DE10305885A1 - New pyrazinopyrimidine or pyrazinoimidazole derivatives useful for weight reduction in mammals, for preventing or treating obesity, type II diabetes or metabolic syndrome and for treating sexual disorders - Google Patents

Abstract

The invention relates to substituted hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione derivatives and their physiologically tolerable salts and physiologically functional derivatives. DOLLAR A Compounds of the formula I, DOLLAR F1 in which the radicals have the meanings indicated, and their physiologically tolerable salts and processes for their preparation are described. The compounds are suitable for. B. as anorectics.

Description

The invention relates to substituted Hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione derivatives and their physiological compatible Salts and physiologically functional derivatives.

The invention was based on the object Connections available to provide weight reduction in mammals and for prevention and treatment of obesity.

worin bedeuten
A 3-12 gliedriger mono-, bi- oder spirobicyclischer Ring, der ein oder mehrere Heteroatome aus der Gruppe N, O und S enthalten kann und der 3-12 gliedrige Ring weitere Substituenten wie F, Cl, Br, NO₂, CF₃, OCF₃, CN, (C₁-C₆)-Alkyl, Aryl, CON(R11)(R12), N(R13)(R14), OH, O-(C₁-C₆)-Alkyl, S-(C₁-C₆)-Alkyl, N(R15)CO(C₁-C₆)-Alkyl oder COO-(C₁-C₆)-Alkyl tragen kann;
R11, R12, R13, R14, R15 unabhängig voneinander H, (C₁-C₆)-Alkyl, Heterocyclus;
n 0, 1;
m 0, 1, 2, 3, 4, 5, 6;
R1 (C₀-C₆)-Alkylen-R8, (C₂-C₆)-Alkenylen-R9, (SO₂)-(C₀-C₆)-Alkylen-R8, (SO₂)-(C₂-C₆)-Alkenylen-R9, (C=O)-(C₀-C₆)-Alkylen-R8, (C=O)-(C₂-C₆)-Alkenylen-R9, (C=O)-NH-(C₀-C₆)-Alkylen-R8, (C=O)-NH-(C₂-C₆)-Alkenylen-R9, COO-(C₀-C₆)-Alkylen-R8, COO-(C₂-C₆)-Alkenylen-R9, Alkinylen-R9, (C₁-C₄-Alkyl)-Heterocyclus;
R8, R9 unabhängig voneinander H, Aryl, Heterocyclus, (C₃-C₈)-Cycloalkyl, wobei die Ringe oder Ringssysteme bis zu 3-fach substituiert sein können mit F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O-(C₁-C₆)-Alkyl, (C₁-C₆)-Alkyl, NH₂; CON(R11)(R12), N(R13)(R14), SO₂-CH₃, COOH, COO-(C₁-C₆)-Alkyl, CONH₂;
R2 H, F, Cl, Br, J, OH, CF₃, NH₂, NO₂, CN, OCF₃, O-(C₁-C₆)-Alkyl, O-(C₁-C₄)-Alkoxy-(C₁-C₄)-alkyl, S-(C₁-C₆)-Alkyl, (C₁-C₆)-Alkyl, (C₂-C₆)-Alkenyl, (C₃-C₈)-Cycloalkyl, O-(C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkenyl, O-(C₃-C₈)-Cycloalkenyl, (C₂-C₆)-Alkinyl, (C₀-C₈)-Alkylen-Aryl, O-(C₀-C₈)-Alkylen-Aryl, S-Aryl, CON(R11)(R12), N(R13)(R14), (C₁-C₆)-Alkyl-N(R13)(R14), NH-SO₂-CH₃, NH-SO₂-R12, NR11-SO₂-R12, N(CO)R11, COOH, COO-(C₁-C₆)-Alkyl, COO-(C₁-C₆)-Alkenyl, CO-N((C₁-C₆)-Alkyl)₂, Heterocyclus, NHCONR11, N(C₁-C₆-Alkyl)N⁺(C₁-C₄-Alkyl)₃;
R3 , R4, R5 unabhängig voneinander H, F, Cl, Br, J, OH, CF₃, NO₂, CN, OCF₃, O-(C₁-C₆)-Alkyl, O-(C₁-C₄)-Alkoxy-(C₁-C₄)-alkyl, S-(C₁-C₆)-Alkyl, (C₁-C₆)-Alkyl, (C₂-C₆)-Alkenyl, (C₃-C₈)-Cycloalkyl, O-(C₃-C₈)-Cycloalkyl, (C₃-C₈)-Cycloalkenyl, O-(C₃-C₈)-Cycloalkenyl, (C₂-C₆)-Alkinyl, (C₀-C₈)-Alkylen-Aryl-, O-(C₀-C₈)-Alkylen-Aryl, S-Aryl, N((C₁-C₆)-Alkyl)₂, SO₂-CH₃, COOH, COO-(C₁-C₆)-Alkyl, CO-N((C₁-C₆)-Alkyl)₂;
sowie deren physiologisch verträglichen Salze.The invention therefore relates to compounds of the formula I

in what mean
A 3-12 membered mono-, bi- or spirobicyclic ring which can contain one or more heteroatoms from the group N, O and S and the 3-12 membered ring further substituents such as F, Cl, Br, NO ₂ , CF ₃ , OCF ₃ , CN, (C ₁ -C ₆ ) alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O- (C ₁ -C ₆ ) alkyl, S- (C ₁ -C ₆ ) alkyl, N (R15) CO (C ₁ -C ₆ ) alkyl or COO- (C ₁ -C ₆ ) alkyl;
R11, R12, R13, R14, R15 independently of one another H, (C ₁ -C ₆ ) alkyl, heterocycle;
n 0.1;
m 0, 1, 2, 3, 4, 5, 6;
R1 (C ₀ -C ₆ ) alkylene-R8, (C ₂ -C ₆ ) alkenylene-R9, (SO ₂ ) - (C ₀ -C ₆ ) alkylene-R8, (SO ₂ ) - (C ₂ -C ₆ ) -alkenylene-R9, (C = O) - (C ₀ -C ₆ ) -alkylene-R8, (C = O) - (C ₂ -C ₆ ) -alkenylene-R9, (C = O) -NH- (C ₀ -C ₆ ) alkylene-R8, (C = O) -NH- (C ₂ -C ₆ ) alkenylene-R9, COO- (C ₀ -C ₆ ) alkylene-R8, COO - (C ₂ -C ₆ ) alkenylene R9, alkynylene R9, (C ₁ -C ₄ alkyl) heterocycle;
R8, R9 independently of one another are H, aryl, heterocycle, (C ₃ -C ₈ ) -cycloalkyl, it being possible for the rings or ring systems to be substituted up to 3 times with F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, NH ₂ ; CON (R11) (R12), N (R13) (R14), SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) alkyl, CONH ₂ ;
R2 H, F, Cl, Br, J, OH, CF ₃ , NH ₂ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, O- (C ₁ -C ₄ ) alkoxy - (C ₁ -C ₄ ) alkyl, S- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) -Cycloalkyl, O- (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkenyl, O- (C ₃ -C ₈ ) -cycloalkenyl, (C ₂ -C ₆ ) alkynyl, (C ₀ -C ₈ ) alkylene aryl, O- (C ₀ -C ₈ ) alkylene aryl, S-aryl, CON (R11) (R12), N (R13) (R14), (C ₁ -C ₆ ) -Alkyl-N (R13) (R14), NH-SO ₂ -CH ₃ , NH-SO ₂ -R12, NR11-SO ₂ -R12, N (CO) R11, COOH, COO- (C ₁ -C ₆ ) -Alkyl, COO- (C ₁ -C ₆ ) alkenyl, CO-N ((C ₁ -C ₆ ) alkyl) ₂ , heterocycle, NHCONR11, N (C ₁ -C ₆ alkyl) N ⁺ (C ₁ -C ₄ alkyl) ₃ ;
R3, R4, R5 independently of one another H, F, Cl, Br, J, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, O- (C ₁ -C ₄ ) Alkoxy- (C ₁ -C ₄ ) alkyl, S- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ - C ₈ ) cycloalkyl, O- (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl, O- (C ₃ -C ₈ ) cycloalkenyl, (C ₂ -C ₆ ) alkynyl, (C ₀ -C ₈ ) alkylene aryl, O- (C ₀ -C ₈ ) alkylene aryl, S-aryl, N ((C ₁ -C ₆ ) alkyl) ₂ , SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) alkyl, CO-N ((C ₁ -C ₆ ) alkyl) ₂ ;
and their physiologically tolerable salts.

Can Residues or substituents multiple times in the compounds of the formula I occur, such as CON (R11) (R12), so they can all independent from each other have the meanings given and the same or different his.

The invention relates to connections of formula I, in the form of their racemates, enantiomerically enriched Mixtures and pure enantiomers as well as their diastereomers and Mixtures of these.

The alkyl, alkenyl and alkynyl residues in the substituents R, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15 can be straight-chain, branched or optionally halogenated.

The term "aryl" is a phenyl or naphthyl group understood.

Heterocycle or heterocyclic radical are understood to mean ring systems which, apart from carbon still contain heteroatoms, such as nitrogen, oxygen or sulfur. Ring systems also belong to this definition, in which the heterocycle or the heterocyclic radical is condensed with benzene nuclei.

Suitable "heterocyclic rings" or "heterocyclic radicals" are acridinyl, Azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, Benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, Benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, Carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, Chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, Dihydrofuro [2,3-b] tetrahydrofuran, furyl, furazanyl, imidazolidinyl, Imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, Indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, Isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, Morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, Oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, Phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, Piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, Pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, Pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.

Pyridyl stands for 2-, 3- as well as 4-pyridyl. Thienyl represents both 2- and 3-thienyl. Furyl stands as well as 2- as well as 3-furyl.

The corresponding ones are still included N-oxides of these compounds, e.g. 1-oxy-2-, 3- or 4-pyridyl.

One or more are still included benzo-fused derivatives of these heterocycles.

The heterocyclic rings or heterocyclic radicals can be substituted one or more times with suitable groups, such as: F, Cl, Br, I, CF ₃ , NO ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl , CONH ₂ , CONH (C ₁ -C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl] ₂ , (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) -alkynyl, O- (C ₁ -C ₆ ) -alkyl, where one, more or all of the hydrogen groups in the alkyl radicals can be replaced by fluorine;
PO ₃ H ₂ , SO ₃ H, SO ₂ -NH ₂ , SO ₂ NH (C ₁ -C ₆ ) alkyl, SO ₂ N [(C ₁ -C ₆ ) alkyl] ₂ , S- (C ₁ - C ₆ ) alkyl, S- (CH ₂ ) _n -phenyl, SO- (C ₁ -C ₆ ) alkyl, SO- (CH ₂ ) _n -phenyl, SO ₂ - (C ₁ -C ₆ ) alkyl , SO ₂ - (CH ₂ ) _n - phenyl, where n can be 0-6 and the phenyl radical can be used up to twice with F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, NH ₂ may be substituted;
C (NH) (NH ₂ ), NH ₂ , NH- (C ₁ -C ₆ ) alkyl, N ((C ₁ -C ₆ ) alkyl) ₂ , NH (C ₁ -C ₇ ) acyl, phenyl , O- (CH ₂ ) _n phenyl, where n = 0-6, where the phenyl ring can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, NH ₂ , NH (C ₁ -C ₆ ) alkyl, N ((C ₁ -C ₆ ) alkyl) ₂ , SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) alkyl, CONH ₂ .

Pharmaceutically acceptable salts are due to their higher Water across from the starting or basic connections particularly suitable for medical Applications. These salts need to a pharmaceutically acceptable one Have anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids, like hydrochloric acid, Hydrogen bromide, phosphorus, metaphosphorus, saltpetre, sulfone and sulfuric acid as well as organic acids, such as. Acetic acid, Benzenesulfone, benzoin, lemon, ethanesulfone, fumar, glucon, Glycol, isethione, milk, lactobion, maleic, apple, methanesulfone, Succinic, p-toluenesulfonic, tartaric and trifluoroacetic acid. For medical For purposes, the chlorine salt is used in a particularly preferred manner. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth salts (such as magnesium and calcium salts).

Salts with a non-pharmaceutical acceptable Anion belong also within the scope of the invention as useful intermediates for the production or cleaning pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in vitro applications.

The term "physiologically functional." Derivative " any physiologically acceptable Derivative of a compound according to the invention of formula I, e.g. an ester which, when administered to a mammal, such as e.g. the human being is able to (directly or indirectly) one Compound of formula I or an active metabolite thereof form.

To the physiologically functional Count derivatives also prodrugs of the compounds according to the invention. Such prodrugs can in vivo to a compound of the invention are metabolized. These prodrugs can themselves be effective or Not.

The compounds of the invention can also are in various polymorphic forms, e.g. as an amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong within the scope of the invention and are another aspect of the invention.

All references refer below on "connection (s) according to formula (I) "on connections) of Formula (I) as described above, and its salts, solvates and physiologically functional derivatives as described herein.

The amount of a compound according to the formula (I) that is required to achieve the desired biological effect to achieve is dependent a number of factors, e.g. the chosen specific compound, the intended use, administration and clinical Condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day each Kilogram body weight, e.g. 3-10 mg / kg / day. An intravenous Dose may e.g. are in the range of 0.3 mg to 1.0 mg / kg, the suitably as an infusion of 10ng to 100ng per kilogram can be administered per minute. Suitable infusion solutions for this Purposes e.g. from 0.1 ng to 10 mg, typically from 1 ng to 10 mg each Milliliters. Single doses can e.g. from 1 mg to 10 g of the active ingredient included. Thus, ampoules can be used for injections for example from 1 mg to 100 mg, and orally administrable single-dose formulations, such as tablets or capsules, for example, from 1.0 to Contain 1000 mg, typically from 10 to 600 mg. In the case of pharmaceuticals compatible Salts, the aforementioned weight data relate to the weight the free compound on which the salt is based. For prophylaxis or therapy of the above conditions, the compounds according to formula (I) itself can be used as a compound, preferably lying however with a tolerable carrier in the form of a pharmaceutical composition.

The carrier must of course be compatible, in the sense that he with is compatible with the other constituents of the composition and not harmful to health for the Patient. The carrier can be a solid or a liquid or both, and is preferably with the compound as a single dose formulated, for example as a tablet, from 0.05% to 95% by weight of the active ingredient may contain. Other pharmaceutically active substances can also be present, including other connections according to formula (I). The pharmaceutical according to the invention Compositions can are produced by one of the known pharmaceutical methods, which consist essentially in that the components with pharmacological acceptable Carriers and / or auxiliaries be mixed.

Pharmaceutical compositions according to the invention are those for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) Administration are suitable, although the most appropriate mode of administration in each individual case on the type and severity of the condition to be treated and of the type of compound used according to the formula (I) dependent is. Also coated formulations and coated slow-release formulations belong in the scope of the invention. Acid and gastric juice-resistant are preferred Formulations. Suitable enteric coatings include Cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

Suitable pharmaceutical compounds for the oral administration can are in separate units, such as capsules, wafer capsules, Lozenges or tablets, each a certain amount the compound according to formula (I) included; as powder or granules; as a solution or suspension in one aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions can As already mentioned, be prepared by any suitable pharmaceutical method, which includes a step in which the active ingredient and the carrier (which consists of one or more additional Constituents) can be brought into contact. Generally will the compositions by uniform and homogeneous mixing of the active ingredient with a liquid and / or finely divided solid carrier, after which the Product is molded if necessary. For example A tablet can be made by using a powder or granules the connection pressed or molded, optionally with one or more additional ones Ingredients. pressed Tablets can by tableting the compound in free flowing form, such as a powder or granules, optionally mixed with a binder, Lubricant, inert thinner and / or one (more) surfactant / dispersant Means are made in a suitable machine. molded Tablets can by molding the powdery, with an inert liquid thinner humidified connection made in a suitable machine become.

Pharmaceutical compositions, the for oral (sublingual) administration are suitable Lozenges, which are a compound of formula (I) with a flavor included, usually Sucrose and gum arabic or tragacanth, and lozenges which are the Compound in an inert base such as gelatin and glycerin or Sucrose and gum arabic include.

Suitable pharmaceutical compositions for the parenteral administration preferably comprise sterile aqueous preparations a compound according to formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the Administration also subcutaneously, intramuscularly or intradermally as an injection can be done. These preparations can preferably be made by mixing the compound with water and the obtained solution sterile and isotonic with the blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be made by using a compound according to formula (I) mixed with one or more conventional solid carriers, for example cocoa butter, and brings the resulting mixture into shape.

Suitable pharmaceutical compositions for the topical application on the skin are preferably as an ointment, cream, Lotion, paste, spray, aerosol or oil. Vaseline, Lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used. The active substance is generally in a concentration of 0.1 to 15% by weight of the composition present, for example from 0.5 to 2%.

Also transdermal administration is possible. Suitable pharmaceutical compositions for transdermal applications can available as individual patches that are for long-term close contact with the patient's epidermis. Such patches included suitably the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is approximately 1% to 35%, preferably approximately 3% to 15%. As a special option the active ingredient, such as in Pharmaceutical Research, 2 (6): 318 (1986), by electrotransport or iontophoresis to be released.

Draw the compounds of formula I. yourself through cheap Effects on fat metabolism, in particular they are Weight loss and after weight loss to maintain reduced weight in mammals and as anorectics suitable. The connections are characterized by their low toxicity and their minor side effects.

The connections can be done alone or in combination with other weight-reducing or anorectic Active ingredients are used. Such other anorectic agents e.g. in the red list, chapter 01 under weight loss / appetite suppressant and can also contain such active ingredients that the energy turnover of the organism increase and thus lead to a weight loss or even those which influence the general metabolism of the organism in such a way that an increased Calorie intake does not increase fat deposits and one normal calorie intake to reduce the fat deposits of the Organism leads. The compounds are suitable for prophylaxis and in particular for Obesity treatment or obesity. The compounds are also suitable for prophylaxis and in particular for the treatment of type II diabetes, arteriosclerosis as well as normalizing lipid metabolism and treatment of high blood pressure. The compounds act as a melanocortin receptor Agonists and are also suitable for the treatment of disorders of the Sensation and other psychiatric indications, such as Depression, anxiety, Anxiety neuroses, schizophrenia as well as for the treatment of disorders associated with the circadian rhythm and to treat drug abuse.

They are also suitable for treatment cancer, arthritis, sleep disorders, Sleep apnea, female and male Sexual disorders, inflammation, Acne, skin pigmentation, metabolic syndrome, disorders of the Steroid metabolism, skin diseases, psoriasis, mycoses, neurodegenerative diseases and Alzheimer's disease.

In another aspect of the invention can the compounds of formula I in combination with one or more other pharmacologically active substances are administered, the selected for example are made of anti-diabetic, anti-obesity, antihypertensive agents, Lipid-lowering agents and agents for treatment and / or prevention complications caused by diabetes or with diabetes are associated.

Suitable antidiabetic agents include Insulins, amylin, GLP-1 and GLP-2 derivatives such as e.g. those, who in WO 98/08871 by Novo Nordisk A / S, and orally effective hypoglycemic Agents.

The Oral Hypoglycemic Active ingredients preferably include sulphonylureas, biguanidines, Meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, Glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as e.g. those described in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S have been disclosed, insulin sensitizers, insulin activators Receptor kinase, inhibitors of liver enzymes involved in stimulation involved in gluconeogenesis and / or glycogenolysis, e.g. inhibitors glycogen phosphorylase, modulators of glucose uptake and excretion, changing the fat metabolism Compounds like antihyperlipidemic Active ingredients and anti-lipidemic Active ingredients, e.g. HMGCoA reductase inhibitors, cholesterol transport / inhibitors Cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of the microsomal triglyceride transfer protein (MTP), compounds, that reduce food intake, PPAR and RXR agonists and drugs that target the ATP-dependent potassium channel of beta cells Act.

In one embodiment of the invention the present compounds administered in combination with insulin.

In another embodiment the present compounds are used in combination with a sulphonylurea such as. Tolbutamide, Glibenclamide, Glimepirid, Glipizid, Gliquidon, Glisoxepid, Glibornurid or Gliclazid administered.

In another embodiment, the present compounds are used in combination with a Biguanid such as metformin administered.

In yet another embodiment are the present compounds in combination with a meglitinide such as. Repaglinide administered.

In yet another embodiment the present compounds in combination with a thiazolidinedione such as. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 by Dr. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione, administered.

In another embodiment the present compounds are used in combination with an α-glucosidase inhibitor such as. Miglitol or Acarbose administered.

In another embodiment the present compounds in combination with an active ingredient administered on the ATP-dependent Potassium channel of the beta cells works, e.g. Tolbutamide, glibenclamide, Glimepiride, glipizide, gliclazid or repaglinide.

In yet another embodiment the present compounds are used in combination with an antihyperlidemic Active ingredient or an anti-lipidemic Active ingredient such as Cholestyramine, colestipol, clofibrate, fenofibrate, Gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, Cerivastatin, Fluvastatin, Probucol, Ezetimibe or Dextrothyroxine administered.

In another embodiment the present compounds in combination with more than one of the above compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea Insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. administered.

Furthermore, the compounds of the invention in combination with one or more anti-obesity or appetite-regulating Active substances are administered.

Such agents can be selected from the group consisting of CART agonists, NPY antagonists, MCH antagonists, Orexin antagonists, H3 antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonin and norepinephrine reuptake inhibitors, 5HT modulators, MAOIs, bombesin agonists, galanin antagonists, Growth hormone, growth hormone releasing compounds, TRH agonists, Decoupling protein 2 or 3 modulators, leptin agonists, Dopamine agonists (bromocriptine, doprexin), lipase / amylase inhibitors, Antagonists of cannabinoid receptor 1, modulators of acylation stimulating protein (ASP), PPAR modulators, RXR modulators, hCNTF mimetics or TR-β agonists.

In one embodiment of the invention the anti-obesity leptin or modified leptin.

In another embodiment is the anti obesity dexamphetamine or amphetamine.

In another embodiment is the anti obesity fenfluramine or dexfenfluramine.

In yet another embodiment is the anti-obesity sibutramine or the mono- and bis-demethylated Active metabolites of sibutramine.

In another embodiment is the anti obesity orlistat.

In another embodiment is the anti obesity mazindol, diethylpropion or phentermine.

Furthermore, the present compounds in combination with one or more antihypertensive agents be administered. examples for antihypertensive agents are beta blockers such as alprenolol, atenol, Timolol, Pindolol, Propanolol and Metoprolol, ACE (Angiotensin Converting Enzyme) inhibitors such as e.g. Benazepril, captopril, enalapril, fosinopril, Lisinopril, Quinapril and Rampril, calcium channel blockers such as nifedipine, Felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alpha blockers such as doxazosin, urapidil, prazosin and terazosin. You can also refer to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, ed., Mack Publishing Co., Easton, PA, 1995.

It is understood that any suitable Combination of the compounds according to the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active Substances as being within the scope of the present invention is considered falling.

The effectiveness of the connections was tested as follows:

Biological test model:

Testing the anorectic effect was carried out on female NMRI mice. After 24 hours Feed withdrawal was over a pharyngeal tube the test preparation administered. In individual housing and with free access to drinking water the animals were offered condensed milk 30 minutes after the preparation was given. Condensed milk consumption was determined every half hour for 7 hours and observed the general condition of the animals. The measured milk consumption was compared to the vehicle-treated control animals.

Table 1: Anorectic effect, measured as a reduction in the cumulative milk consumption of traded animals compared to control animals

The table shows that the compounds of formula I show a good anorectic effect and are therefore very suitable as anti-obesity.

The examples below and manufacturing methods serve to explain the invention without to limit them.

General procedures

The used in the synthesis Starting materials were supplied by chemical suppliers such as Aldrich, Acros, Sigma, Fluka, Nova Biochem, Advanced Chemtech, Bachem, Lancaster and other companies.

In the synthesis, the functional Groups of the amino acid derivatives used to avoid side reactions during the coupling steps Protected groups protected. examples for suitable protecting groups and their use are in The Peptides, supra, 1981 and in vol. 9, Udenfriend and Meienhofer (ed.) 1987 (incorporated herein by reference).

For the preparation of the compounds according to the invention general methods of solid phase synthesis were used. Such methods are used, for example, by Steward and Young in Solid Phase Peptide Synthesis (Freeman & Co., San Francisco 1969) (incorporated herein by reference).

Unless otherwise stated, the connections with TentaGel HL12019 Resin (Rapp Polymer, Tübingen) synthesized. This commercially available Contains polymer a bromoacetal linker. This type of coupling can be achieved through the Vojkovsky, T. et al., J. Org. Chem. 1998, 63, 3162-3163, and Patek, M., Lecture at Combinatorial Chemistry 2000, London, 11–14. 7th Methods described in 2000 (incorporated herein by reference) can be incorporated into all types of Hydroxy-TentaGel.

In the first synthesis step (general Synthesis scheme, see Scheme 1), amine was exchanged in DMSO of bromine used in the bromoacetal bond at a high temperature. The resulting secondary Amine on the polymer was coupled to Fmoc-protected amino acid. The coupling was done using DIC / HOAt or HATU / DIEA, usually in DMF. The coupling was carried out for 16 hours at room temperature (RT) or 4-5 At 55 ° C for hours carried out. The protection of the Fmoc group was removed with 50% piperidine in DMF (5 + 15 minutes). To determine the substitution, the Amount of Fmoc released from the absorbance of the solution at 302 nm after cancellation the protection, the volume of the washing liquid and the weight of the polymer used in the synthesis according to the description in Krchnak, V. et al., Collect. Czech. Chem. Commun. 53 (1988) 2542 (is incorporated here by reference).

The free amino group of the structure bound to the solid phase was then coupled with Fmoc-beta-alanine (or Fmoc-alpha-amino acid or substituted beta-amino acid). Coupling was done with N, N'-diisopropylcarbodiimide (DIC) in the presence of HOBt, usually in DMF. The completeness of the Kopp lung was monitored by the ninhydrin test.

The removal of the protection of the Fmoc group was performed with 50% piperidine in DMF for 5 + 15 minutes. The Amount of Fmoc released was from the absorbance of the solution 302 nm after removal of the protection, the volume of the washing liquid and the weight of the polymer used in the synthesis.

The free amino group to the Solid phase bound structure was then up to 2 equivalents a suitable sulfonyl chloride / DIEA sulfonylated in DCM or acetonitrile.

Completeness of sulfonylation was monitored by the ninhydrin test.

After completion of the assembly of the precursor of Linear compound on the polymer became the solid phase in turn washed with DMF and DCM or THF and dried in vacuo.

The cyclical spin-off of the targeted Connection was made with formic acid 18-24 For hours at room temperature, for 6 hours at 50 ° C or through Combination of the two conditions. The polymer was filtered off and with DCM or formic acid washed. The washing liquid was introduced into the formic acid solution. The solution was evaporated. The residue was dissolved in a mixture of water and acetonitrile and freeze-dried.

The dried compound was by HPLC with a suitable gradient of 0.1% TFA in water and purified acetonitrile (ACN). After catching the peak, the contains the intended synthetic product, the solution was the Freeze-dried compound. To confirm that the correct compound is synthesized had been linked to a qualitative determination Electrospray mass spectrum (LC / MS) and / or subjected to an NMR analysis.

A HPLC was used for analysis Sample of the connection with the HPLC system from Beckman (existing from the solvent delivery system 126, the programmable detector module 166 and the autosampler 507e and controlled with data station with Gold Nouveau software) a YMC ODS-AM 4.6 × 250 mm column (S-5 (5 μm), YMC, Inc. Wilmington, NC, USA) analyzed at 230 nm. At this A flow rate of 1ml / min and a gradient of water / 0.1% TFA buffer and ACN (HPL quality) as eluent used.

Scheme 1:

The connections can be made in Analogous to the synthesis described on the resin can also be carried out in solution. (Scheme 2). Instead of the functionalized resin, the first Stage 2-bromo-1,1-diethoxy-ethane reacted with a primary amine.

Scheme 2:

The product obtained is reacted with the amino acid analogously to the solid phase synthesis. Instead of the FMOC, the allyloxycarbonyl protective group (Aloc) can be used as the amino protecting group of the amino acid, which is introduced (Aloc-Cl, triethylamine) and split off (Pd (PPh ₃ ) ₄ , dimethylbarbituric acid) using methods known from the literature.

The amino carboxylic acid with the radical R4 is in Presence of triethylamine reacted with the sulfonyl chloride. The free carboxylic acid is by the carbodiimide method (EDC, HOBt) with the free amine, which was obtained by cleavage of the Aloc group.

The acidic cyclization of the thus obtained linear precursor and subsequent further functionalization is ongoing analog, as described above.

To clean the product was a sample of the freeze-dried raw substance in a mixture from 0.1% aqueous TFA with 10-50 % Acetonitrile or in acetic acid solved. The solution the connection became common filtered through a syringe using a 0.45 μm filter ACRODISC 13 CR PTFE (Gehpan Sciences; Ann Arbor, MI, USA) was. A corresponding volume of the filtered solution Compound was in a semi-preparative C 18 pillar (YMC ODS-AM, S-5 (5 μm), 20 × 150 mm, YMC, Inc., Wilmington, NC, USA). The throughput speed a gradient of water / 0.1% TFA buffer and ACN (HPL quality) as eluent was performed using the SYSTEM GOLD HPLC from Beckman (System Gold, programmable solvent module 126 and programmable detector module 166, controlled by SYSTEM GOLD software). The elution of the compound was monitored by UV detection at 230 or 280 nm. After identification of the peak of the compound to be synthesized with LC / MS was the Compound caught, freeze-dried and a biological exam subjected.

After cleaning, connections were made obtained with basic groups as trifluoroacetates. Hydrochloride these compounds can be treated by treating the trifluoroacetate the compound with an excess of HCl / dioxane display easily. After evaporation of the solvents, the hydrochloride was Compound precipitated with diethyl ether and isolated by filtration.

LC / MS was done with PE Sciex API 150EX and Sciex MassChrom software, equipped with a liquid handler Gilson 215, two liquid modules Shimadzu LC-10AD, a Shimadzu SPD-10A detector, a Keystone column Betasil C-18 (2x30 mm, 3 μm, Flow rate of the acetonitrile / water / 0.1% TFA gradient 0.7 ml / min) in ES + mode.

In the NMR analysis, the samples were measured in DMSO-d ₆ (Aldrich) with an Avance DPX 300 from Bruker.

Abbreviations

Unless otherwise stated, the abbreviations used in the examples below have the following meanings:
ACN = acetonitrile
Aloc = allyloxycarbonyl
DIC = diisopropylcarbodiimide
EDC =
FMOC = 9-fluorenylmethyloxycarbonyl
DCE = 1,2-dichloroethart
DIEA = diisopropylethylamine
NaBH ₃ CN = sodium cyanoborohydride
DMAP = N, N'-dimethylaminopyridine
DMF = N, N-dimethylformamide
THF = tetrahydrofuran
DIC = diisoporpylcarbodiimide
DMSO = dimethyl sulfoxide
DCM = dichloromethane (also known as methylene chloride)
HOBt = 1-hydroxybenzotriazole
HOAt = 1-hydroxy-7-azabenzotriazole
HATU = dimethylamino - ([1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene dimethylammonium hexafluorophosphate
HOAc = acetic acid
Et3N = triethylamine
HCl = hydrochloric acid
HBr = hydrobromic acid
HPLC = high performance liquid chromatography

The following examples serve to the closer explanation of the invention without the same as described in the examples Products and designs limit.

Example 1 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

0.5 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution (Reagent 1) in DMSO was added and the mixture was left for 15 hours long at 60 ° C stored in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) -4-chlorophenylalanine (Reagent 2) (3 equivalents) was awarded HOAt (3 equivalents) and DIC (3 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was over Let stand at room temperature overnight. The polymer was 6 times washed with DMF. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes). Fmoc-beta-alanine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was washed 5 times with DMF and 4 times with DCM and with a solution of 1.5 equivalents of 2,4-dichlorobenzenesulfonyl chloride (Reagent 3) and 3 equivalents of DIEA in acetonitrile (final concentration tion: 0.1-0.15 M) and reacted at room temperature for 5 hours. It was then washed 5 times with DMF and 5 times with DCM and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 543.06 (calculated, monoisotopic); measured value (M + H) ⁺ : 544.3.

Example 2 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

0.3 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution (Reagent 1) in DMSO was added and the mixture was left for 15 hours long at 60 ° C stored in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) -4-chlorophenylalanine (Reagent 2) (3 equivalents) was awarded with HATU (3 equivalents) and DIEA (9 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was left at 55 ° C for 4 hours. The polymer was Washed 6 times with DMF. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes). Fmoc-beta-alanine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2-methoxy-4-chlorobenzenesulfonyl chloride (Reagent 3) and 3 equivalents DIEA in acetonitrile (final concentration: 0.1-0.15 M) and at room temperature Implemented for 5 hours. Then it was 5 times with DMF and washed 5 times with THF and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 539.10 (calculated, monoisotopic); measured value (M + H) ⁺ : 540.3.

Example 3 6-Benzyl-1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

0.3 g of TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp Polymer, Tübingen) was washed with DMSO. 20 equivalents of 2M isopropylamine solution in DMSO were added and the mixture was kept in a closed vessel at 60 ° C for 15 hours. The polymer was washed 7 times with DMF. Fmoc- (S) -4-phenylalanine (3 equivalents) was treated with HATU (3 equivalents) and DIEA (9 equivalents valente) in DMF coupled to the secondary amine on the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was left at 55 ° C for 4 hours. The polymer was washed 6 times with DMF. The Fmoc protecting group was removed with 50% piperidine in DMF (5 + 15 minutes).

Fmoc-beta-alanine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2-methoxy-4-chlorobenzenesulfonyl chloride and 3 equivalents of DIEA in acetonitrile (Final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was washed 5 times with DMF and 5 times with THF and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 505.14 (calculated, monoisotopic); measured value (M + H) ⁺ : 506.3.

Example 4 1- (5-Chloro-2-methoxy-benzenesulfonyl) -6- (3,4-dichloro-benzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

0.3 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) -3,4-dichlorophenylalanine (3 equivalents) was awarded with HATU (3 equivalents) and DIEA (9 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was left at 55 ° C for 4 hours. The polymer was Washed 6 times with DMF. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

Fmoc-beta-alanine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2-methoxy-4-chlorobenzenesulfonyl chloride, 3 equivalents of DIEA in acetonitrile (Final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was washed 5 times with DMF and 5 times with THF and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 573.07 (calculated, monoisotopic); measured value (M + H) ⁺ : 574.3.

Example 5 8-Allyl-1- (naphthalenes-2-sulfonyl) -6- (4-nitro-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

0.3 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M allylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF.

Fmoc- (S) - 4-nitrophenylalanine (3 equivalents) was awarded with HATU (3 equivalents) and DIEA (9 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. Das The reaction mixture was left at 55 ° C for 4 hours. The polymer was Washed 6 times with DMF. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

Fmoc-beta-alanine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2-naphthylsulfonyl chloride and 3 equivalents DIEA in acetonitrile (final concentration: 0.1-0.15 M) and at room temperature Implemented for 5 hours. Then it was 5 times with DMF and washed 5 times with THF and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 534.16 (calculated, monoisotopic); measured value (M + H) ⁺ : 535.3.

Example 6 3-Amino-6- (4-chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7- dion structure:

0.35 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) -4-chlorophenylalanine (3 equivalents) was awarded HOAt (3 equivalents) and DIC (3 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was over Let stand at room temperature overnight. The polymer was used 6 times DMF washed. The Fmoc protecting group was treated with 50% piperidine Split off DMF (5 + 15 minutes). Z- (S) -Dap (Fmoc) (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2-methoxy-5-chlorobenzenesulfonyl chloride and 3 equivalents of DIEA in DCM (final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was it was washed 5 times with DMF and 5 times with DCM and dried in vacuo.

For cyclative cleavage, 10 ml of formic acid were added to the dry polymer, shaken at room temperature for 16 hours and at 50-55 ° C. for 6 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The residue was treated with 5 ml 37% HBr / HOAc at room temperature for 2 hours and evaporated in vacuo. The hydrobromide of the product was precipitated by adding diethyl ether and filtered off. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 554.12 (calculated, monoisotopic); measured value (M + H) ⁺ : 555.3.

Example 7 3-Amino-6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

0.7 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF.

Fmoc- (S) -4-chlorophenylalanine (3 equivalents) was awarded HOAt (3 equivalents) and DIC (3 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was over Let stand at room temperature overnight. The polymer was 6 times washed with DMF. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes). Z- (S) -Dap (Fmoc) (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2,4-dichlorobenzenesulfonyl chloride and 3 equivalents DIEA in DCM (final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was it was washed 5 times with DMF and 5 times with DCM and dried in vacuo.

For cyclical cleavage, 15 ml of formic acid were added to the dry polymer, shaken at room temperature for 16 hours and at 50-55 ° C. for 6 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The residue was treated with 10 ml 37% HBr / HOAc at room temperature for 2 hours and evaporated in vacuo. The hydrobromide of the product was precipitated by adding diethyl ether and filtered off. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 558.07 (calculated, monoisotopic); measured value (M + H) ⁺ : 559.3.

Example 8 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -3-hydroxy-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7- dion structure:

0.5 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) - 4-chlorophenylalanine (3 equivalents) was awarded HOAt (3 equivalents) and DIC (3 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was over Let stand at room temperature overnight. The polymer was used 6 times DMF washed. The Fmoc protecting group was treated with 50% piperidine Split off DMF (5 + 15 minutes). Fmoc- (R, S) -isoserine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with DCM and with a solution of 1.5 equivalents 2-methoxy-5-chlorobenzenesulfonyl chloride and 3 equivalents of DIEA in DCM (final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was it was washed 5 times with DMF and 5 times with DCM and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The two title diastereoisomers were separated by HPLC after purification. The system and process described under "General Methods" were used. MG = 555.10 (calculated, monoisotopic); measured value (M + H) ⁺ : 556.3 (both diastereoisomers).

Example 9 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -3-diethylamino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7- dion structure:

50 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2-methoxy-5-chlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine- 4,7-dione hydrochloride (Example 6) was dissolved in 3 ml of methanol and mixed with 100 ul acetic acid. 100 μl of acetaldehyde and 1 ml of 1M sodium cyanoborohydride solution in THF were added to this solution. After 2 hours the reaction mixture was evaporated, suspended in 5% Et ₃ N in ethyl acetate and filtered through a small silica gel column. The eluent was evaporated and the crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 610.18 (calculated, monoisotopic); measured value (M + H) ⁺ : 611.4.

Example 10 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-3-isopropylamino-hexahydro-pyrazino [1,2-a] pyrimidine-4,7- dion structure:

50 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2-methoxy-5-chlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine- 4,7-dione (Example 6) were dissolved in 5 ml of methanol and mixed with 200 ul acetic acid. 400 μl of acetone and 1 ml of 1M sodium cyanoborohydride solution in THF were added to this solution. After 3 hours the reaction mixture was evaporated, suspended in 5% Et ₃ N in ethyl acetate and filtered through a small column of silica gel. The eluent was evaporated and the crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 596.16 (calculated, monoisotopic); measured value (M + H) ⁺ : 597.3.

Example 11 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-dimethylamino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

200 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) was dissolved in 15 ml of methanol and mixed with 600 ul acetic acid. 0.5 ml of 37% aqueous formaldehyde and 3 ml of 1M sodium cyanoborohydride solution in THF were added to this solution. After 2 hours the reaction mixture was evaporated, suspended in 5% Et ₃ N in ethyl acetate and filtered through a small silica gel column. The eluent was evaporated and the crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 586.10 (calculated, monoisotopic); measured value (M + H) ⁺ : 587.3.

Example 12 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-3-pyrrol-1-yl-hexahydropyrazino [1,2-a] pyrimidine-4, 7-dione structure:

64 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) was suspended in 1 ml of water and 1 ml of DCE was added. This mixture was mixed with 2 equivalents of 2,5-dimethoxytetrahydrofuran and stirred at 80 ° C for 1 hour. The DCE phase was removed and the aqueous phase was extracted twice with DCE. The combined extracts were evaporated and the crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 608.08 (calculated, monoisotopic); measured value (M + H) ⁺ : 609.4.

Example 13 3-Azetidin-1-yl-6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione structure:

32 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) was suspended in 1 ml of water and 2 ml of 1-butanol were added. 1 mmol of potassium carbonate and 200 μl of 1,3-dibromopropane were added to this mixture. The reaction mixture was stirred at 90 ° C for 16 hours and evaporated. The residue was suspended in 5% Et ₃ N / ethyl acetate, filtered and evaporated. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 598.10 (calculated, monoisotopic); measured value (M + H) ⁺ : 599.3.

Example 14 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-3-pyrrolidin-1-yl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione structure:

32 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) was suspended in 1 ml of water and 2 ml of 1-butanol were added. To this mixture was added 1 mmol of potassium carbonate and 200 ul of 1,4-dibromobutane. The reaction mixture was stirred at 90 ° C for 16 hours and evaporated. The residue was suspended in 5% Et ₃ N / ethyl acetate, filtered and evaporated. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 612.11 (calculated, monoisotopic); measured value (M + H) ⁺ : 613.4.

Example 15 N- [6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidine-3 -yl] methanesulfonamide structure:

64 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) was dissolved in 3 ml of DCM. 0.5 mmol of triethylamine and 1.5 equivalents of methanesulfonyl chloride were added to the solution. After 2 hours, 0.5 ml of dimethylamine in THF was added and the solvents were evaporated in vacuo. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 636.04 (calculated, monoisotopic); measured value (M + H) ⁺ : 637.4.

Example 16 5- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -7-isopropyl-tetrahydro-imidazo [1,2-a] pyrazine-3,6-dione Structure:

0.3 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) - 4-chlorophenylalanine (3 equivalents) was awarded HOAt (3 equivalents) and DIC (3 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was over Let stand at room temperature overnight. The polymer was used 6 times DMF washed. The Fmoc protecting group was treated with 50% piperidine Split off DMF (5 + 15 minutes). Fmoc-glycine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with acetonitrile and with a solution of 1.5 equivalents 2-methoxy-4-chlorobenzenesulfonyl chloride and 3 equivalents of DIEA in acetonitrile (Final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was it was washed 5 times with DMF and 5 times with DCM and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 24 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 525.09 (calculated, monoisotopic); measured value (M + H) ⁺ : 526.3.

Example 17 5- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -7-isopropyl-2-methyl-tetrahydro-imidazo [1,2-a] pyrazine-3,6- dion structure:

0.3 g TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol / g, Rapp polymers, Tübingen) were washed with DMSO. 20 equivalents 2M isopropylamine solution in DMSO were added and the mixture was stirred for 15 hours 60 ° C in kept in a closed container. The polymer was washed 7 times with DMF. Fmoc- (S) - 4-chlorophenylalanine (3 equivalents) was awarded HOAt (3 equivalents) and DIC (3 equivalents) in DMF to the secondary Amine coupled to the polymer. The final concentration was 0.2-0.3 M. The reaction mixture was over Let stand at room temperature overnight. The polymer was used 6 times DMF washed. The Fmoc protecting group was treated with 50% piperidine Split off DMF (5 + 15 minutes).

Fmoc- (R) alanine (3 equivalents) was then awarded HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: approx. 0.2 M) over a period of at least 4 hours docked. The Fmoc protecting group was treated with 50% piperidine split off in DMF (5 + 15 minutes).

The polymer was treated 5 times with DMF and Washed 4 times with acetonitrile and with a solution of 1.5 equivalents 2-methoxy-4-chlorobenzenesulfonyl chloride and 3 equivalents of DIEA in acetonitrile (Final concentration: 0.1-0.15 M) added and reacted at room temperature for 5 hours. Then was it was washed 5 times with DMF and 5 times with DCM and dried in vacuo.

For cyclical cleavage, 10 ml of formic acid were added to the dry polymer and shaken at room temperature for 24 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze-dried. The pure title compound was separated off by HPLC purification. The system and method described under "General Methods" were used. MG = 539.10 (calculated, monoisotopic); measured value (M + H) ⁺ : 540.3.

Example 18 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -3-dimethylamino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7- dion structure:

The compound in Example 18 was prepared according to the procedure described in Example 11, starting from (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2-methoxy-5-chlorobenzenesulfonyl) -3-amino-8- Isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione (Example 6), synthesized.
MG = 582.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 583.3.

Example 19 3- (Bis-cyclopropylmethylamino) -6- (4-chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure:

The compound in Example 19 was synthesized according to the procedure described in Example 9 using 10 equivalents of cyclopropanecarboxaldehyde.
MG = 662.21 (calculated, monoisotopic); Measured value (M + H) ⁺ : 663.4.

Example 20 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-isobutylamino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

The compound in Example 20 was synthesized according to the procedure described in Example 11 using 4 equivalents of isobutyraldehyde.
MG = 614.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 615.4.

Example 21 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-diisobutylamino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

The compound in Example 21 was synthesized according to the procedure described in Example 11 using 20 equivalents of isobutyraldehyde.
MG = 670.19 (calculated, monoisotopic); Measured value (M + H) ⁺ : 671.3.

Example 22 6- (4-Chlorobenzyl) -3- (cyclopropylmethylamino) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione structure:

The compound in Example 22 was used according to the procedure described in Example 11 Synthesis of 5 equivalents of cyclopropylcarboxaldehyde.
MG = 612.11 (calculated, monoisotopic); Measured value (M + H) ⁺ : 613.4.

Example 23 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-diethylamino-8-isopropylhexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 23 was prepared according to the procedure described in Example 9, starting from (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl- hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione (Example 7) was synthesized.
MG = 614.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 615.3.

Example 24 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-3-isopropylamino-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

The compound in Example 24 was prepared according to the procedure described in Example 10, starting from (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl- hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione (Example 7).
MG = 600.11 (calculated, monoisotopic); Measured value (M + H) ⁺ : 601.3.

Example 25 6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-3- (isopropyl-methylamino) -hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione structure:

The compound in Example 25 was prepared using the procedure described in Example 11 starting from (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-3-isopropylamino- hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione (Example 24).
MG = 614.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 615.4.

Example 26 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-3-pyrrolidin-1-yl-hexahydro-pyrazino [1,2-a] pyrimidine- 4,7-dione structure:

The compound in Example 26 was prepared according to the procedure described in Example 14, starting from (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2-methoxy-5-chlorobenzenesulfonyl) -3-amino-8- Isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione (Example 6), synthesized.
MG = 608.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 609.4.

Example 27 {4- [6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-4,7-dioxooctahydropyrazino [1,2-a] pyrimidine-3- ylamino] -butyl} -triethyl-ammonium structure:

32 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) in 1 ml dichloroethane was treated with 200 μl triethylamine and 100 μl 1,4-dibromobutane. The reaction mixture was kept at 60 ° C for 60 hours. The precipitate was filtered off and the filtrate was evaporated in vacuo. The pure title compound trifluoroacetate was separated off by HPLC after cleaning the filter residue. The system and procedure described under "General Procedures" were used.
MG = 714.24 (calculated, monoisotopic); Measured value (M + H) ⁺ : 714.4.

Example 28 {3- [6- (4-Chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidine- 3-ylamino] -propyl} -triethyl-ammonium structure:

32 mg (3S, 6S, 9aS) -6- (4-chlorobenzyl) -1- (2,4-dichlorobenzenesulfonyl) -3-amino-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione hydrobromide (Example 7) in 1 ml dichloroethane were treated with 200 μl triethylamine and 100 μl 1,3-dibromopropane. The reaction mixture was kept at 60 ° C for 60 hours. The precipitate was filtered off and the filtrate was evaporated in vacuo. The pure title compound trifluoroacetate was separated off by HPLC after cleaning the filter residue. The system and procedure described under "General Procedures" were used.
MG = 700.23 (calculated, monoisotopic); Measured value (M + H) ⁺ : 700.4.

Example 29 1- (5-Chloro-2-methoxy-benzenesulfonyl) -6-cyclohexylmethyl-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 29 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-cyclohexylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 511.19 (calculated, monoisotopic); Measured value (M + H) ⁺ : 512.3.

Example 30 1- (5-Chloro-2-methoxy-benzenesulfonyl) -6-cyclohexyl-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 30 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-cyclohexylglycine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 497.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 498.3.

Example 31 1- (5-Chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-6-phenethyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 31 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-homophenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 519.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 520.3.

Example 32 1- (5-Chloro-2-methoxy-benzenesulfonyl) -6-indan-1-yl-8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 32 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-indanylglycine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 531.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 532.3.

Example 33 1- (5-Chloro-2-methoxy-benzenesulfonyl) -6- [2- (4-hydroxyphenyl) ethyl] -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4, 7-dione structure:

The compound in Example 33 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc homotyrosine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 535.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 536.3.

Example 34 8-Isopropyl-6- (4-methoxy-benzyl) -1- (2-methoxy-5-methyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 34 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-O-methyltyrosine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 515.21 (calculated, monoisotopic); Measured value (M + H) ⁺ : 516.3.

Example 35 6- (4-Fluoro-benzyl) -8-isopropyl-1- (2-methoxy-5-methyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 35 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-fluorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 503.19 (calculated, monoisotopic); Measured value (M + H) ⁺ : 504.3.

Example 36 8-Isopropyl-1- (2-methoxy-5-methyl-benzenesulfonyl) -6- (4-methyl-benzyl) -hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 36 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-methylphenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 499.21 (calculated, monoisotopic); Measured value (M + H) ⁺ : 500.3.

Example 37 6- (4-Bromo-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 37 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-bromophenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 583.05 (calculated, monoisotopic); Measured value (M + H) ⁺ : 584.3.

Example 38 1- (5-Chloro-2-methoxy-benzenesulfonyl) -6- (4-fluoro-benzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 38 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-fluorophenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 523.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 524.3.

Example 39 1- (5-Chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-6- (4-methyl-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 39 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-methylphenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonylchloride
MG = 519.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 520.3.

Example 40 1- (4-Bromo-2-ethyl-benzenesulfonyl) -8-isopropyl-6- (4-methoxy-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 40 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-O-methyltyrosine
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 577.12 (calculated, monoisotopic); Measured value (M + H) ⁺ : 578.3.

Example 41 6- (4-Bromo-benzyl) -1- (4-bromo-2-ethyl-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 41 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-bromophenylalanine
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 625.02 (calculated, monoisotopic); Measured value (M + H) ⁺ : 626.4.

Example 42 1- (4-Bromo-2-ethyl-benzenesulfonyl) -6- (4-fluoro-benzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 42 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-fluorophenylalanine
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 565.10 (calculated, monoisotopic); Measured value (M + H) ⁺ : 566.3.

Example 43 1- (4-Bromo-2-ethylbenzenesulfonyl) -8-isopropyl-6- (4-methyl-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 43 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-methylphenylalanine
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 561.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 562.3.

Example 44 8-Isopropyl-6- (4-methoxy-benzyl) -1- (3-trifluoromethyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 44 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-O-methyltyrosine
Reagent 3: 3-trifluoromethylbenzene sulfonyl chloride
MG = 539.17 (calculated, monoisotopic); Measured value (M + H) ⁺ : 540.3.

Example 45 6- (4-Bromo-benzyl) -8-isopropyl-1- (3-trifluoromethyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 45 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-bromophenylalanine
Reagent 3: 3-trifluoromethylbenzene sulfonyl chloride
MG = 587.07 (calculated, monoisotopic); Measured value (M + H) ⁺ : 588.3.

Example 46 6- (4-Fluoro-benzyl) -8-isopropyl-1- (3-trifluoromethyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 46 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-fluorophenylalanine
Reagent 3: 3-trifluoromethylbenzene sulfonyl chloride
MG = 527.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 528.3.

Example 47 8-isopropyl-6- (4-methyl-benzyl) -1- (3-trifluoromethyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 47 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-methylphenylalanine
Reagent 3: 3-trifluoromethylbenzene sulfonyl chloride
MG = 523.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 524.3.

Example 48 1- (2,5-Dimethyl-benzenesulfonyl) -8-isopropyl-6- (4-methoxy-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 48 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-O-methyltyrosine
Reagent 3: 2,5-dimethylbenzene sulfonyl chloride
MG = 499.21 (calculated, monoisotopic); Measured value (M + H) ⁺ : 500.3.

Example 49 6- (4-Bromo-benzyl) -1- (2,5-dimethyl-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 49 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Frnoc-4-bromophenylalanine
Reagent 3: 2,5-dimethylbenzene sulfonyl chloride
MG = 547.11 (calculated, monoisotopic); Measured value (M + H) ⁺ : 548.3.

Example 50 1- (2,5-Dimethyl-benzenesulfonyl) -6- (4-fluoro-benzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 50 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-fluorophenylalanine
Reagent 3: 2,5-dimethylbenzene sulfonyl chloride
MG = 487.19 (calculated, monoisotopic); Measured value (M + H) ⁺ : 488.3.

Example 51 1- (2,5-Dimethyl-benzenesulfonyl) -8-isopropyl-6- (4-methyl-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 51 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-methylphenylalanine
Reagent 3: 2,5-dimethylbenzene sulfonyl chloride
MG = 483.22 (calculated, monoisotopic); Measured value (M + H) ⁺ : 484.3.

Example 52 6- (4-Chloro-benzyl) -1- (4-chloro-2,5-dimethyl-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

The compound in Example 52 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2,5-dimethyl-4-chlorobenzene sulfonyl chloride
MG = 537.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 538.3.

Example 53 6- (4-Chlorobenzyl) -8-isopropyl-1- (2-nitro-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 53 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-nitrobenzene sulfonyl chloride
MG = 520.12 (calculated, monoisotopic); Measured value (M + H) ⁺ : 521.3.

Example 54 6- (4-Chloro-benzyl) -1- (2,4-dichloro-5-methyl-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

The compound in Example 54 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2,4-dichloro-5-methylbenzene sulfonyl chloride
MG = 557.07 (calculated, monoisotopic); Measured value (M + H) ⁺ : 558.3.

Example 55 6- (4-Chloro-benzyl) -1- (2-chloro-4-trifluoromethyl-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure:

The compound in Example 55 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-chloro-4-trifluoromethylbenzene sulfonyl chloride
MG = 557.08 (calculated, monoisotopic); Measured value (M + H) ⁺ : 578.3.

Example 56 6- (4-Chlorobenzyl) -8-isopropyl-1- (2-methyl-5-nitro-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 56 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methyl-5-nitrobenzene sulfonyl chloride
MG = 534.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 535.3.

Example 57 1- (4-Bromo-2-trifluoromethoxy-benzenesulfonyl) -6- (4-chlorobenzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 57 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-trifluoromethoxy-4-bromobenzene sulfonyl chloride
MG = 637.03 (calculated, monoisotopic); Measured value (M + H) ⁺ : 638.4.

Example 58 6- (1-Benzyl-1H-imidazol-4-ylmethyl) -1- (4-bromo-2-ethyl-benzenesulfonyl) -8- (2-pyridin-4-yl-ethyl) -hexahydro-pyrazino [ 1,2-a] pyrimidine-4,7-dione structure:

The compound in Example 58 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: 2- (4-pyridyl) ethylamine
Reagent 2: Fmoc-histidine (benzyl)
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 690.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 691.4.

Example 59 1- (5-Chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-6- (4-nitro-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 59 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-nitrophenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 550.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 551.3.

Example 60 6- (4-Chlorobenzyl) -8-isopropyl-1- (naphthalenes-2-sulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 60 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-naphthyl sulfonyl chloride
MG = 525.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 526.3.

Example 61 6- (3,4-dichlorobenzyl) -8-isopropyl-1- (naphthalenes-2-sulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 61 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-3,4-dichlorophenylalanine
Reagent 3: 2-naphthyl sulfonyl chloride
MG = 559.11 (calculated, monoisotopic); Measured value (M + H) ⁺ : 560.3.

Example 62 6- (3,4-dichlorobenzyl) -1- (3,4-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 62 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-3,4-dichlorophenylalanine
Reagent 3: 3,4-dimethoxybenzene sulfonyl chloride
MG = 569.12 (calculated, monoisotopic); Measured value (M + H) ⁺ : 570.3.

Example 63 8-Allyl-1- (4-bromo-2-ethylbenzenesulfonyl) -6- (4-chloro-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 63 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: allylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 579.06 (calculated, monoisotopic); Measured value (M + H) ⁺ : 580.3.

Example 64 8-Allyl-1- (4-bromo-2-ethyl-benzenesulfonyl) -6- (4-nitro-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 64 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: allylamine
Reagent 2: Fmoc-4-nitrophenylalanine
Reagent 3: 2-ethyl-4-bromobenzene sulfonyl chloride
MG = 590.08 (calculated, monoisotopic); Measured value (M + H) ⁺ : 591.3.

Example 65 8-Allyl-1- (5-chloro-2-methoxy-benzenesulfonyl) -6- (3,4-dichloro-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure :

The compound in Example 65 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: allylamine
Reagent 2: Fmoc-3,4-dichlorophenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 571.05 (calculated, monoisotopic); Measured value (M + H) ⁺ : 572.3.

Example 66 8-Allyl-1- (naphthalenes-2-sulfonyl) -6- (4-nitro-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 66 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: allylamine
Reagent 2: Fmoc-4-nitrophenylalanine
Reagent 3: 2-naphthyl sulfonyl chloride
MG = 534.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 535.3.

Example 67 1- (5-Chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-6-pyridin-4-ylmethyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 97 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-pyridylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 506.14 (calculated, monoisotopic); Measured value (M + H) ⁺ : 507.3.

Example 68 1- (5-Bromo-2-methoxy-benzenesulfonyl) -6- (4-chloro-benzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 68 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-bromobenzene sulfonyl chloride
MG = 583.05 (calculated, monoisotopic); Measured value (M + H) ⁺ : 584.3.

Example 69 6- (4-Chlorobenzyl) -8-isopropyl-1- (2-methoxy-5-methylbenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 69 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 519.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 520.3.

Example 70 6- (4-Chlorobenzyl) -8-isopropyl-1- (2-trifluoromethoxy-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 70 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-trifluoromethoxy benzene sulfonyl chloride
MG = 559.12 (calculated, monoisotopic); Measured value (M + H) ⁺ : 560.3.

Example 71 6- (4-Chlorobenzyl) -8-isopropyl-1- (2-methanesulfonyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 71 was used according to the procedure described in Example 2 The following reagents are synthesized:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methylsulfonyl-benzene-sulfonyl chloride
MG = 553.11 (calculated, monoisotopic); Measured value (M + H) ⁺ : 554.3.

Example 72 3- [6- (4-Chlorobenzyl) -8-isopropyl-4,7-dioxo-hexahydro-pyrazino 1,2-a] pyrimidine-1-sulfonyl] benzonitrile Structure:

The compound in Example 72 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 3-cyanobenzene sulfonyl chloride
MG = 500.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 501.3.

Example 73 6- (4-Chlorobenzyl) -8-isopropyl-1- (3-trifluoromethyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 73 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 3-trifluoromethylbenzene sulfonyl chloride
MG = 543.12 (calculated, monoisotopic); Measured value (M + H) ⁺ : 544.3.

Example 74 6- (4-Chlorobenzyl) -8-isopropyl-1- (2,4,6-trichlorobenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 74 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2,4,6-trichlorobenzene sulfonyl chloride
MG = 577.02 (calculated, monoisotopic); Measured value (M + H) ⁺ : 578.3.

Example 75 6- (4-Chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 75 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2,5-dimethoxybenzene sulfonyl chloride
MG = 535.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 536.3.

Example 76 6- (4-Chlorobenzyl) -1- (2,5-dichlorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 76 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2,5-dichlorobenzene sulfonyl chloride
MG = 543.06 (calculated, monoisotopic); Measured value (M + H) ⁺ : 544.3.

Example 77 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxooctahydro-pyrazino [1,2-a] pyrimidine-2-carboxylic acid allylester structure :

The compound in Example 77 was synthesized according to the procedure described in Example 1 using the reagents listed below and with the following modifications:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
After this step and after the removal of the Fmoc protection, the coupling of Fmoc-beta-alanine from the process in Example 1 was replaced by an Fmoc-Asp (OH) -O-allyl coupling under the same conditions. After removal of the Fmoc protection, the synthesis was continued according to the procedure for Example 1 with Reagent 3. Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 623.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 624.4.

Example 78 1- (5-Chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-6- (4-methoxy-benzyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 78 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-O-methyltyrosine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 535.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 536.3.

Example 79 2- (4-Amino-butyl) -6- (4-chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione structure:

The compound in Example 79 was synthesized according to the procedure described in Example 1 using the reagents listed below and with the following modifications:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
After this step and after the removal of the Fmoc protection, the coupling of Fmoc-beta-alanine from the process in Example 1 was replaced by an Fmoc-beta-homolysin (Boc) coupling under the same conditions. After removal of the Fmoc protection, the synthesis was continued according to the procedure for example 1 with reagent 3.
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 610.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 611.4.

Example 80 6- (4-Chlorobenzyl) -8-ethyl-1- (2-methoxy-5-methylbenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 80 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: ethylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 505.14 (calculated, monoisotopic); Measured value (M + H) ⁺ : 506.3.

Example 81 6- (4-Chlorobenzyl) -1- (2-methoxy-5-methyl-benzenesulfonyl) -8-methyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 81 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: methylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylberizole sulfonyl chloride
MG = 491.13 (calculated, monoisotopic); Measured value (M + H) ⁺ : 492.3.

Example 82 6- (4-Chloro-benzyl) -8-isobutyl-l- (2-methoxy-5-methyl-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 82 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isobutylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 533.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 534.3.

Example 83 6- (4-Chlorobenzyl) -8-isobutyl-1- (2-methoxy-5-methylbenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 83 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: 2-butylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 533.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 534.3.

Example 84 1- (5-Chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-6-pyridin-3-ylmethyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 96 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-3-pyridylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 506.14 (calculated, monoisotopic); Measured value (M + H) ⁺ : 507.3.

Example 85 6- (4-chlorobenzyl) -8-cyclopropyl-1- (2-methoxy-5-methylbenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 85 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: cyclopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 517.14 (calculated, monoisotopic); Measured value (M + H) ⁺ : 518.3.

Example 86 6- (4-Chlorobenzyl) -8-cyclopentyl-1- (2-methoxy-5-methylbenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 86 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: cyclopentylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 545.18 (calculated, monoisotopic); Measured value (M + H) ⁺ : 546.3.

Example 87 6- (4-Chlorobenzyl) -1- (2-methoxy-5-methyl-benzenesulfonyl) -8-propyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 87 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: n-propylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 519.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 520.3.

Example 88 8-Allyl-6- (4-chlorobenzyl) -1- (2-methoxy-5-methylbenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 88 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: allylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-methylbenzene sulfonyl chloride
MG = 517.14 (calculated, monoisotopic); Measured value (M + H) ⁺ : 518.2.

Example 89 1- (5-Bromo-2-methoxy-benzenesulfonyl) -6- (4-chloro-benzyl) -8-ethyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 89 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: ethylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-bromobenzene sulfonyl chloride
MG = 569.04 (calculated, monoisotopic); Measured value (M + H) ⁺ : 570.3.

Example 90 6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-ethyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 90 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: ethylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-5-chlorobenzene sulfonyl chloride
MG = 525.09 (calculated, monoisotopic); Measured value (M + H) ⁺ : 526.3.

Example 91 1- (4-Bromo-2-ethyl-benzenesulfonyl) -6- (4-chloro-benzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 91 was synthesized according to the procedure described in Example 2 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-ethyl-5-bromobenzene sulfonyl chloride
MG = 581.08 (calculated, monoisotopic); Measured value (M + H) ⁺ : 582.3.

Example 92 6- (4-Chlorobenzyl) -1- (2,5-dimethyl-benzenesulfonyl) -8-ethyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 92 was used according to the procedure described in Example 2 The following reagents are synthesized:
Reagent 1: ethylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2,5-dimethylbenzene sulfonyl chloride
MG = 489.15 (calculated, monoisotopic); Measured value (M + H) ⁺ : 490.3.

Example 93 2-Chloro-5- [6- (4-chloro-benzyl) -8-isopropyl-4,7-dioxo-hexahydro-pyrazino [1,2-a] pyrimidine-1-sulfonyl] -benzenesulfonamide Structure:

The compound in Example 93 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-sulfonylamido-4-chlorobenzene sulfonyl chloride
MG = 588.07 (calculated, monoisotopic); Measured value (M + H) ⁺ : 589.3.

Example 94 6- (4-Chlorobenzyl) -1- (2,4-dichloro-6-methylbenzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 94 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methyl-4,6-dichlorobenzene sulfonyl chloride
MG = 557.08 (calculated, monoisotopic); Measured value (M + H) ⁺ : 558.3.

Example 95 6- (4-Chlorobenzyl) -8-isopropyl-1- (2-methoxy-4-methylbenzenesulfonyl) hexahydropyrazino [1,2-a] pyrimidine-4,7-dione Structure:

The compound in Example 95 was synthesized according to the procedure described in Example 1 using the following reagents:
Reagent 1: isopropylamine
Reagent 2: Fmoc-4-chlorophenylalanine
Reagent 3: 2-methoxy-4-methylbenzene sulfonyl chloride
MG = 519.16 (calculated, monoisotopic); Measured value (M + H) ⁺ : 520.3.

Example 96 N- [6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxooctahydro-pyrazino [1,2-a] pyrimidine-3 -yl] -acetamide structure:

a) 2-Allyloxycarbonylamino-3- (4-chlorophenyl) propionic acid

Starting from 10 g of 4-chlorophenylalanine and 8 ml of chloroformic acid allyl ester, the product is obtained in accordance with literature regulations (ET3N, methanol).
MG = 283.71 (calculated); Measured value (M + H) ⁺ : 284.1.

 b) {2- (4-Chlorophenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -carbamic acid allyl ester

7.8 ml of DIC are added dropwise to a solution of 5.7 g of 2-allyloxycarbonylamino-3- (4-chlorophenyl) propionic acid, 3.5 g of (2,2-diethoxy-ethyl) isopropylamine, 6.8 g of HOAt in 30 ml of DMF and stirred for 12 hours. The reaction solution is concentrated under reduced pressure and purified by flash chromatography on silica gel with the eluent ethyl acetate / n-heptane = 1/3. The desired product with MG = 440.97 (calculated) is obtained; Measured value (M + H) ⁺ : 441.15

c) 2-Amino-3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-propionamide

To a solution of 13.2 g of {2- (4-chloro-phenyl) -1 - [(2,2-diethoxy-ethyl) -isopropylcarbamoyl] -ethyl} -carbamic acid allyl ester, 18.9 g of dimethylbarbituric acid in 140 ml of methylene chloride is added Argon protective gas atmosphere 10 mg of palladium tetrakistriphenylphosphine and stirred for 12 h. The reaction solution is concentrated under reduced pressure and by flash chromatography on silica gel (eluent methylene chloride, 1% Et3N, 0-10% methanol). The desired product with MG = 356.90 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 311.10

d) 2-Benzyloxycarbonylamino-3- (5-chloro-2-methoxy-benzenesulfonylamino) propionic acid

A solution of 3.8 g of 5-chloro-2-methoxybenzenesulfonyl chloride in 5 ml of dioxane is added dropwise to a solution of 2.3 g of 3-amino-2-benzyloxycarbonylamino-propionic acid in 20 ml of 1N NaOH solution. The mixture is stirred for 12 hours under pH control (pH> 7), the pH is lowered below 7 by adding citric acid and the reaction solution is then extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated under reduced pressure and used in the next reaction step without further purification.
Product with MG = 442.88 (calculated); Measured value (M + H) ⁺ : 442.95

e) (2- (5-Chloro-2-methoxy-benzenesulfonylamino) -1- {2- (4-chloro-phenyl) -1 - [(2,2-diethoxyethyl) isopropylcarbamoyl] ethyl carbamoyl} ethyl) -carbamic acid benzyl ester

52 mg EDC, 45 mg HOBt and 100 μl N-ethylmorpholine are added to a solution of 124 mg 2-benzyloxycarbonylamino-3- (5-chloro-2-methoxybenzenesulfonylamino) propionic acid in 1 ml DMF. A solution of 100 mg of 2-amino-3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-propiona is added dropwise mid in 1 ml DMF and let stir for 12 h. The reaction solution is filtered, ethyl acetate is added and the mixture is then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. After drying the organic phase with Chromabond XTR, the mixture is concentrated under reduced pressure and the residue is purified by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90 ) Cut.
The desired product with MG = 781.76 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 735.1

f) [6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidine-3 yl] -carbamic acid benzyl ester

A solution of 218 mg (2- (5-chloro-2-methoxy-benzenesulfonylamino) -1- {2- (4-chlorophenyl) -1 - [(2,2-diethoxyethyl) isopropyl carbamoyl] -ethylcarbamoyl} -ethyl) -carbamic acid benzyl ester in 3 ml of formic acid is stirred at room temperature for 12 h and then at 55 ° C. for 5 h. The reaction solution is concentrated under reduced pressure and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). The desired product with MG = 689.62 (calculated) is obtained; Measured value (M + H) ⁺ : 689.41

g) 3-Amino-6- (4-chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro- pyrazino [1,2-a] pyrtmidine-4,7-dione

A solution of 79 mg [6- (4-chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidin-3-yl] -carbamic acid benzyl ester in 2 ml of a 33% solution of HBr in glacial acetic acid is stirred for 2 h. The reaction solution is mixed with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium carbonate and concentrated under reduced pressure, and the residue is separated on HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90) ,
The desired product with MG = 555.48 (calculated) is obtained; Measured value (M + H) ⁺ : 555.12

h) N- [6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidine -3-yl] -acetamide

A solution of 7 mg of 3-amino-6- (4-chloro-benzyl) -1- (5-chloro-2-methoxybenzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7 -dione, 2.4 μl acetic anhydride, 0.5 mg DMAP in 1.5 ml pyridine is stirred for 12 h. The reaction solution is concentrated and purified by flash chromatography on silica gel with the eluent methylene chloride with a gradient of 0-10% methanol.
The desired product with MG = 597.52 (calculated) is obtained; Measured value (M + H) ⁺ : 597.13

Example 97 N- [6- (4-Chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidine -3-yl] methanesulfonamide structure:

To a solution of 5 mg of 3-amino-6- (4-chloro-benzyl) -1- (5-chloro-2-methoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine- 4,7-dione in 1 ml methylene chloride and 3 μl Et3N, 1.8 μl mesyl chloride is added dropwise at 0 ° C. The mixture is stirred for 2 h and then extracted with aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The desired product with MG = 633.57 (calculated) is obtained as residue; Measured value (M + H) ⁺ : 633.10

Example 98 6- (4-Chlorobenzyl) -8-isopropyl-1- (4-methoxy-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (4-Chloro-phenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-methoxy-benzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 96e) starting from 3- (4-methoxy-benzenesulfonylamino) propionic acid. The desired product with MG = 598.16 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 552.1

b) 6- (4-chlorobenzyl) -8-isopropyl-1- (4-methoxy-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

A solution of 167 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-methoxybenzenesulfonylamino) propionylamino] propionamide in 3 ml Formic acid is stirred for 12 hours at room temperature. The reaction solution is concentrated under reduced pressure and the residue is separated by HPLC (Knauer Eurospher-100-10-C 18, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) 80/20 -> 10/90). The desired product with MG = 506.02 (calculated) is obtained; Measured value (M + H) ⁺ : 506.34

Example 99 1- (4-chlorobenzenesulfonyl) -6- (4-chlorobenzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (4-Chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-chlorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 96e) starting from 3- (4-chlorobenzenesulfonylamino) propionic acid. The desired product with MG = 602.58 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 556.1

b) 6- (4-Chlorobenzyl) -8-isopropyl-1- (4-chlorobenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-chlorobenzenesulfonylamino) propionylamino ] propionamide. The desired product with MG = 510.44 (calculated) is obtained; Measured value (M + H) ⁺ : 510.30

Example 100 6- (4-Chlorobenzyl) -1- (3,4-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (3,4-Dimethoxy-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from 3,4-dimethoxybenzenesulfonyl chloride and 3-aminopropionic acid. The desired product with MG = 289.31 (calculated) is obtained; Measured value (M + H) ⁺ : 290.1

b) 3- (3,4-Dimethoxy-phenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-chlorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 96e) starting from 3- (3,4-dimethoxybenzenesulfonylamino) propionic acid. The desired product with MG = 628.19 (calculated) is obtained; Measured value (M + H) ⁺ : 582.3

c) 6- (4-Chlorobenzyl) -1- (3,4-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (3,4-dimethoxyphenyl) -N- (2,2-diethoxyethyl) -N-isopropyl-2- [3- (4-chlorobenzenesulfonylamino) propionylamino] propionamide. The desired product with MG = 536.05 (calculated) is obtained; Measured value (M + H) ⁺ : 536.36

Example 101 1- (3-Chlorobenzenesulfonyl) -6- (4-chlorobenzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (2-Chlorobenzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 100a) starting from 2-chlorobenzenesulfonyl chloride. The desired product with MG = 263.70 (calculated) is obtained; Measured value (M + H) ⁺ : 264.05

b) 3- (4-Chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (2-chlorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 96e) starting from 3- (2-chlorobenzenesulfonylamino) propionic acid. You get the desired product with product
MG = 602.58 (calculated); Measured value (MC ₂ H ₆ O + H) ⁺ : 556.7

c) 1- (3-Chlorobenzenesulfonyl) -6- (4-chlorobenzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (2-chlorobenzenesulfonylamino) propionylamino ] propionamide. You get that ge desired product with MG = 510.44 (calculated); Measured value (M + H) ⁺ : 510.10

Example 102 6- (4-Chlorobenzyl) -1- (4-fluoro-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (4-Chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-fluorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 100a) starting from 3- (4-fluorobenzenesulfonylamino) propionic acid. The desired product with MG = 586.13 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 540.7

b) 6- (4-chlorobenzyl) -8-isopropyl-1- (4-fluoro-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-fluorobenzenesulfonylamino) propionylamino ] propionamide. The desired product with MG = 493.99 (calculated) is obtained; Measured value (M + H) ⁺ : 494.13

Example 103 6- (4-Chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (2,5-Dimethoxy-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 100a) starting from 2,5-dimethoxybenzenesulfonyl chloride. The desired product with MG = 289.31 (calculated) is obtained; Measured value (M + H) ⁺ : 290.1

b) 3- (2,5-Dimethoxy-phenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-chlorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to example196e) starting from 3- (2,5-dimethoxybenzenesulfonylamino) propionic acid. The desired product with MG = 628.19 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 582.7

c) 6- (4-Chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (2,5-dimethoxy-phenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (4-chlorobenzenesulfonylamino) propionylamino] propionamide. The desired product with MG = 536.05 (calculated) is obtained; Measured value (M + H) ⁺ : 536.16

Example 104 N- [6- (4-chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidine-3 -yl] methanesulfonamide structure:

a) 2-Benzyloxycarbonylamino-3- (2,5-dimethoxy-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from 2,5-dimethoxybenzenesulfonyl chloride. The desired product with MG = 438.46 (calculated) is obtained; Measured value (M + H) ⁺ : 439.1

b) N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (2,5-dimethoxy-benzenesulfonylamino) -2- methanesulfonylamino-propionamide

The synthesis is carried out analogously to Example 96e) starting from 2-benzyloxycarbonylamino-3- (2,5-dimethoxy-benzenesulfonylamino) propionic acid. The desired product with MG = 777.34 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 731.9

c) [6- (4-Chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidin-3-yl ] -carbamic acid benzyl ester

The synthesis is carried out analogously to Example 96f) starting from N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxyethyl) isopropylcarbamoyl] ethyl} -3- (2,5 - dimethoxybenzenesulfonylamino) -2-methanesulfonylamino-propionamide. The desired product with MG = 685.20 (calculated) is obtained; Measured value (M + H) ⁺ : 685.38

d) 3-Amino-6- (4-chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 96g) starting from [6- (4-chlorobenzyl) -1- (2,5-dimethoxybenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydrophyrazino [1,2 - a] pyrimidin-3-yl] carbamic acid benzyl ester. The desired product with MG = 551.07 (calculated) is obtained; Measured value (M + H) ⁺ : 551.15

e) 3-Amino-6- (4-chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 97 starting from 3-amino-6- (4-chlorobenzyl) -1- (2,5-dimethoxy-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine- 4,7-dione. The desired product with MG = 629.16 (calculated) is obtained; Measured value (M + H) ⁺ : 629.15

Example 105 6- (4-Chlorobenzyl) -1- (3-fluoro-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (3-Fluoro-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 100a) starting from 3-fluoro-benzenesulfonyl chloride. The desired product with MG = 247.25 (calculated) is obtained; Measured value (M + H) ⁺ : 248.05

b) 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (3-fluorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 100a) starting from 3- (3-fluorobenzenesulfonylamino) propionic acid. The desired product with MG = 586.13 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 540.7

c) 6- (4-Chlorobenzyl) -8-isopropyl-1- (3-fluoro-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (3-fluorobenzenesulfonylamino) propionylamino ] -propionamide. The desired product with MG = 493.99 (calculated) is obtained; Measured value (M + H) ⁺ : 494.25

Example 106 N- [6- (4-Chlorobenzyl) -1- (3-fluoro-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidin-3-yl ] -methanesulfonamide structure:

a) 2-Benzyloxycarbonylamino-3- (3-fluoro-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from 3-fluoro-benzenesulfonyl chloride. The desired product with MG = 396.40 (calculated) is obtained; Measured value (M + H) ⁺ : 397.10

b) N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (3-fluoro-benzenesulfonylamino) -2-methanesulfonylamino- propionamide

The synthesis is carried out analogously to Example 96e) starting from 2-benzyloxycarbonylamino-3- (3-fluoro-benzenesulfonylamino) propionic acid. The desired product with MG = 735.28 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 689.7

c) [6- (4-Chlorobenzyl) -1- (3-fluoro-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidin-3-yl] - carbamic acid benzyl ester

The synthesis is carried out analogously to Example 96f) starting from N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxyethyl) isopropylcarbamoyl] ethyl} -3- (3-fluoro -benzenesulfonylamino) -2-methanesulfonylamino-propionamide. The desired product with MG = 643.14 (calculated) is obtained; Measured value (M + H) ⁺ : 643.31

d) 3-Amino-6- (4-chlorobenzyl) -1- (3-fluoro-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 96g) starting from [6- (4-chlorobenzyl) -1- (3-fluoro-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a ] pyrimidin-3-yl] carbamic acid benzyl ester. The desired product with MG = 509.00 (calculated) is obtained; Measured value (M + H) ⁺ : 509.15

e) 3-Amino-6- (4-chlorobenzyl) -1- (3-fluoro-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 97 starting from 3-amino-6- (4-chlorobenzyl) -1- (3-fluorobenzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7- dion. The desired product with MG = 587.09 (calculated) is obtained; Measured value (M + H) ⁺ : 587.41

Example 107 N- [1-benzenesulfonyl-6- (4-chloro-benzyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidin-3-yl] methanesulfonamide structure:

a) 2-Benzyloxycarbonylamino-3- (benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from benzenesulfonyl chloride. The desired product with MG = 378.41 (calculated) is obtained; Measured value (M + H) ⁺ : 379.10

b) N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (benzenesulfonylamino) -2-methanesulfonylamino-propionamide

The synthesis is carried out analogously to Example 96e) starting from 2-benzyloxycarbonylamino-3- (benzenesulfonylamino) propionic acid. The desired product with MG = 717.29 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 671.7

c) [6- (4-Chlorobenzyl) -1- (benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidin-3-yl] carbamic acid benzyl ester

The synthesis is carried out analogously to Example 96f) starting from N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxyethyl) isopropylcarbamoyl] ethyl} -3- (benzenesulfonylamino) - 2-methanesulfonylamino-propionamide. The desired product with MG = 625.14 (calculated) is obtained; Measured value (M + H) ⁺ : 625.33

d) 3-Amino-6- (4-chlorobenzyl) -1- (benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 96g) starting from [6- (4-chlorobenzyl) -1- (benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydrophyrazino [1,2-a] pyrimidine-3 -yl] -carbamic acid benzyl ester. The desired product with MG = 491.00 (calculated) is obtained; Measured value (M + H) ⁺ : 491.10

e) 3-Amino-6- (4-chlorobenzyl) -1- (benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 97, starting from 3-amino-6- (4-chlorobenzyl) -1- (benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione. The desired product with MG = 569.09 (calculated) is obtained; Measured value (M + H) ⁺ : 569.13

Example 108 1-benzenesulfonyl-6- (4-chlorobenzyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (4-Chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (benzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 100a) starting from 3- (benzenesulfonylamino) propionic acid. The desired product with MG = 568.13 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 522.7

b) 6- (4-chlorobenzyl) -8-isopropyl-1- (benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (benzenesulfonylamino) propionylamino] propionamide.
The desired product with MG = 475.99 (calculated) is obtained; Measured value (M + H) ⁺ : 476.14

Example 109 6- (4-Chlorobenzyl) -1- (2-fluoro-benzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (2-Fluoro-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 100a) starting from 2-fluoro-benzenesulfonyl chloride. The desired product with MG = 247.25 (calculated) is obtained; Measured value (M + H) ⁺ : 248.05

b) 3- (4-Chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (2-fluorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 100a) starting from 3- (2-fluorobenzenesulfonylamino) propionic acid. The desired product with MG = 586.13 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 540.7

c) 6- (4-Chlorobenzyl) -8-isopropyl-l- (2-fluoro-benzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (2-fluorobenzenesulfonylamino) propionylamino ] -propionamide. The desired product with MG = 493.99 (calculated) is obtained; Measured value (M + H) ⁺ : 494.13

Example 110 N- [6- (4-Chlorobenzyl) -1- (2-fluoro-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydro-pyrazino [1,2-a] pyrimidin-3-yl ] -methanesulfonamide structure:

a) 2-Benzyloxycarbonylamino-3- (2-fluoro-benzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from 2-fluoro-benzenesulfonyl chloride. The desired product with MG = 396.40 (calculated) is obtained; Measured value (M + H) ⁺ : 397.10

b) N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (2-fluoro-benzenesulfonylamino) -2-methanesulfonylamino- propionamide

The synthesis is carried out analogously to Example 96e) starting from 2-benzyloxycarbonylamino-3- (2-fluoro-benzenesulfonylamino) propionic acid. The desired product with MG = 735.28 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 689.7

c) [6- (4-chlorobenzyl) -1- (2-fluoro-benzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidin-3-yl] = carbamic acid benzyl ester

The synthesis is carried out analogously to Example 96f) starting from N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxyethyl) isopropylcarbamoyl] ethyl} -3- (2-fluoro -benzenesulfonylamino) -2-methanesulfonylamino-propionamide. The desired product with MG = 643.14 (calculated) is obtained; Measured value (M + H) ⁺ : 643.31

d) 3-Amino-6- (4-chlorobenzyl) -1- (2-fluoro-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 96g) starting from [6- (4-chlorobenzyl) -1- (2-fluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidine -3-yl] -carbamic acid benzyl ester. The desired product with MG = 509.00 (calculated) is obtained; Measured value (M + H) ⁺ : 509.15

e) 3-Amino-6- (4-chlorobenzyl) -1- (2-fluoro-benzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 97 starting from 3-amino-6- (4-chlorobenzyl) -1- (2-fluorobenzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7- dion. The desired product with MG = 587.09 (calculated) is obtained; Measured value (M + H) ⁺ : 587.12

Example 111 N- [6- (4-chlorobenzyl) -1- (2,4-difluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydrophyrazino [1,2-a] pyrimidine-3 -yl] methanesulfonamide structure:

a) 2-Benzyloxycarbonylamino-3- (2,4-difluorobenzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from 2,4-difluorobenzenesulfonyl chloride. The desired product with MG = 414.40 (calculated) is obtained; Measured value (M + H) ⁺ : 415.10

b) N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (2,4-difluorobenzenesulfonylamino) -2- methanesulfonylamino-propionamide

The synthesis is carried out analogously to Example 96e) starting from 2-benzyloxycarbonylamino-3- (2,4-difluorobenzenesulfonylamino) propionic acid. The desired product with MG = 753.27 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 707.7

c) [6- (4-Chlorobenzyl) -1- (2,4-difluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidin-3-yl ] -carbamic acid benzyl ester

The synthesis is carried out analogously to the example 96f) starting from N- {2- (4-chlorophenyl) -1- (2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (2,4-difluorobenzenesulfonylamino) -2 -methanesulfonylamino-propionamide. You get the wished Product with MG = 661.14 (calculated); Measured value (M + H) +: 661.32

d) 3-Amino-6- (4-chlorobenzyl) -1- (2,4-difluorobenzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 96g) starting from [6- (4-chlorobenzyl) -1- (2,4-difluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydrophyrazino [1,2 -a] pyrimidin-3-yl] carbamic acid benzyl ester. The desired product with MG = 527.00 (calculated) is obtained; Measured value (M + H) ⁺ : 527.10

e) 3-amino-6- (4-chlorobenzyl) -1- (2,4-difluorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [ 1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Ex. 97 starting 3-amino-6- _(4-C hloro-benzyl) -1- (2,4-difluoro-benzenesulfonyl) -8-isopropyl-hexahydro- pyrazino [1,2-a] pyrimidine -4,7-dion.
The desired product with MG = 605.09 (calculated) is obtained; Measured value (M + H) ⁺ : 605.11

Example 112 6- (4-Chlorobenzyl) -1- (2,4-difluorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (2,4-Difluorobenzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 100a) starting from 2,4-difluorobenzenesulfonyl chloride. The desired product with MG = 265.25 (calculated) is obtained; Measured value (M + H) ⁺ : 266.05

b) 3- (4-chloro-phenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (2,4-difluorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 100a) starting from 3- (2,4-difluorobenzenesulfonylamino) propionic acid. The desired product with MG = 604.13 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 558.7

c) 6- (4-Chlorobenzyl) -8-isopropyl-1- (2,4-difluorobenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (2,4-difluorobenzenesulfonylamino) -propionylamino] - propionamide. The desired product with MG = 511.99 (calculated) is obtained; Measured value (M + H) ⁺ : 512.12

Example 113 6- (4-Chlorobenzyl) -1- (3,4-dfluorobenzenesulfonyl) -8-isopropyl-hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione Structure:

a) 3- (3,4-Difluorobenzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 100a) starting from 3,4-difluorobenzenesulfonyl chloride. The desired product with MG = 265.25 (calculated) is obtained; Measured value (M + H) ⁺ : 266.05

b) 3- (4-chloro-phenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (3,4-difluorobenzenesulfonylamino) propionylamino] propionamide

The synthesis is carried out analogously to Example 100a) starting from 3- (3,4-difluorobenzenesulfonylamino) propionic acid. The desired product with MG = 604.13 (calculated) is obtained; Measured value (M + H) ⁺ : 558.7

c) 6- (4-Chlorobenzyl) -8-isopropyl-1- (3,4-difluorobenzenesulfonyl) hexahydro-pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 98b) starting from 3- (4-chlorophenyl) -N- (2,2-diethoxy-ethyl) -N-isopropyl-2- [3- (3,4-difluorobenzenesulfonylamino) propionylamino] propionamide. The desired product is obtained with MG = 511.99 (calculated); measured value (M + H) ⁺ : 512.12

Example 114 N- [6- (4-chlorobenzyl) -1- (3,4-difluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidine-3 -yl] methanesulfonamide structure:

a) 2-Benzyloxycarbonylamino-3- (3,4-difluorobenzenesulfonylamino) propionic acid

The synthesis is carried out analogously to Example 96d) starting from 3,4-difluorobenzenesulfonyl chloride. The desired product with MG = 414.40 (calculated) is obtained; Measured value (M + H) ⁺ : 415.10

f) N- {2- (4-chloro-phenyl) -1 - [(2,2-diethoxy-ethyl) -isopropyl-carbamoyl] -ethyl} -3- (3,4-difluorobenzenesulfonylamino) -2- methanesulfonylamino-propionamide

The synthesis is carried out analogously to Example 96e) starting from 2-benzyloxycarbonylamino-3- (3,4-difluorobenzenesulfonylamino) propionic acid. The desired product with MG = 753.27 (calculated) is obtained; Measured value (MC ₂ H ₆ O + H) ⁺ : 707.7

g) [6- (4-Chlorobenzyl) -1- (3,4-difluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydropyrazino [1,2-a] pyrimidin-3-yl ] -carbamic acid benzyl ester

The synthesis is carried out analogously to Example 96f) starting from N- {2- (4-chlorophenyl) -1 - [(2,2-diethoxyethyl) isopropylcarbamoyl] ethyl} -3- (3,4 -difluoro-benzenesulfonylamino) -2-methanesulfonylamino-propionamide. The desired product with MG = 661.14 (calculated) is obtained; Measured value (M + H) ⁺ : 661.31

h) 3-Amino-6- (4-chlorobenzyl) -1- (3,4-difluorobenzenesulfonyl) -8-isopropylhexahydro- pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Ex. 96g) starting from [6- (4-chlorobenzyl) -1- (3,4-difluorobenzenesulfonyl) -8-isopropyl-4,7-dioxo-octahydrophyrazino [1,2 -a] pyrimidin-3-yl] carbamic acid benzyl ester. The desired product with MG = 527.00 (calculated) is obtained; Measured value (M + H) ⁺ : 527.10

i) 3-Amino-6- (4-chlorobenzyl) -1- (3,4-difluorobenzenesulfonyl) -8-isopropylhexahydro- pyrazino [1,2-a] pyrimidine-4,7-dione

The synthesis is carried out analogously to Example 97 starting from 3-amino-6- (4-chlorobenzyl) -1- (3,4-difluorobenzenesulfonyl) -8-isopropyl-hexahydropyrazino [1,2-a] pyrimidine- 4,7-dione. The desired product with MG = 605.09 (calculated) is obtained; Measured value (M + H) ⁺ : 605.11

Claims (16)

Compounds of formula I,

in which A is a 3-12-membered mono-, bi- or spirobicyclic ring which can contain one or more heteroatoms from the group N, O and S and the 3-12-membered ring further substituents such as F, Cl, Br, NO ₂ , CF ₃ , OCF ₃ , CN, (C ₁ -C ₆ ) alkyl, aryl, CON (R11) (R12), N (R13) (R14), OH, O- (C ₁ -C ₆ ) alkyl, S- (C ₁ -C ₆ ) alkyl, N (R15) CO (C ₁ -C ₆ ) alkyl or COO- (C ₁ -C ₆ ) alkyl; R11, R12, R13, R14, R15 independently of one another H, (C ₁ -C ₆ ) alkyl, heterocycle; n 0.1; m 0, 1, 2, 3, 4, 5, 6; R1 (C ₀ -C ₆ ) alkylene-R8, (C ₂ -C ₆ ) alkenylene-R9, (SO ₂ ) - (C ₀ -C ₆ ) alkylene-R8, (SO ₂ ) - (C ₂ -C ₆ ) -alkenylene-R9, (C = O) - (C ₀ -C ₆ ) -alkylene-R8, (C = O) - (C ₂ -C ₆ ) -alkenylene-R9, (C = O) -NH- (C ₀ -C ₆ ) alkylene-R8, (C = O) -NH- (C ₂ -C ₆ ) alkenylene-R9, COO- (C ₀ -C ₆ ) alkylene-R8, COO - (C ₂ -C ₆ ) alkenylene R9, alkynylene R9, (C ₁ -C ₄ alkyl) heterocycle; R8, R9 independently of one another are H, aryl, heterocycle, (C ₃ -C ₈ ) -cycloalkyl, it being possible for the rings or ring systems to be substituted up to 3 times with F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, NH2, CON (R11) (R12), N (R13) (R14), SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) alkyl, CONH ₂ ; R2 H, F, Cl, Br, J, OH, CF ₃ , NH ₂ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, O- (C ₁ -C ₄ ) alkoxy - (C ₁ -C ₄ ) alkyl, S- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₈ ) -Cycloalkyl, O- (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkenyl, O- (C ₃ -C ₈ ) -cycloalkenyl, (C ₂ -C ₆ ) alkynyl, (C ₀ -C ₈ ) alkylene aryl, O- (C ₀ -C ₈ ) alkylene aryl, S-aryl, CON (R11) (R12), N (R13) (R14), (C ₁ -C ₆ ) -Alkyl-N (R13) (R14), NH-SO ₂ -CH ₃ , NH-SO ₂ -R12, NR11-SO ₂ -R12, N (CO) R11, COOH, COO- (C ₁ -C ₆ ) -Alkyl, COO- (C ₁ -C ₆ ) alkenyl, CO-N ((C ₁ -C ₆ ) alkyl) ₂ , heterocycle, NHCONR11, N (C ₁ -C ₆ alkyl) N ⁺ (C ₁ -C ₄ alkyl) ₃ ; R3, R4, R5 independently of one another H, F, Cl, Br, J, OH, CF ₃ , NO ₂ , CN, OCF ₃ , O- (C ₁ -C ₆ ) alkyl, O- (C ₁ -C ₄ ) Alkoxy- (C ₁ -C ₄ ) alkyl, S- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ - C ₈ ) cycloalkyl, O- (C ₃ -C ₈ ) cycloalkyl, (C ₃ -C ₈ ) cycloalkenyl, O- (C ₃ -C ₈ ) cycloalkenyl, (C ₂ -C ₆ ) alkynyl, (C ₀ -C ₈ ) alkylene aryl, O- (C ₀ -C ₈ ) alkylene aryl, S-aryl, N ((C ₁ -C ₆ ) alkyl) ₂ , SO ₂ -CH ₃ , COOH, COO- (C ₁ -C ₆ ) alkyl, CO-N ((C ₁ -C ₆ ) alkyl) ₂ ; and their physiologically tolerable salts. Medicaments containing one or more of the compounds according to claim 1. Medicaments containing one or more of the compounds according to claim 1 and one or more anorectic agents. Medicaments containing one or more of the compounds according to claim 1 and one or more statins. Compounds according to claim 1 for use as a medication for the prophylaxis or treatment of obesity. Compounds according to claim 1 for use as a medicament for the prophylaxis or treatment of the type II diabetes. Compounds according to claim 1 for the prophylaxis or treatment of the metabolic syndrome. Compounds according to claim 1 for the treatment of female and male sexual disorders. Compounds according to claim 1 in combination with at least one other anorectic agent for use as a medicament for the prophylaxis or treatment of Obesity. Compounds according to claim 1 in combination with at least one other anorectic agent for use as a medicament for the prophylaxis or treatment of type II diabetes. Process for the manufacture of a medicament containing one or more of the compounds according to claim 1, characterized in that that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture into a suitable for administration Is brought into shape. Use of the compounds according to claim 1 for the preparation a medication for weight loss in mammals. Use of the compounds according to claim 1 for the preparation a drug for the prophylaxis or treatment of obesity. Use of the compounds according to claim 1 for the preparation a medication for the prophylaxis or treatment of type II diabetes. Use of the compounds according to claim 1 for the preparation a drug for the prophylaxis or treatment of the metabolic Syndrome. Use of the compounds according to claim 1 for the preparation a drug for the treatment of female and male Sexual disorders.