacuo. After cooling the product was filtered and washed with water. Yield 0.94 g (57 %), m.p. 192-195~C.

Example 115 3,4-Dihydroxy-5-cyanobenzoic acid To a solution containing 2.3 g of 4-acetoxy-3-cyano-5-methoxybenzoic acid in 10 ml of dichloromethane 40 ml of 1 molar PBr3 in dichloromethane was added. The mixture was stirred over night at room temperature. The solvent was evaporated in vacuo and to the residue ice-water was added.
The product was filtered and washed with water. Yield 1.25 g (74 %), m.p. 269-271~C.

Example 116 3,4-Dihydroxy-5-nitrophenylalanine hydrobromide A solution containing 1.2 g of 4-hydroxy-3-methoxy-~-nitrophenylalanine hydrosulfate in 10 ml of conc. hydrobromic acid was refluxed for 2 h. The solution was concentrated in vacuo and allowed to stand over night in a refrigerator. The product was filtered and washed with hydrobromic acid and dried. Yield 0.25 g, m.p. 170C (decomp.).

~xample 117 3,5-Dicyanocatechol A solut;on containing 0.83 g of 3,5-diformylcatechol and 0.90 g of hydroxylamine hydrochloride in 30 ml of formic acid was refluxed for 16 hours. Formic acid was evaporated in vacuo and water was added to the residue. The solution was extracted with ether. The solvent was evaporated and the residue was crystallized from ethanol-water. Yield 0.28 g (43 %), m.p. 300~C (decomp.~. ' ` ~ ~ 334967 Example 118 N,N-diethyl-5-chloro-2,3-dihydroxybenzenesulfonamide To a solution containing 0.7 g of N,N-diethyl-S-chloro-3,4-dimethoxybenzenesulfonamide in 10 ml of dichloromethane 9.0 ml of 1 molar BBr3 in dichloromethane was added. The solution was stirred overniqht at room temperature. Water and hydrochloric acid were added and the mixture was extracted with dichloromethane. The solvent was evaporated. Yield 0.3 g (47 ~), m.p. 62-64C.

Example 119 4-Chloro-6-methylsulfonylcatechol The procedure described in Example 118 was repeated u~ing 4-chloro-2-methoxy-6-methylsulfonylphenol. Yield 50 %, m.p.
142-145C.

Example 120 4-Nitro-6-methylsulfonylcatechol The procedure described in Example 118 was repeated u~ing 2-methoxy-4-nitro-6-methylsulfonylphenol. Yield 21 %, m.p.
221-224C.

Example 121 3,~-Dihydroxy-5-methylsulfonylbenzaldehyde The procedure described in Example 118 was repeated using 4-hydroxy-3-methoxy-5-methylsulfonylbenzaldehyde. Yield 17 %, m.p. 169-171C.

Example 122 N-(3-hydroxypropyl~-3,4-dihydroxy-~-nitrobenzamide ~ ' 53 1 3~4967 The procedures described in Examples 43 and 44 were repeated using 3,4-diacetoxy-5-nitrobenzoic acid and 3-aminopropan-1-ol. Yield 85 %, m.p. 160-163C.

Example 123 Neopentyl 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl~acrylate The procedure described in Example 4 was repeated using 3,4-dihydroxy-5-nitrobenzaldehyde and neopentyl cyanoacetate.
Yield 67 %, m.p. 173-179C.

Example 124 N-(3-hydroxypropyl)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide , The procedure described in Example 99 was repeated using N-~3-hydroxypropyl)cyanoacetamide and 3,4-dihydroxy-5-nitro-benzaldehyde. Yield 52 %, m.p. 223-228C.

Example 125 2,3-Dihydroxy-S-nitrobenzonitrile The procedure described in Example 118 was repeated using 2-hydroxy-3-methoxy-5-nitrobenzonitrile. Yield 45 %.

Example 126 3,5-Dicyanocatechol To a solution containing 2,4-dicyano-6-methoxyphenol in 20 ml of dichloromethane 20 ml of 1 molar solution of BBr3 in dichloromethane was added. The solution was stirred overnight at room temperature. Water and hydrochloric acid were added and the mixture was extracted with dichloromethane. The solvent was evaporated. Yield 0.8 g (50 %), m.p. 300C
(decomp.~.

Example 127 1,2-Diacetoxy-3,5-dinitrobenzene A catalytic amount of concentrated sulfuric acid was added to a solution containing 2.0 g of 3,5-dinitrocatechol in 15 ml of acetanhydride and the solution was mixed for ~ hours in 50-60C. Ice water was added to the rection mixture and the solution was mixed in 0C whereby the product was crystallized. The product was filtered and washed with water and dried. Yield 2.75 g (97~), m.p. 115-117C.

Example 128 1,2-Dipropionyloxy-3,5-dinitrobenzene The procedure of Example 127 was repeated using propionic acid anhydride instead of acetanhydride. Yield 2,8 g (90%), m.p. 72-73C.

Example 129 1,2-D;butyryloxy-3,5-dinitrobenzene The procedure described in Example 127 was repeated using butyrylanhydride instead o acetanhydride. Yield 70%, m.p.
55-60.

Example 130 2-sutyryloxy-4,6-dinitrophenol 8.7 ml of nitric acid (d=1.42) was added stirring and cooling to a solution containing 2.4 g of catechol dibutyrate in 25 ml o acetic acid. The solution was stirred for further hours and ice water was added thereto. The product was iltered and washed with water. Yield 1.85 g (53%), m.p.
6S-7~C.

~ ` 55 1 334967 Example 131 2-Pivaloyloxy-4,6-dinitrophenol

6.7 ml of nitric acid (d=1.42) was added stirring and cooling (in 20-25C) to a solution containing 1.94 g of catechol monopivaloate in 20 ml of acetic acid. The solution was stirred for ~ hours in 50C. Ice water was added and the product was filtered and washed with water. Yield 1.75 g (62.5~3, m.p. 132-135~C.

Example 132 2-Benzoyloxy-4,6-dinitrophenol A mixture containing 2.0 g of 3,5-dinitrocatechol in 5 ml of benzoylchloride was cooked for 4 hou~s in 100C. When cooled petroleum ether (b.p. 40C) was added and the prod~ct was filtered and washed with petroleum ether. The raw product was crystallized from ethanol. Yield 2.5 g (82%), m.p. 150-152C.

Example 133 3-(4-Hydroxy-S-nitro-3-pivaloyloxybenzylidene)-2,4-pentane-dione A mixture containing 2.0 g of the product obtained according to Example 7 in S ml of pivaloylchloride was heated for 4 hours in 100C. The excess pivaloylchloride was evaporated away in reduced pressure and ether was added to the residue.
The product was filtered and washed with ether. Yield 1.41 g (58%), m.p. 143-145nC.

Example 134 2-(2,6-Dimethylbenzoyloxy)-4,6-dinitrophenol A mixture containing 2.0 g of 3,5-dinitrocatechol in S ml of ~ ~` 56 1334967 2,6-dimethylbenzoylchloride was heated foc 20 hours in 100C.
The excess 2,6-dimethylbenzoylchloride was removed in high vacuum The residue was purified in silikagel column Yield 1 5 g (45~), yellow viscous oil, which was crystallized from petroleum ether, m p 163-165C.

Example 135 2-(2,6-dimethoxybenzoyloxy)-4,6-dinitrophenol The procedure of Example 134 was repeated using 2,6-dimet-hoxybenzoylchloride. Yield ~.3 g ~36%), m.p. 217-218C.

Example 136 2~ Methylcyclohexylcarbonyloxy~-4,6-dinitrophenol The procedure of Example 134 was repeated using 1-methylcyclohexylcarboxylic acid chloride. Yield 1.6 g (49%~, yellow viscous oil.

Example 137 1,2-Bis(2,6-dimethylbenzoyloxy)-3,5-dinitrobenzene The procedu{e of Example 134 was repeated using a temperature of 134C. The product was crystallized from 50 ~ ethanol.
M.p. 175-178C. Yield 60~.

Example 138 .
1,2-Bis(3-ethoxycarbonylpropionyloxy)-3,5-dinitrobenzene A solution containing 1 g of 3,5-dinitrocathecol in 2,5 ml of et~yl ester chloride of succinic acid was heated for 3 h in lOO~C. The product was purified in silicagel colu~n. M.p.
60-63C.

Claims (47)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A method for the preparation of a pharmacologically active catechol derivative of formula (I'):

(I') or a salt thereof, wherein R1 and R2 independently represent hydrogen, C1-C4 alkyl carbonyl or phenyl carbonyl, C1-C2 alkylcarbamoyl; X represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents or wherein R4 represents cyano or C1-C4 alkyl carbonyl, and R5 represents cyano, C1-C4 alkoxycarbonyl, carboxy C1-C4 alkenyl, nitro, C1-C4 alkyl carbonyl, C1-C4 hydroxyalkyl, carboxy C1-C4 alkyl or one of the following groups: phenyl carbonyl or car-bamoyl which is unsubstituted or substituted with one or more C1-C4 alkyl or C1-C4 hydroxyalkyl;

wherein R8 represents hydrogen and R9 represents an adamantyl group;

said method comprising one of the following steps:
* condensing in the presence of an acid or a base catalyst a compound of formula (II):

(II) wherein R1 , R2 and X are as defined above, with a compound of formula (III):
having an active methyl or methylene group and wherein R4 and R5 are as defined above, to obtain a compound of formula (I'a):
(I'a) wherein the substituents are as defined above and wherefrom the double bond is or is not reduced to a single bond, said compound of formula (I'a) corresponding to the compound of formula (I') wherein R3 is a group:

or as defined above;

* reacting a compound of formula (X):

(X) wherein R1 and R2 are as defined above and Y comprises halogen or another activated group with an amine of formula (XI):

wherein R8 and R9 are as defined above to obtain a compound of formula (I'e):

(I'e) wherein R1, R2, X, R8 and R9 are as defined above, which corresponds to a compound of formula (I') wherein R3 is the substituted carbamido group of formula:

2. A pharmacologically active catechol derivative of the formula (I'):

(I') or a salt thereof, wherein R1 and R2 independently represent hydrogen, C1-C4 alkyl carbonyl or phenyl carbonyl, C1-C2 alkylcarbamoyl; X represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents or wherein R4 represents cyano or C1-C4 alkyl carbonyl, and R5 represents cyano, C1-C4 alkoxycarbonyl, carboxy C1-C4 alkenyl, nitro, C1-C4 alkyl carbonyl, C1-C4 hydroxyalkyl, carboxy C1-C4 alkyl or one of the following groups: phenyl carbonyl or car-bamoyl which is unsubstituted or substituted with one or more C1-C4 alkyl or C1-C4 hydroxyalkyl;

wherein R8 represents hydrogen and R9 represents an adamantyl group.
3. A method or the preparation of pharmacologically active catechol derivative of the formula (I'):

(I') wherein R1 and R2 independently represent hydrogen, C1-C4 alkyl carbonyl or phenyl carbonyl, C1-C2 alkylcarbamoyl; X
represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents or wherein R4 represents cyano or C1-C4 alkyl carbonyl, and R5 represents cyano, C1-C4 alkoxycarbonyl, carboxy C1-C4 alkenyl, nitro, C1-C4 alkyl carbonyl, C1-C4 hydroxyalkyl, carboxy C1-C4 alkyl or one of the following groups: phenyl carbonyl or car-bamoyl which is unsubstituted or substituted with one or more C1-C4 alkyl or C1-C4 hydroxyalkyl; comprising the step of condensing in the presence of an acid or a base catalyst, a compound of formula (II):

(II) wherein R1 , R2 and X are as deined above, with a compound of formula (III):

having an active methyl or methylene group and wherein R4 and R5 are as defined above, to obtain a compound of formula (I'a):
(I'a) wherein the substituents are as defined above and wherefrom the double bond is or is not reduced to a single bond.
4. A pharmacologically active catechol derivative of the formula (I'):

(I') wherein R1 and R2 independently represent C1-C4 alkyl carbonyl or phenyl carbonyl, C1-C2 alkylcarbamoyl; X represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents or wherein R4 represents cyano or C1-C4 alkyl carbonyl, and R5 represents cyano, C1-C4 alkoxycarbonyl, carboxy C1-C4 alkenyl, nitro, C1-C4 alkyl carbonyl, C1-C4 hydroxyalkyl, carboxy C1-C4 alkyl or one of the following groups: phenyl carbonyl or car-bamoyl which is unsubstituted or substituted with one or more C1-C4 alkyl or C1-C4 hydroxyalkyl.
5. A pharmacologically active catechol derivative according to claim 4, wherein R3 represents:

wherein R4 represents cyano or C1-C4 alkyl carbonyl, and R5 represents cyano, C1 - C4 alkyl carbonyl or carbamoyl which is unsubstituted or substituted with one or more C1 - C4 alkyl or C1 - C4 hydroxyalkyl.
6. A pharmacologically active catechol derivative according to claim 4, wherein R4 is cyano or R5 is carbamoyl unsubstituted or substituted with one or more C1 - C4 alkyl or C1 - C4 hydroxalkyl.
7. A method for the preparation of a pharmacologically active catechol derivative of the formula (I'):

(I') wherein R1 and R2 independently represent hydrogen, C1-C4 alkyl carbonyl or phenyl carbonyl, C1-C2 alkylcarbamoyl; X

represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents wherein R8 represents hydrogen and R9 represents an adamantyl group: comprising the steps of reacting a compound of formula X:
(X) wherein R1 and R2 are as defined above and Y comprises halogen or another activated group with an amine of formula (XI):

wherein R8 and R9 are as defined above to obtain a compound of formula (I'e):

(I'e) wherein R1 , R2 , X, R8 and R9 are as defined above.
8. A pharmacologically active catechol derivative of the formula (I'):

(I') wherein R1 and R2 independently represent hydrogen, C1-C4 alkyl carbonyl or phenyl carbonyl, C1-C2 alkylcarbamoyl; X
represents an electronegative substituent selected from the group consisting of halogen, nitro, cyano, aldehyde and trifluoromethyl; and R3 represents wherein R8 represents hydrogen and R9 represents an adamantyl group.
9. A method for the preparation of 3, 4- dihydroxy-5-nitro-.omega. ,.omega. -dicyanostyrene, comprising reacting 2,4-dihydroxy-5-nitro benzaldehyde with malonodinitrile in the presence of an acid or base catalyst.
10. 3, 4- dihydroxy-5-nitro-.omega. ,.omega. -dicyanostyrene.
11. A method for the preparation of N-methyl-N-propargyl-5-(3,4-dihydroxy-5-nitrophenyl)pentanoic acid amide, comprising reacting 5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid chloride with methyl propargylamine.
12. N-methyl-N-propargyl-5-(3,4-dihydroxy-5-nitrophenyl)pentanoic acid amide.
13. A method for the preparation of N-(1-adamantyl)-5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid amide, comprising reacting 5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid chloride with 1-aminoadamantane.
14. N-(1-Adamantyl)-5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid amide.
15. A method of preparation of N-isopropyl-5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid amide, comprising reacting 5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid chloride with isopropylamine.
16. N-Isopropyl-5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid amide.
17. A method of preparation of 5-(3,4-dihydroxy-5-nitrophenyl) pentanoic acid amide, comprising hydrolyzing 5-(4-hydroxy-3-methoxy-5-nitrophenyl) pentanoic acid with a strong acid in a solvent.
18. 5-(3,4-Dihydroxy-5-nitrophenyl) pentanoic acid amide.
19. A method of preparation of 2,5-bis(3,4-dihydroxy-5-nitrobenzylidene) cyclopentanone, comprising reacting 3,4-dihydroxy-5-nitrobenzaldehyde with cyclopentanone in the presence of an acid catalyst.
20. 2,5-Bis(3,4-dihydroxy-5-nitrobenzylidene) cyclopentanone.
21. A method of preparation of 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione comprising reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2,4-pentanedione.
22. 3-(3,4-dihydroxy-5-nitrobenzylidene)-2,4-pentanedione.
23. A method of preparation of N-(1-adamantyl)-3,4-dihydroxy-5-nitrobenzamide comprising reacting 3,4-diacetoxy-5-nitrobenzoic acid chloride with 1-aminoadamantane hydrochloride and hydrolyzing thus obtained N-(1-adamantyl)-3,4-diacetoxy-5-nitrobenzamide with a strong acid in a solvent.
24. N-(1-Adamantyl)-3,4-dihydroxy-5-nitrobenzamide.
25. A method of preparation of N-(1-adamantyl)-3,4-dihydroxy-5-cyanobenzamide comprising reacting 3,4-diacetoxy-5-cyanobenzoic acid chloride with 1-aminoadamantane hydrochloride and hydrolyzing thus obtained N-(1-adamantyl)-3,4-diacetoxy-5-cyanobenzamide with a strong acid in a solvent.
26. N-(1-Adamantyl)-3,4-dihydroxy-5-cyanobenzamide.
27. A method of preparation of ethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylate by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with ethylcyanoacetate.
28. Ethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylate.
29. A method of preparation of methyl 3-(3,4-dihydroxy-5-nitrobenzylidene)-4-ketopentanoate by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with levulinic acid.
30. Methyl 3-(3,4-dihydroxy-5-nitrobenzylidene)-4-ketopentanoate.
31. A method of preparation of 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with cyanoacetamide.
32. 2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide.
33. A method of preparation of N,N-dimethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with N,N-dimethylcyanoacetamide.
34. N,N-Dimethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide.
35. A method of preparation of N,N-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrobenzaldehyde with N,N-diethylcyanoacetamide.
36. N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide.
37. A method of preparation of N-isopropyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with N-isopropylcyanoacetamide.
38. N-Isopropyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide.
39. A method of preparation of N'-methyl-N''-[2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acryl]piperazine by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with N'-methyl-N''-cyanoacetylpiperazine.
40. N'-Methyl-N''-[2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acryl]piperazine.
41. A method of preparation of neopentyl 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylate by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with neopentyl cyanoacetate.
42. Neopentyl 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylate.
43. A method of preparation of N-(3-hydroxypropyl)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with N-(3-hydroxypropyl)-2-cyanoacetamide.
44. N-(3-Hydroxypropyl)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide.
A pharmaceutical composition comprising a pharmacologically acceptable carrier in admixture with at least one catechol derivative of formula (I') as claimed in claim 2, and a salt thereof.
46. A pharmaceutical composition comprising a pharmacologically acceptable carrier in admixture with at least one catechol derivative of formula (I') as claimed in claim 4, 5 or 6, and a salt thereof.
47. A pharmaceutical composition comprising a pharmacologically acceptable carrier in admixture with at least one catechol derivative of formula (I') as claimed in claim 8, 10 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 or 44.
CA 552987 1986-11-28 1987-11-27 Pharmacologically active compounds, methods for the preparation thereof and compositions containing the same Expired - Lifetime CA1334967C (en)

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