DE19604388A1 - New aryl-alkyl diazinone derivatives - Google Patents

Abstract

Arylalkyl diazinone derivatives of formula (I) and their salts are new. R<1>, R<2> = H or A; R<3>, R<4> = OH, OA, SA, SOA, SO2A, halo, methylendioxy, nitro, amino, NHA or NAA'; A, A' = 1-10C alkyl (optionally substituted by F or Cl), 3-7C cycloalkyl or 4-8C methylene cycloalkyl; B = YR<5> or OYR<5>; Q = absent or 1-4C alkenyl; Y = absent or 1-10C alkenyl; X = CH2 or S; R<5> = amino, NHA, NAA' or a 3-8 membered heterocycle containing at least one N atom (optionally monosubstituted by A or OH), and other CH2 groups may be replaced by NH, NA, S or O; and halo = F, Cl or Br.

Description

The invention relates to arylalkyl-diazinone derivatives of the formula I.

wherein
R¹ and R² are each independently H or A,
R³ and R⁴ each independently of one another -OH, OA, -SA, -SO-A, -SO₂-A, Hal, methylenedioxy, -NO₂, -NH₂, -NHA or -NAA ',
A and A 'each independently of the other alkyl with 1 to 10 C atoms, which can be substituted by 1 to 5 F and / or Cl atoms, cycloalkyl with 3-7 C atoms or methylene cycloalkyl with 4-8 C atoms ,
B -Y-R⁵ or -OY-R⁵,
Q is absent or alkylene with 1-4 C atoms,
Y is absent or alkylene with 1-10 C atoms,
X CH₂ or S,
R⁵ NH₂, NHA, NAA 'or an unsubstituted or simply substituted by A or OH substituted 3-8-membered heterocycle with at least one N atom, in which further CH₂ groups can be replaced by NH, NA, S or O,
Hal F, Cl, Br or I
mean,
and their physiologically acceptable salts.

Thiadiazinone derivatives are known for example from DE 41 34 893.

The invention was based on the problem of new connections Find valuable properties, especially those that are used Manufacture of drugs can be used.

It has been found that the compounds of formula I and their salts good tolerance very valuable pharmacological properties to sit.

In particular, they show phosphodiesterase IV inhibition and can be used to treat asthmatic diseases. The anti-asthmatic effect can e.g. B. by the method of T. Olsson, Acta allergologica 26 438-447 (1971).

The compounds also show an inhibitory effect on the Formation of TNF (tumor necrosis factor) and are therefore suitable for Treatment of allergic and inflammatory diseases, autoimmune diseases and graft rejection reactions. You can also go to Treatment of memory disorders can be used.

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used. They can also be used as Intermediates for the production of other active pharmaceutical ingredients be set.  

The invention accordingly relates to the compounds of Formula I and a process for the preparation of compounds of Formula I according to claim 1 and its salts, where B is -O-Y-R⁵, characterized in that a compound of formula II

wherein
R¹, R², R³, R⁴, Q and X have the meanings given,
with a compound of formula III

L-CO-B III

wherein
B -OY-R⁵,
L means Cl, Br, OH or a reactive esterified OH group and
R⁵ has the meaning given
implements
or
that one for the preparation of compounds of formula I according to claim 1 and their salts,
where B is -Y-R⁵,
a compound of formula IV

wherein
R¹, R², R³, R⁴, Q, X and Y have the meanings given, and
L means Cl, Br, OH or a reactive esterified OH group, with a compound of formula V.

H-R⁵ V

wherein
R⁵ has the meaning given
implements
or
that one for the preparation of compounds of formula I according to claim 1 and their salts,
a compound of formula VI

wherein
R¹, R², R³, R⁴ and X have the meanings given, with a compound of formula VII

wherein
Q and B have the meanings given, and
L denotes Cl, Br, OH or a reactive esterified OH group,
implements
and / or that a basic compound of formula I is converted into one of its salts by treatment with an acid.

Above and below have the radicals R¹, R², R³, R⁴, R⁵ B, L, Q, X and Y. the meanings given for the formulas I, II, III, IV and V, if not expressly stated otherwise.

A and A ′ are preferably each independently alkyl, more preferably substituted by 1 to 5 fluorine and / or chlorine atoms Alkyl.

In the above formulas, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and preferably means methyl, ethyl, trifluoromethyl, Pentafluoroethyl or propyl, further preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neo-pentyl or isopentyl.

Cycloalkyl preferably has 3-7 C atoms and preferably represents cyclo propyl and cyclobutyl, further preferred for cyclopentyl and cyclohexyl, also for cycloheptyl.  

Methylene cycloalkyl preferably has 4-8 C atoms and preferably represents Methylene cyclopropyl and methylene cyclobutyl, further preferred for Methylene cyclopentyl and methylene cyclohexyl, also for methylene cycloheptyl.

Alkylene is preferably unbranched and preferably means methylene or ethylene, further preferably propylene, butylene, pentylene, hexylene, Heptylene, octylene, also nonylene or decylene.

Of the radicals R¹ and R², one is preferably H, during the others preferably propyl or butyl, but particularly preferably ethyl or Methyl means. Furthermore, R 1 and R 2 together are also preferred each hydrogen.

Hal is preferably F, Cl or Br, but also I.

The radicals R³ and R⁴ can be the same or different and are in the 3- or 4-position of the phenyl ring. For example, they mean independently of one another hydroxy, -S-CH₃, -SO-CH₃, -SO₂CH₃, F, Cl, Br or I or together methylenedioxy. They are particularly preferred but each for methoxy, ethoxy, propoxy, cyclopentoxy, or for Fluorine, difluoro, trifluoromethoxy, 1-fluoro, 2-fluoro, 1,2-difluoro, 2,2-difluoro, 1,2,2-trifluoro or 2,2,2-trifluoroethoxy.

The radical R⁵ is preferably 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 4- or 5-imidazolidinyl, 1-, 2-, or 3-pyrazolidinyl, 2-, 3-, 4- or 5-oxazolidinyl, 1-, 2-, 3- or 4-isoxazolidinyl, 2-, 3-, 4- or 5-thiazolidinyl, 2-, 3-, 4- or 5-isothiazolidinyl, 1-, 2-, 3- or 4-piperidinyl, 1- or 2-piperazinyl, further preferably 1,2,3-tetrahydro-triazol-1-, -2- or -4-yl, 1,2,4-tetrahydro-triazol-1-, -2-, -3-, -4- or 5-yl, 1-, -2- or 5-tetrahydro- tetrazolyl, 1,2,3-tetrahydro-oxadiazol-2-, -3-, -4- or -5-yl, 1,2,4-tetrahydro-oxadiazol-2-, -3- or -4- or -5-yl, 1,3,4-tetrahydro- thiadiazol-2-, -3-, -4- or -5-yl, 1,2,4-tetrahydro-thiadiazol-2-, -3-, -4- or -5-yl, 1,2,3-thiadiazol-2-, -3-, -4- or -5-yl, 2-, 3- or 4-morpholinyl,  2-, 3- or 4-thiomorpholinyl, pyrrolidino, piperazino, methylpiperazino, Morpholino, Thiomorpholino or Piperidino or 4-Hydroxy-piperidino.

For the entire invention applies that all residues that occur multiple times kick, may be the same or different, d. H. independently of each other are.

Accordingly, the invention relates in particular to those gene compounds of formula I in which at least one of the above Radicals has one of the preferred meanings given above. Some preferred groups of compounds can follow through the sub-formulas Ia to Ig are expressed, that of the formula I ent speak and in which the unspecified radicals that in the formula I. have given meaning, but in what

in Ia
R1 H,
R² H or A,
R³ and R⁴ are each independently OA,
XS,
Q methylene or ethylene and
B Y-R⁵
mean;

in Ib
R1 H,
R² is methyl or ethyl,
R³ and R⁴ are each independently OA,
XS,
Q methylene or ethylene and
B Y-R⁵
mean;

in Ic
R1 H,
R² H or A,
R³ and R⁴ are each independently OA,
XS,
Q methylene or ethylene and
B -OY-R⁵
mean;

in Id
R1 H,
R² H or A,
R³ and R⁴ are each independently OA,
X CH₂,
Q methylene or ethylene and
B Y-R⁵
mean;

in Ie
R1 H,
R² H or A,
R³ and R⁴ are each independently OA,
X CH₂,
Q methylene or ethylene and
B -OY-R⁵
mean;

in If
R1 H,
R² H or A,
R³ OA,
R⁴ OCH₃,
X CH₂,
Q methylene or ethylene,
B -OY-R⁵ and
Y alkylene with 1-6 C atoms
mean;

in Ig
R1 H,
R² H or A,
R³ OA,
R⁴ OCH₃,
XS,
Q methylene or ethylene,
B -OY-round
Y alkylene with 1-6 C atoms

mean.

The compounds of formula I and also the starting materials for their Production are otherwise made according to methods known per se as described in the literature (e.g. in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart;), are described, under reaction conditions that are known and suitable for the implementations mentioned. It can one also of known variants not mentioned here in detail Make use.

In the compounds of formulas II and IV, R¹, R², R³ and R⁴ have the indicated meanings, in particular the specified preferred Meanings.

In the compounds of the formula II and IV, Q is preferably Methylene or ethylene, further preferably for propylene or butylene.

B has the indicated preferred in the compounds of formula III Meaning, while L in the compounds of the formula III and IV Cl, Br, OH or a reactive esterified OH group.

If L is a reactive esterified OH group, this is preferably alkylsulfonyloxy with 1-6 C atoms (preferably methyl sulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy, and also 2-naphthalenesulfonyloxy).

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

On the other hand, it is possible to carry out the reaction in stages.

The compounds of the formula I can preferably be obtained by compounds of formula II with compounds of formula III implements.  

Some of the starting materials of formulas II and III are known. Provided if they are not known, they can be made according to methods known per se getting produced.

Thiadiazinones of the formula II are z. B. known from DE 195 02 699. Pyridazinones of formula II are e.g. B. described in DE 195 14 568.

Precursors of the thiadiazinones of the formula II and their preparation are, for. B. described in German patent application P 41 34 893.

Precursors of the pyridazinones of the formula II are z. B. in Eur. J. Med. Chem. Chim. Therapist 9, 644-650 (1977).

In detail, the compounds of the formula II are reacted with the compounds of formula III in the presence or absence of a inert solvent at temperatures between about -20 and about 150 °, preferably between 20 and 100 °.

The addition of an acid-binding agent, for example an alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or one other weak acid salt of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of a organic base such as triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component may be beneficial.

Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or Dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol mono methyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles like Acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Nitro compounds  such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

Compounds of formula I can also be obtained by Reacts compounds of formula IV with compounds of formula VII. The starting compounds of the formula IV and VII are generally known. If they are not known, they can be known Methods are made.

Precursors of the compounds of formula IV are in particular from DE 195 02 699 and DE 195 14 568 are known.

The reaction of the compounds of formula IV with compounds of Formula VII is carried out under similar conditions regarding the reaction time, temperature and solvent, as this is for the implementation of the Compounds of formula II described with compounds of formula III is.

Compounds of formula I can also be obtained by Reacts compounds of formula VI with compounds of formula VII. The starting compounds of the formulas VI and VII are generally known. If they are not known, they can be known Methods are made.

Precursors of the compounds of formula VI are in particular from DE 195 02 699 and DE 195 14 568 are known.

The reaction of the compounds of formula VI with compounds of Formula VII is carried out under similar conditions regarding the reaction time, temperature and solvent, as this is for the implementation of the Compounds of formula II described with compounds of formula III is.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation In particular acids are considered, the physiologically harmless  Deliver salts. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorine hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyc misch mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malein acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.

On the other hand, if desired, the free bases of the formula I can be from their salts with bases (e.g. sodium or potassium hydroxide or -carbonate) are set free.

Compounds of formula I can have one or more centers of asymmetry contain. In this case, they are usually in racemic form. Racemates obtained can be mecha by methods known per se nisch or chemically separated into their enantiomers. Preferably are from the racemic mixture by reaction with a optically active release agent diastereomers formed.

Of course, it is also possible to use optically active compounds of the formula I. according to the methods described above, by choosing Aus used materials that are already optically active.

Formula I includes all stereoisomers and mixtures thereof, e.g. B. the racemate.

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts  Provision of pharmaceutical preparations, especially on non-chemical paths. Here you can use at least one fixed, liquid and / or semi-liquid carrier or auxiliary and given if in combination with one or more other active ingredients appropriate dosage form are brought.

The invention also relates to medicaments of the formula I and their physiologically acceptable salts as phosphodiesterase IV inhibitors.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or Veterinary medicine can be used. Organic come as carriers or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and with the new Compounds do not react, e.g. water, vegetable oils, Benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, Gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, Vaseline. Tablets, pills, Dragees, capsules, powders, granules, syrups, juices or drops, for rectal application suppositories, for parenteral application solutions gene, preferably oily or aqueous solutions, further suspensions, Emulsions or implants, for topical use, ointments, creams or powder. The new compounds can also be lyophilized and the obtained lyophilisates z. B. for the production of injectables be used. The specified preparations can be sterilized be and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmo table pressure, buffer substances, color, taste and / or contain several other active ingredients, e.g. B. one or more vitamins.

The compounds of formula I and their physiologically acceptable Salts can help fight diseases where one Increase in the level of cAMP (cyclo-adenosine monophosphate)  Inhibiting or preventing inflammation and muscle relaxation, be used. Special uses can be the fiction appropriate compounds in the treatment of allergies, asthma, chronic bronchitis, atopic dermatitis, psoriasis and others Find skin diseases and autoimmune diseases.

All temperatures above and below are given in ° C. In the The following examples mean "customary workup": If there is required to add water, if necessary, depending on constitution of the end product to pH values between 2 and 10, extracted with Ethyl acetate or dichloromethane, separates, dries the organic phase over sodium sulfate, evaporated and purified by chromatography Silica gel and / or by crystallization.

example 1

A solution of 1.1 g of 3- (4-aminobenzyl) -5- (3,4-dimethoxyphenyl) -3,6- dihydro-1,3,4-thiadiazin-2-one ("A") and 0.8 ml pyridine in 50 ml dichlor methane is mixed with 0.9 g chloroformic acid 3- (N, N-diethylamino) propyl ester, dissolved in 10 ml dichloromethane, added and 1 hour in the room temperature stirred. The solvent is removed and applied as usual is working. 1.2 g of N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1 are obtained, 3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- (N, N-diethyl amino) propyl ester, hydrochloride, mp 116 °.

Analogously, by reacting "A" with chloroformic acid 2- (N, N-diethylamino) ethyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 2- ( N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 2- ( N, N-diisopropylamino) ethyl ester, hydrochloride, mp 218 °;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 6- ( N, N-dimethylamino) hexyl ester, amorphous;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 2- ( N, N-dimethylamino) -1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid- (1- methyl 4-piperidyl) ester, mp 183 °;
with chloroformic acid 2- (4-hydroxy-1-piperidyl) ethyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine - 3-ylmethyl) phenyl] carbamic acid- (4- hydroxy-1-piperidyl) ethyl ester,
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid-2-morpholino -ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 3-morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-3-ylmethyl) phenyl] carbamic acid-2-thiomorpholino -ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid-3-thiomorpholino -propyl ester;
with 2-piperazino ethyl chloroformate:
N- (4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid-2-piperazino -ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid-3-piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 2-pyrrolidino -ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid-3-pyrrolidino propyl ester.

Analogously, reaction of 3- (3-aminobenzyl) -5- (3,4-di methoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- ( N, N-diethylamino) propyl ester, hydrochloride, mp 161 °;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- ( N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- ( N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid 6- ( N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- ( N, N-dimethylamino) -1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- (3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid- (1- methyl 4-piperidyl) ester; -
with 2-morpholino-ethyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2-morpholino -ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-3-ylmethyl) phenyl] carbamic acid-3-morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-3-ylmethyl) phenyl] carbamic acid-2-thiomorpholino -ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid-3-thiomorpholino -propyl ester;
with 2-piperazino ethyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-3-ylmethyl) phenyl] carbamic acid-2-piperazino -ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-azin-3-ylmethyl) phenyl] carbamic acid-3-piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-3-ylmethyl) phenyl] carbamic acid-2-pyrrolidino -ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadia-3-ylmethyl) phenyl] carbamic acid-3-pyrrolidino propyl ester.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3-ethoxy-4-methoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-3 - (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 - (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 - (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-6 - (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 - (N, N-dimethylamino) -1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid- ( 1-methyl-4-piperidyl) ester, mp 153 °;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 -morpholino-ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-3 -morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 -thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-3 -thiomorpholino-propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 -piperazino-ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-3 -piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-2 -pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia diazin-3-ylmethyl) phenyl] carbamic acid-3 -pyrrolidino propyl ester.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3,4-di methoxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 3- (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 2- (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 2- (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 6- (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 2- (N, N-dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - (1-methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thia-diazin-3-ylmethyl) phenyl] - carbamic acid 2-morpholino-ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- (4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 2-thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 3-thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 2-piperazino ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 3-piperazino propyl ester;
with 2-pyrrolidinoethyl chloroformate:
N- (4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid - 2-pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thi-a-diazin-3-ylmethyl) phenyl] 3-pyrrolidino-propyl carbamate.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - 3- (N, N-diethylamino) propamic acid carbamate;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 2- (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 2- (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 6- (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 2- (N, N-dimethyl amino) -1-methyl ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid (1-methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thia-diazin-3-ylmethyl) phenyl ] -carbamic acid 2-morpholino ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - 3-morpholino propyl carbamic acid;
with 2-thiomorpholino ethyl chloroformate:
N- (4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 2-thiomorpholino ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - 3-thiomorpholino carbamic acid propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 2-piperazino ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - 3-piperazino-propyl carbamic acid;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - carbamic acid 2-pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -6-ethyl-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - 3-pyrrolidinopropyl carbamic acid.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3-cyclopentyloxy-4-methoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 6- (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid- (1st -methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia-diazin-3-ylmethyl) phenyl] carbamic acid - 2-morpholino ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- thiomorpholino-- ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- piperazino ethyl ester;
with 3-piperazino-propyl chloroformate:
N- (4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- pyrrolidino propyl ester.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3-propoxy-4-methoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 6- (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid- (1st -methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia-diazin-3-ylmethyl) phenyl] carbamic acid - 2-morpholino ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- piperazino ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- pyrrolidino propyl ester.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3-isopropoxy-4-methoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diisopropyl amino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 6- (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid- (1st -methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thia-diazin-3-ylmethyl) phenyl] carbamic acid - 2-morpholino ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- piperazino ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- pyrrolidino propyl ester.

Analogously, reaction of 3- (4-aminobenzyl) -5- (3-fluoro-methoxy-4-methoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N , N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 6- (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid- (1st -methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- morpholino ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- morpholino propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- thiomorpholino-- ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- piperazino ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 2- pyrrolidino ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (3,6-Dihydro-5- (3-fluoromethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid 3- pyrrolidino propyl ester.

Example 2

A solution of 0.9 g of 2-chloro-N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) - 2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] acetamide ("B") (made by reaction of 3- (4-aminobenzyl) -5- (3,4-dimethoxyphenyl) -3,6- dihydro-1,3,4-thiadiazin-2-one with chloroacetyl chloride) in 40 ml of ethanol refluxed for 5 hours with 0.4 g morpholine. You remove that Solvent and works up as usual. Obtained after recrystallization to make N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-- 3-ylmethyl) phenyl] -2-morpholinoacetamide, amorphous.

Analogously, the following compounds are obtained by reacting "B" with the corresponding amines
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N, N -diethylamino) -acetamide, amorphous;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N, N -diisopropylamino) -acetamide;
N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-thiomorpholinoacetamide;
N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperidinoacetamide, amorphous;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4-hydroxy -piperidino) -acetamide;
N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperazinoacetamide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4-methyl -piperazino) -acetamide, dihydrochloride, mp 124 °;
N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-pyrrolidino-acetamide, amorphous.

Analogously, reaction of 2-chloro-N- [3- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) -phenyl] -aceta-mid with the corresponding amines compounds below
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4-morpholinyl ) -acetamide, amorphous;
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N, N -diethylamino) -acetamide, amorphous;
N- (3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N, N -diisopropylamino) -acetamide
N- [3- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-thiomorpholinoacetamide;
N- [3- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl-2-piperidinoacetamide;
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4-hydroxy -piperidino) -acetamide;
N- [3- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperazinoacetamide;
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4-methyl -piperazino) -acetamide;
N- [3- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-pyrrolidino-acetamide.

Analogously, the reaction of 3-chloro-N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) -phenyl] -propi-on acid amide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4-morpholinyl ) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N, N -diethylamino) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N, N -diisopropylamino) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-thiomorpholino-propionic acid amide ;
N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperidino-propionic acid amide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4-hydroxy -piperidino) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperazino-propionic acid amide;
N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-pyrrolidino-propionic acid amide.

Analogously, 2-chloro-N- [4- (3,6-dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl) phenyl -] - acetamide with the corresponding amines according to the following compounds
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -morpholinyl) -acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diethylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diisopropylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-thiomorpholino- acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperidino- acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -hydroxy-piperidino) -acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperazino- acetamide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-pyrrolidino- acetamide.

Analogously, 2-chloro-N- [4- (3,6-dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl) -pheny-l] - acetamide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -morpholinyl) -acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diethylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diisopropylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-thiomorpholino- acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperidino- acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -hydroxy-piperidino) -acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperazino- acetamide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-pyrrolidino- acetamide.

Analogously, 2-chloro-N- [4- (3,6-dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl) - phenyl] -acetamide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -morpholinyl) -acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diethylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diisopropylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-thiomorpholino- acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperidino- acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -hydroxy-piperidino) -acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperazino- acetamide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-pyrrolidino- acetamide.

Analogously, 2-chloro-N- [4- (3,6-dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl -) - phenyl] -acetamide with the corresponding amines according to the following compounds
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -morpholinyl) -acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diethylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (N , N-diisopropylamino) acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-thiomorpholino- acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperidino- acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2- (4th -hydroxy-piperidino) - acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-piperazino- acetamide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -2-pyrrolidino- acetamide.

Analogously, 3-chloro-N- [4- (3,6-dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl) phenyl -] - propionic acid amide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -morpholinyl) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diethylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diisopropylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-thiomorpholino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl-3-piperidino-propionic acid amide ;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -hydroxy-piperidino) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperazino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-pyrrolidino- propionic acid amide.

Analogously, reaction of 3-chloro-N- [4- (3,6-dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl) -pheny-l] - propionic acid amide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -morpholinyl) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diethylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diisopropylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-thiomorpholino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperidino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -hydroxy-piperidino) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperazino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-propoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-pyrrolidino- propionic acid amide.

Analogously, the reaction of 3-chloro-N- [4- (3,6-dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl) phenyl] propionic acid amide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -morpholinyl) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diethylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diisopropylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-thiomorpholino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperidino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -hydroxy-piperidino) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperazino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-isopropoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-pyrrolidino- propionic acid amide.

Analogously, reaction of 3-chloro-N- [4- (3,6-dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazine-3- ylmethyl -) - phenyl] propionic acid amide with the corresponding amines compounds below
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (4th -morpholinyl) -propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diethylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- (N , N-diisopropylamino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-thiomorpholino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperidino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2 H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3- ( 4-hydroxy-piperidino) propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-piperazino- propionic acid amide;
N- [4- (3,6-Dihydro-5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] -3-pyrrolidino- propionic acid amide.

Example 3

A solution of 1.1 g of 2- (4-aminobenzyl) -6- (3,4-dimethoxyphenyl) - 2,3,4,5-tetrahydro-pyridazin-3-one ("C") and 0.8 ml pyridine in 50 ml dichlor methane is mixed with 0.9 g chloroformic acid 3- (N, N-diethylamino) propyl ester, dissolved in 10 ml dichloromethane, added and 1 hour in the room temperature stirred. The solvent is removed and applied as usual is working. N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5- tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N, N-diethy-l amino) propyl ester.

Analogously, by converting "C"
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N-diethylamino ) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N-diisopropylamino ) - ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N, N-dimethylamino ) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N-dimethylamino ) -1-methyl ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid- (1-methyl-4-piperidyl ) ester;
with chloroformic acid 2- (4-hydroxy-1-piperidyl) ethyl ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid- (4-hydroxy-1-piperidyl ) ethyl ester,
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholino-ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino-propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazino-ethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidino-ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidino-propyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3-ethoxy-4-methoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N, N -diethylamino) - propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diethylamino) - ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N - diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N, N -dimethylamino) - hexyl ester, amorphous;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid- (1-methyl-4 -piperidyl) ester, cyclohexane sulfamate, mp 152 °;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholinoethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino-ethyl ester ;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazinoethyl ester; -
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidinoethyl ester- ;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidinopropyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3,4-dimethoxyphenyl) -5-ethyl-2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N , N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N , N-diethylamino) - ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N , N-diisopropyl amino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N , N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N , N-dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid (1-methyl -4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholino- ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino- propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino- ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino- propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazino- ethyl ester; -
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3,4-Pimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidino- ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidino- propyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3-ethoxy-4-methoxyphenyl) -5-ethyl-2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-3 - (N, N-diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-2 - (N, N-diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- (4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-2 - (N, N-diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-6 - (N, N-dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-2 - (N, N-dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid- ( 1-methyl-4-piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-2 -morpholino- ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-3 -morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-3 -thiomorpholino-propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-2 -piperazino-ethyl ester; -
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-3 -piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-2 -pyrrolidino-ethyl ester-;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-5-ethyl-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-3 -pyrrolidino-propyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3-cyclopentyloxy-4-methoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid-3- (N, N - diethylamino) propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N - diethylamino) ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N - diisopropylamino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N, N - dimethylamino) hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N - dimethylamino) -1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid- (1-methyl-4 - piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholino-ethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino-ethyl ester;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino-propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazinoethyl ester;
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidino-ethyl ester;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidinopropyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3-propoxy-4-methoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N, N -diethylamino) - propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diethylamino) - ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diisopropyl amino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N, N -dimethylamino) - hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid- (1-methyl-4 -piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3-Prnpoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholinoethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino-ethyl ester ;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3-propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino-propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazinoethyl ester; -
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidinoethyl ester- ;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidinopropyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3-isopropoxy-4-methoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N, N -diethylamino) - propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diethylamino) - ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diisopropyl amino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N, N -dimethylamino) - hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid- (1-methyl-4 -piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholinoethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino-ethyl ester ;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazinoethyl ester; -
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidino-ethyl ester- ;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidinopropyl ester.

Analogously, reaction of 2- (4-aminobenzyl) -6- (3-fluoro-methoxy-4-methoxyphenyl) -2,3,4,5-tetrahydro-pyridazin-3-one is obtained
with chloroformic acid 3- (N, N-diethylamino) propyl ester:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N, N -diethylamino) - propyl ester;
with 2- (N, N-diethylamino) ethyl chloroformate:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diethylamino) - ethyl ester;
with ethyl chloroformate 2- (N, N-diisopropylamino):
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -diisopropyl amino) ethyl ester;
with chloroformic acid 6- (N, N-dimethylamino) hexyl ester:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 6- (N, N -dimethylamino) - hexyl ester;
with chloroformic acid 2- (N, N-dimethylamino) -1-methyl-ethyl ester:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2- (N, N -dimethylamino) - 1-methyl-ethyl ester;
with chloroformic acid (1-methyl-4-piperidyl) ester:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid- (1-methyl-4 -piperidyl) ester;
with 2-morpholino-ethyl chloroformate:
N- [4- (6- (3-fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-morpholinoethyl ester;
with 3-morpholino-propyl chloroformate:
N- [4- (6- (3-fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-morpholino-propyl ester;
with 2-thiomorpholino ethyl chloroformate:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-thiomorpholino-ethyl ester ;
with 3-thiomorpholino-propyl chloroformate:
N- [4- (6- (3-fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-thiomorpholino-propyl ester;
with 2-piperazino ethyl chloroformate:
N- [4- (6- (3-fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-piperazinoethyl ester; -
with 3-piperazino-propyl chloroformate:
N- [4- (6- (3-fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-piperazino-propyl ester;
with ethyl 2-pyrrolidino chloroformate:
N- [4- (6- (3-fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 2-pyrrolidino-ethyl ester- ;
with 3-pyrrolidino-propyl chloroformate:
N- [4- (6- (3-Fluoromethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3-pyrrolidinopropyl ester.

Example 4

A solution of 0.9 g of 2-chloro-N- [4- (6- (3-ethoxy-4-methoxyphenyl) -3-oxo- 2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] acetamide ("D") (made by reaction of 2- (4-aminobenzyl) -6- (3-ethoxy-4-methoxyphenyl) - 2,3,4,5-tetrahydro-pyridazin-3-one with chloroacetyl chloride) in 40 ml of ethanol is refluxed for 5 hours with 0.4 g of morpholine. One removes the solvent and works up as usual. After recrystallization one obtains N- [4- (6- (3-ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro- pyridazin-2-ylmethyl) phenyl] -2- (4-morpholinyl) acetamide, mp 150 °.

Analogously, the following compounds are obtained by reacting "D" with the corresponding amines
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (N, N-diethylamino ) -acetamide, fumarate, mp 161 °;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (N, N-diisopropylamino ) acetamide;
N- [4- (6- (3-ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-thiomorpholinoacetamide;
N- [4- (6- (3-ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-piperidinoacetamide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4-hydroxy-piperidino ) acetamide;
N- [4- (6- (3-ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-piperazinoacetamide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-pyrrolidino-acetamide.

Analogously, 2-chloro-N- [4- (6- (3,4-dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) -phenyl] -acetam is obtained by reacting 2-chloro-N- -id with the corresponding amines compounds below
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -2- (4-morpholinyl) acetamide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -2- (N, N-diethylamino) - acetamide
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -2- (N, N-diisopropylamino) - acetamide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-thiomorpholinoacetamide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-piperidinoacetamide;
N- [4- (6- (3,4-dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4-hydroxy-piperidino) -acetamide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-piperazinoacetamide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-pyrrolidino-acetamide.

Analogously, 3-chloro-N- [4- (6- (3,4-dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyradazin-2-ylmethyl) phenyl] propio is obtained by reacting 3-chloro-N- -n acid amide with the corresponding amines compounds below
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-morpholinyl) propionic acid amide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -3- (N, N-diethylamino) - propionic acid amide.
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -3- (N, N-diisopropylamino) - propionic acid amide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-thiomorpholino-propionic acid amide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperidino-propionic acid amide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-hydroxy-piperidino) - propionic acid amide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperazino-propionic acid amide;
N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-pyrrolidino-propionic acid amide.

Analogously, by reacting 2-chloro-N- [4- (6- (3-propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] - - acetamide with the corresponding amines below compounds
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4-morpholinyl) - acetamide.
N- [4- (6- (3-propoxy-4-methoxyphenyl) 3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (N, N-diethylamino) -acetamide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (N, N-diisopropylamino ) acetamide;
N- [4- (6- (3-propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-thiomorpholinoacetamide;
N- [4- (6- (3-propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-piperidinoacetamide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4-hydroxy-piperidino ) acetamide;
N- [4- (6- (3-propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) -2-piperazinoacetamide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-pyrrolidino-acetamide.

Analogously, by reaction of 2-chloro-N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] - - acetamide with the corresponding amines below compounds
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4-morpholinyl) - acetamide;
N- (4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (N, N-diethylamino ) acetamide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (N, N-diisopropylamino ) acetamide;
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-thiomorpholinoacetamide;
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-piperidinoacetamide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4-hydroxy-piperidino ) acetamide;
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) -2-piperazinoacetamide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2-pyrrolidino-acetamide.

Analogously, 2-chloro-N- [4- (6- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl is obtained by reacting 2-chloro-N- ] -acetamide with the corresponding amines compounds below
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -2- (4-morpholinyl) -acetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -2- (N, N-diethylamino ) - acetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -2- (N, N-diisopropylamino ) - acetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2 09099 00070 552 001000280000000200012000285910898800040 0002019604388 00004 08980,3,4,5-tetra hydro-pyridazin-2-ylmethyl) -phenyl] - 2-thiomorpholinoacetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -2-piperidinoacetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -2- (4-hydroxy- piperidino) - acetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) -2-piperazinoacetamide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -2-pyrrolidino-acetamide.

Analogously, reaction of 3-chloro-N- [4- (6- (3-ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] - - Propionic acid amide with the corresponding amines compounds below
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-morpholinyl) - propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (N, N-diethylamino ) propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (N, N-diisopropylamino ) -propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-thiomorpholino-propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperidino-propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-hydroxy-piperidino ) -propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperazino-propionic acid amide;
N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-pyrrolidino-propionic acid amide.

Analogously, by reaction of 3-chloro-N- [4- (6- (3-propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] - - Propionic acid amide with the corresponding amines compounds below
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-morpholinyl) - propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (N, N-diethylamino ) propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (N, N-diisopropylamino ) -propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-thiomorpholino-propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperidino-propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-hydroxy-piperidino ) -propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperazino-propionic acid amide;
N- [4- (6- (3-Propoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-pyrrolidino-propionic acid amide.

Analogously, reaction of 3-chloro-N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] - - Propionic acid amide with the corresponding amines compounds below
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl-3- (4-morpholinyl) propionic acid amide
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (N, N-diethylamino ) propionic acid amide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (N, N-diisopropylamino ) -propionic acid amide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-thiomorpholino-propionic acid amide
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2, 3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperidino-propionic acid amide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3- (4-hydroxy-piperidino ) -propionic acid amide;
N- [4- (6- (3-isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-piperazino-propionic acid amide;
N- [4- (6- (3-Isopropoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -3-pyrrolidino-propionic acid amide.

Analogously, reaction of 3-chloro-N- [4- (6- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] gives -propionic acid amide with the corresponding amines below compounds
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -3- (4-morpholinyl) -propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -3- (N, N-diethylamino ) - propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -3- (N, N-diisopropylamino) - propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -3-thiomorpholino-propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -3-piperidino-propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -3- (4-hydroxy- piperidino) propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -3-piperazino-propionic acid amide;
N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetra hydro-pyridazin-2-ylmethyl) phenyl] -3-pyrrolidino-propionic acid amide.

Example 5

A solution of 5- (3,4-dimethoxy) -3,6-dihydro-1,3,4-thiadiazin-2-one in Acetone is mixed with N- [4- (chloromethyl) phenyl] carbamic acid 3- (N, N- diethylamino) propyl ester with the addition of potassium carbonate for 4 hours cooked. The insoluble residue is filtered off and the solution constricted. After the usual work-up, N- [4- (3,6-dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] - 3- (N, N-diethylamino) propamic acid carbamate, hydrochloride, mp 116 °.

The following examples relate to pharmaceutical preparations:

Example A Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate in 3 l of double distilled water with 2 n Hydrochloric acid adjusted to pH 6.5, sterile filtered, poured into injection glasses fills, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g NaH₂PO₄ · 2 H₂O, 28.48 g Na₂HPO₄ · 12 H₂O and 0.1 g benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8 makes up to 1 l and sterilized by radiation. This solution can be found in Form of eye drops can be used.

Example D ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.

Example F Dragees

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G Capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of formula I in 60 l of double distilled Water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

Example I Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 l of isotonic NaCl solution and fills the solution into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. A spray (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (11)

1. Compounds of formula I. wherein
R¹ and R² are each independently H or A,
R³ and R⁴ each independently of one another -OH, OA, -SA, -SO-A, -SO₂-A, Hal, methylenedioxy, -NO₂, -NH₂, -NHA or -NAA ',
A and A 'each independently of the other alkyl with 1 to 10 C atoms, which can be substituted by 1 to 5 F and / or Cl atoms, cycloalkyl with 3-7 C atoms or methylene cycloalkyl with 4-8 C atoms ,
B -Y-R⁵ or -OY-R⁵,
Q is absent or alkylene with 1-4 C atoms,
Y is absent or alkylene with 1-10 C atoms,
X CH₂ or S,
R⁵ NH₂, NHA, NAA 'or an unsubstituted or simply substituted by A or OH substituted 3-8-membered heterocycle with at least one N atom, in which further CH₂ groups can be replaced by NH, NA, S or O,
Hal F, Cl, Br or
mean,
and their physiologically acceptable salts. 2. An enantiomer of a compound of formula I according to claim 1. 3. (a) N- [4- (3,6-Dihydro-5- (3,4-dimethoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid -3- (N, N-diethylamino) propyl ester;

• (b) N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid -3- (N, N-diethylamino) propyl ester;
• (c) N- [4- (6- (3,4-Dimethoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- (N, N-diethylamino) propyl ester;
• (d) N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] carbamic acid 3- ( N, N-diethylamino) propyl ester;
• (e) N- [4- (6- (3-Ethoxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydropyridazin-2-ylmethyl) phenyl] -2- (4- methylpiperazino) acetamide;
• (f) N- [4- (6- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxo-2,3,4,5-tetrahydro-pyridazin-2-ylmethyl) phenyl] -2- (4- methylpiperazino) - acetamide;
• (g) N- [4- (3,6-Dihydro-5- (3-ethoxy-4-methoxyphenyl) -2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl) phenyl] carbamic acid -2- (4-methyl piperazino) acetamide;

according to claim 1. 4. A process for the preparation of compounds of formula I according to claim 4 and their salts, wherein B is -OY-R⁵, characterized in that a compound of formula II wherein
R¹, R², R³, R⁴, Q and X have the meanings given,
with a compound of formula IIIL-CO-B IIIworin
B -OY-R⁵,
L means Cl, Br, OH or a reactive esterified OH group and
R⁵ has the meaning given
implements
or
that one for the preparation of compounds of formula I according to claim 1 and their salts, wherein B is -Y-R⁵, a compound of formula IV wherein
R¹, R², R³, R⁴, Q, X and Y have the meanings given, and
L Cl, Br, OH or a reactive esterified OH group
means
with a compound of the formula VH-R⁵ Vworin
R⁵ has the meaning given
implements
or
that one for the preparation of compounds of formula I according to claim 1 and their salts,
a compound of formula VI wherein
R¹, R², R³, R⁴ and X have the meanings given, with a compound of formula VII wherein
Q and B have the specified compounds, and
L denotes Cl, Br, OH or a reactive esterified OH group,
implements
and / or that a basic compound of formula I is converted into one of its salts by treatment with an acid. 5. Process for the preparation of pharmaceutical preparations, thereby characterized in that a compound of formula I according to An saying 1 and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi-liquid Bring carrier or excipient into a suitable dosage form.   6. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I according to claim 1 and / or one of their physiologically acceptable salts. 7. Compounds of formula I according to claim 1 and their physiological harmless salts to combat asthma, allergies and inflammatory diseases, autoimmune diseases and transplant rejection reactions. 8. Medicament of formula I according to claim 1 and their physiological harmless salts as phosphodiesterase IV inhibitors. 9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a Drug. 10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the Fighting disease.