CN1751046A - Substituted hexahydropyrazino(1,2-a)pyrimidin-4,7-dion derivatives, method for the production and use thereof as medicaments - Google Patents
Substituted hexahydropyrazino(1,2-a)pyrimidin-4,7-dion derivatives, method for the production and use thereof as medicaments Download PDFInfo
- Publication number
- CN1751046A CN1751046A CNA2004800042121A CN200480004212A CN1751046A CN 1751046 A CN1751046 A CN 1751046A CN A2004800042121 A CNA2004800042121 A CN A2004800042121A CN 200480004212 A CN200480004212 A CN 200480004212A CN 1751046 A CN1751046 A CN 1751046A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- aryl
- group
- reagent
- coo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, in addition to the physiologically compatible salts thereof and physiologically functional derivatives. The invention also relates to compounds of formula (I), wherein the radicals have the cited meanings, the physiologically compatible salts thereof and methods for the production thereof. Said compounds can be used, for example, as anorectics.
Description
The hexahydropyrazine that the present invention relates to replace is [1,2-a] pyrimidine-4, the salt that can tolerate on 7-derovatives and the physiology thereof and neurological progression derivative also.
The purpose of this invention is to provide and to cause that weight of mammal alleviates and be applicable to the medicine of prevention and treatment obesity.
Therefore the present invention relates to the salt that can tolerate on formula I compound and the physiology thereof,
Wherein the implication of each symbol is
That A represents to contain the heteroatomic 3-12 unit of one or more N of being selected from, O and S is single-, two-or spiral shell two rings, and described 3-12 unit ring can contain other substituting group 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 are H, (C independently of one another
1-C
6)-alkyl, heterocycle;
N is 0,1;
M is 0,1,2,3,4,5,6;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-and heterocycle, wherein alkylidene group can be replaced by F;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or loop systems can be substituted maximum 3 times of base replacement, and described substituting group is selected from 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 is H, F, Cl, Br, I, OH, CF
3, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, CON (R11) (R12), N (R13) (R14), (C
1-C
6)-alkyl-N (R13) (R14), COOH, COO-(C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, CO-N ((C
1-C
6)-alkyl)
2, heterocycle, wherein heterocycle cannot be by the nitrogen-atoms combination;
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-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
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-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
Be preferably as follows the salt that can tolerate on formula I compound and the physiology thereof, wherein the implication of each symbol is
A for the heteroatomic 3-12 unit that can contain one or more N of being selected from, O and S single-, two-or spiral shell two rings, and described 3-12 unit ring can contain other substituting group 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 are H, (C independently of one another
1-C
6)-alkyl, heterocycle;
M is 1;
N is 0,1;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-heterocycle;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or loop systems can be substituted maximum 3 times of base replacement, and described substituting group is selected from 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 is H, F, Cl, Br, I, OH, CF
3, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, CON (R11) (R12), N (R13) (R14), (C
1-C
6)-alkyl-N (R13) (R14), COOH, COO-(C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, CO-N ((C
1-C
6)-alkyl)
2, heterocycle, wherein heterocycle cannot be by the nitrogen-atoms combination;
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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-(
C3-C
8)-cycloalkyl, (C
3-C
8)-cycloalkenyl group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-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
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-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
Be preferably as follows the salt that can tolerate on formula I compound and the physiology thereof especially, wherein the implication of each symbol is
A is an aryl, and wherein aryl rings can be substituted the base replacement, and described substituting group is selected from 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 are H, (C independently of one another
1-C
6)-alkyl;
M is 1;
R1 is (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or loop systems can be substituted maximum 3 times of base replacement, and described substituting group is selected from 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 is H, F, Cl, Br, I, OH, CF
3, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, N (R13) be OH, (C (R14)
1-C
6)-alkyl-N (R13) (R14);
R3 is H;
R4, R5 are H, F, Cl, Br, OH, CF independently of one another
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
Especially especially be preferably as follows the salt that can tolerate on formula I compound and the physiology thereof, wherein the implication of each symbol is
A is an aryl, and wherein aryl rings can be substituted the base replacement, and described substituting group is selected from 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 are H, (C independently of one another
1-C
6)-alkyl;
M is 1;
N is 0,1;
R1 is (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl;
R2 is H, OH, (C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, (C
1-C
6)-alkyl-N (R13) (R14);
R3 is H;
R4 is F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R5 is H, F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
If in formula I compound, more than group or substituting group such as CON (R11) (R12) occurred once, they can all have described implication and can be identical or different independently of one another so.
The present invention relates to the racemic modification of formula I compound, the mixture and the pure enantiomorph of enantiomeric excess, and relate to its diastereomer and composition thereof.
Alkyl in substituent A, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15, alkenyl and alkynyl can be straight chain, side chain or halogenation or not halogenated.Alkyl in substituent A, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15 also can be a cyclic.
Term " aryl " is meant phenyl or naphthyl.
For example, heterocycle or heterocyclic radical are meant that de-carbon also comprises the loop systems as nitrogen, oxygen or sulfur heteroatom outward.Wherein heterocycle or heterocyclic radical and phenyl ring condensed loop systems are also contained in this definition.
" heterocycle " that suits and " heterocyclic radical " are acridyl, the azocine base, benzimidazolyl-, benzofuryl, benzothienyl benzoxazolyl, benzothiazolyl, the benzotriazole base, the benzo tetrazyl, the benzoisoxazole base, the benzisothiazole base, the benzimidazoline base, carbazyl, the 4aH-carbazyl, carbolinyl, quinazolyl, quinolyl, the 4H-quinazolyl, quinoxalinyl, quinuclidinyl, chromanyl, benzopyranyl, the cinnolines base, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran also [2,3-b] tetrahydrofuran (THF), furyl, the furazan base, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, indolinyl, the indolizine base, indyl, the 3H-indyl, isobenzofuran-base, different coumaran base, iso indazolyl, iso-dihydro-indole-group, pseudoindoyl, isoquinolyl (benzimidazolyl-), isothiazolyl isoxazolyl, morpholinyl, naphthyridinyl, octahydro isoquinolyl oxadiazole base, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base oxazolidinyl oxazolyl oxazolidinyl, pyrimidyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl, Phenoxathiinyl phenoxazinyl, 2, the 3-phthalazinyl, piperazinyl, piperidyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, Bi Ding Bing oxazolyl, the pyridine-imidazole base, the pyrido thiazolyl, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, the 2H-pyrryl, pyrryl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, 6H-1,2,5-thiadiazine base, thiazolyl, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thienyl, triazolyl, tetrazyl and xanthenyl.
Pyridyl is meant 2-, 3-and 4-pyridyl.Thienyl is meant 2-and 3-thienyl.Furyl is meant 2-and 3-furyl.
Also comprise these compound corresponding N-oxide compounds, that is, for example 1-oxygen base-2-, 3-or 4-pyridyl.
Comprise that also these heterocycles and phenyl ring condense the derivative of one or many.
Heterocycle or heterocyclic group can be replaced one or many by suitable group, for example, and 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, wherein one or more or all hydrogen in the alkyl group can be replaced by fluorine; PO
3H
2, SO
3H, SO
2-NH
2, SO
2NH (C
1-C
6)-alkyl, SO
2N[(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, wherein n can be 0-6, and phenyl group can be replaced twice at the most by following groups: F, Cl, Br, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, NH
2C (NH) (NH
2), NH
2, NH-(C
1-C
6)-alkyl, N ((C
1-C
6)-alkyl)
2, NH (C
1-C
7)-acyl group, phenyl, O-(CH
2)
n-phenyl, wherein n can be 0-6, and wherein phenyl ring can be replaced 1-3 time by following groups: 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
Pharmacy acceptable salt is particularly suitable for medicinal application, because their water-soluble primary or the basic compound of being higher than.These salt must have pharmaceutically acceptable negatively charged ion or positively charged ion.The suitable pharmaceutically-acceptable acid addition of The compounds of this invention is inorganic acid salt example hydrochloric acid salt, hydrobromate, phosphoric acid salt, metaphosphate, nitrate, sulfonate and vitriol, and organic acid salt such as acetate, benzene sulfonate, benzoate, Citrate trianion, esilate, fumarate, gluconate, glycollate, isethionate, lactic acid salt, Lactobionate, maleate, malate, mesylate, succinate, tosilate, tartrate and trifluoroacetate.Especially preferably hydrochloride is used as medicine.Suitable pharmaceutically acceptable basic salt is ammonium salt, an alkali metal salt (as sodium and sylvite) and alkaline earth salt (as magnesium and calcium salt).
Have pharmaceutically unacceptable anionic salt equally also in scope of invention of the present invention, it can and/or be used for non-treatment, for example external application as the intermediate of preparation or purifying pharmacy acceptable salt.
The term of Shi Yonging " neurological progression derivative " means the derivative that can tolerate on any physiology of formula I compound of the present invention herein, ester for example, these compounds can (directly or indirectly) form formula I compound or their active metabolite after giving the Mammals such as the mankind.
The neurological progression derivative also comprises the prodrug of The compounds of this invention.Such prodrug metabolism in vivo is a The compounds of this invention.These prodrugs itself can be active, also can be inactive.
The compounds of this invention also can exist with various polymorphics, for example amorphous and crystal polymorphic.The polymorphic of all The compounds of this invention all is contained in the scope of the present invention and is another aspect of the present invention.
All " formula (I) compounds " of hereinafter mentioning mean formula mentioned above (I) compound and salt, solvate and their neurological progression derivative described herein.
The amount that can reach formula (I) compound of required physiologic effect depends on many factors, for example selected specific compound, purposes, administering mode and patient's clinical condition.Usually, the per daily dose scope is per kilogram of body weight 0.3mg-100mg (being generally 3mg-50mg), for example 3-10mg/kg/ days.Vein dosage can be for example 0.3mg-1.0mg/kg, and the dosage range of optimal infusion administration is per kilogram of body weight per minute 10ng-100ng.The suitable infusion solution that is used for this purpose can comprise for every milliliter, and for example 0.1ng-10mg is generally 1ng-10mg.Single dose can comprise, for example the 1mg-10g activeconstituents.Therefore the injection ampoule can comprise, 1mg-100mg for example, and single-dose preparations that can the oral administration administration, for example tablet or capsule comprise, and for example 1.0-1000mg is generally 10-600mg.If pharmacy acceptable salt, the aforementioned weight data of mentioning is based on the weight of the free cpds of salt.When preventing or treating above-mentioned disease, formula (I) compound can use with compound itself, but they preferably use with the pharmaceutical compositions that contains acceptable carrier.Certainly, carrier must be acceptable, compatible with other composition of composition, and healthy harmless to patient.Carrier can all have for solid or liquid or the two, and preferably is formulated as the preparation of single dose with compound, and described single dose for example tablet can contain the activeconstituents of 0.05%-95% weight.The pharmaceutically active substance that can also comprise other comprises other formula (I) compound.Pharmaceutical composition of the present invention can be by known pharmaceutical methods preparation, and described method mainly comprises this composition and pharmaceutically acceptable carrier and/or mixed with excipients.
Pharmaceutical composition of the present invention is those compositions that are suitable for oral, rectum, part, per os (for example hypogloeeis) and parenteral (for example subcutaneous, muscle, intracutaneous or vein) administration, although depend on the character of employed formula (I) compound under the character of the disease of being treated and seriousness and the every kind of situation in the optimal mode of the administration on each particular individual.Coated preparation and coated slow release agent are equally also within the scope of the invention.The preparation of preferred antiacid and anti-gastric juice.The dressing of suitable anti-gastric juice comprises the anionic polymer of rhodia phthalic ester, phthalic acid polyvinyl acetate, Hydroxypropyl Methylcellulose Phathalate and methacrylic acid and methyl methacrylate.
The medicinal compound that is applicable to oral administration can be the individual formulation that contains specified amount formula (I) compound, as capsule, cachet, the tablet that can suck or tablet; Powder or granule; The solution of water or on-aqueous liquid or suspension; Oil-in-water or water-in-oil emulsion.As mentioned above, these compositions can be by any suitable pharmaceutical methods preparation, and described method comprises the step that activeconstituents is contacted with carrier (can contain one or more other components).Usually, described composition is by preparing activeconstituents and liquid and/or superfine solid carrier uniform mixing, then, and when needing, with described product moulding.Therefore, for example, tablet can prepare with one or more other component compressing tablets or casting mold when needing by powder or the particle with described compound.For example, compressed tablet can be by the compound with free-flowing form, and the compressing tablet preparation in suitable machine as powder or particle mixes with tackiness agent, lubricant, inert diluent and/or one or more surfactant/dispersant when needing.Molded tablet can be by preparing with powder type and with the moistening compound casting mold of inert liquid diluent in suitable machine.
The pharmaceutical composition that is applicable to per os (hypogloeeis) administration comprises and contains formula (I) compound and correctives, but be generally the suction tablet of sucrose and gum arabic or tragacanth and the lozenge of compound as described in inert base contains in as gelatin and glycerine or sucrose and gum arabic.
The pharmaceutical composition of suitable parenteral admin preferably comprises the aseptic aqueous solution preparation of formula (I) compound, and described preparation preferably oozes with blood of treatment acceptor etc.Although these preparations also can preferably pass through intravenously administrable by subcutaneous, muscle or intradermal injection administration.These preparations preferably prepare by compound being mixed with water and the sterile solution that obtains and blood etc. being oozed.Composition for injection of the present invention is by containing the active compound of 0.1-5% weight.
The pharmaceutical composition of suitable rectal administration preferably exists with the suppository form of single dose.These compositions can by with formula (I) compound and one or more conventional solid carriers for example theobroma oil mix, and the mixture molding that obtains is prepared.
The preferred form of the pharmaceutical composition of suitable local skin medication is: forms such as ointment, emulsion, washing lotion, paste, sprays, aerosol or oily matter exist.Can adopt following carrier: paraffin wax, lanolin, polyoxyethylene glycol, alcohol and two or more these mixture of ingredients.The concentration of activeconstituents is generally the 0.1-15% of composition weight, for example 0.5-2%.
Also can percutaneous dosing.The suitable pharmaceutical composition that uses through skin can exist with the form of single plaster, and this form is fit to closely contact with patient's epidermis for a long time.Described plaster contains dissolving aptly and/or is dispersed in the tackiness agent or is dispersed in activeconstituents in the polymkeric substance in the optional buffered aqueous solution.The concentration of suitable activeconstituents is about 1%-35%, preferably about 3%-15%.As a kind of special case, activeconstituents can discharge by electromigration or iontophoresis, Pharmaceutical Research for example, 2 (6): described in 318 (1986).
Being characterized as of formula I compound has useful effect to lipid metabolism, and they weight of mammal is alleviated and the body weight after the back that loses weight keeps alleviating effective especially, can be used as anorectic medicaments.The characteristics of this compounds are their hypotoxicity and less side effect.
This compounds can be separately or is lost weight or subtract the appetite active component with other and unite use.Other of the type subtracts the appetite activeconstituents for example at Rote Liste, the 1st chapter, address in the medicine/appetite suppressant part that loses weight, thereby and can comprise that also activeconstituents or those modes that the calorie picked-up does not cause the organism fatty deposits to increase and calorie picked-up normally causes the organism fatty deposits to reduce with increase that increase organism Conversion of energy causes losing weight influence the general metabolic activeconstituents of organism.This compounds is suitable for prevention and particularly treats overweight or fat.Metabolism normalizing and treatment hypertension that this compounds is further adapted for prevention and particularly treats type ii diabetes, atherosclerosis and make lipoid cpd.This compounds can be used as the novel melanocortin receptor antagonist, also is suitable for treating healthy unbalance and for example depression, anxiety state, anxiety neurosis, schizophrenia and disorder and the drug abuse relevant with circadian rhythm of other psychotic symptoms.
This compounds also is suitable for treating cancer, sacroiliitis, somnopathy, sleep apnea, women and male sexual disorder, inflammation, acne, cutaneous pigmentation, metabolism syndrome, steroid metabolism disorder, dermatosis, psoriatic, mycosis, neurodegenerative disease and Alzheimer in addition.
According to a further aspect in the invention, formula I compound can with one or more other medicines activeconstituents Combined Preparation, described activeconstituents for antidiabetic drug for example, anti-obesity medicine, hypotensive activeconstituents, fat-reducing medicament and treat and/or prevent by diabetes cause or with the activeconstituents of diabetes complications associated with arterial system.
Suitable antidiabetic drug comprises the derivative of Regular Insulin, amylin, GLP-1 and GLP-2, as is disclosed among the WO 98/08871 of Novo Nordisk A/S those, and the Orally active blood-sugar decreasing active.
The Orally active blood-sugar decreasing active preferably includes sulfonylurea, biguanides, meglitinide class; oxadiazole alkane two ketones, thiazolidinediones, alpha-glucosidase inhibitors, glucagon receptor antagonist, the GLP-1 agonist, potassium channel openers, as be disclosed in the WO 97/26265 of Novo Nordisk A/S and among the WO 99/03861 those, insulin sensitizer, the insulin receptor kinase activator, the liver enzyme inhibitor relevant with stimulating gluconeogenesis and/or glycogenolysis be the glycogen phosphorglase inhibitor for example, glucose uptake and glucose are drained conditioning agent, change for example HMGCoA reductase inhibitor of lipometabolic compound such as lipidemia activeconstituents and anti-lipid activeconstituents, cholesterol transport/cholesterol uptake inhibitor, bile acide reuptake inhibithors or microsomal triglyceride transfer protein (MTP) inhibitor, reduce the compound of ingestion of food, PPAR and rxr agonist and the activeconstituents that acts on β cell ATP-dependency potassium channel.
In one embodiment of the invention, The compounds of this invention can with the insulin combination administration.
In further embodiment, The compounds of this invention can with sulfonylurea such as tolbutamide, U26452, glimepiride, Glipizide, gliquidone, glisoxepide, glibornuride or gliclazide Combined Preparation.
In another embodiment, The compounds of this invention can with biguanides such as N1,N1-Dimethylbiguanide Combined Preparation.
In another embodiment, The compounds of this invention can with meglitinide class such as repaglinide Combined Preparation.
In another embodiment, The compounds of this invention can with the thiazolidinedione Combined Preparation, as troglitazone, ciglitazone, pioglitazone, rosiglitazone or be disclosed in compound among the WO 97/41097 of doctor's Reddy WARF, 5-[[4-[(3 particularly, 4-dihydro-3-methyl-4-oxo-2-quinazolyl methoxyl group) phenyl] methyl]-2, the 4-thiazolidinedione.
In further embodiment, The compounds of this invention can with alpha-glucosidase inhibitor such as miglitol or acarbose Combined Preparation.
In another embodiment, The compounds of this invention can with the activeconstituents Combined Preparation that acts on β cell ATP-dependency potassium channel, described activeconstituents is for example tolbutamide, U26452, glimepiride, Glipizide, gliclazide or repaglinide.
In another embodiment, The compounds of this invention can with lipidemia activeconstituents or anti-lipid activeconstituents Combined Preparation, described activeconstituents is for QUESTRAN for example, colestipol, chlorine Bei Te, fenofibrate, gemfibrozil, lovastatin, Pravastatin, Simvastatin, atorvastatin, Cerivastatin, fluvastatin, probucol, according to Ezetimibe or dextrothyroxine.
In further embodiment, The compounds of this invention can with more than one compound Combined Preparation mentioned above, as with Combined Preparation such as sulfonylurea and N1,N1-Dimethylbiguanide, sulfonylurea and acarbose, repaglinide and N1,N1-Dimethylbiguanide, Regular Insulin and sulfonylurea, Regular Insulin and N1,N1-Dimethylbiguanide, Regular Insulin and troglitazone, Regular Insulin and lovastatin.
The compounds of this invention also can with one or more anti-obesity medicines or appetite stimulator activeconstituents Combined Preparation.
This active component can be selected from following: the CART agonist; the NPY antagonist; the MCH antagonist; increase the food factor (orexin) antagonist; the H3 antagonist; the TNF agonist; the CRF agonist; CRF BP antagonist; excellent Luo Keding (urocortin) agonist; β 3 agonists; MSH (melanophorin) agonist; the CCK agonist; serotonin reuptake inhibitor; the blended serotonin-and NRI; the 5HT conditioning agent; the MAO inhibitor; the bombesin agonist; Gan Bingsu (galanin) antagonist; tethelin; tethelin-release compound; the TRH agonist; uncoupling protein 2 or 3 conditioning agents; the leptin agonist; dopamine agonist (bromocriptine, Doprexin); lipase/amylase inhibitor; hemp ester acceptor 1 antagonist; short acylated protein (ASP) conditioning agent; the PPAR conditioning agent; the RXR conditioning agent; hCNTF agonist or TR-beta-agonists.
In one embodiment of the invention, the anti-obesity medicine is the leptin of leptin or modification.
In another embodiment, the anti-obesity medicine is dexamphetamine or Amphetamine.
In another embodiment, the anti-obesity medicine is Phenfluoramine or dexfenfluramine.
In another embodiment, the anti-obesity medicine is list-and two demethylation active metabolites of sibutramine or sibutramine.
In further embodiment, the anti-obesity medicine is an orlistat.
In another embodiment, the anti-obesity medicine is Mazindol, Diethylpropion or phentermine.
The compounds of this invention can also with one or more antihypertensive active composition drug combinations.The example of antihypertensive active composition has beta-blocker such as alprenolol, atenolol USP 23, timolol, pindolol, Proprasylyte and metoprolol, ACE (angiotensin-converting enzyme) inhibitor, as Zinadril Briem, captopril, enalapril, fosinopril, lisinopril, quinapril and Ramipril, calcium channel blocker, as nifedipine, felodipine, nicardipine, Isrodipine, nimodipine, diltiazem and verapamil, and alpha blocker, as Doxazosin, urapidil, Prazosin and terazosin.In addition can be with reference to Remington:The Science and Practice of Pharmacy, the 19th edition, Gennaro compiles, Mack Publishing Co., Easton, PA, 1995.
The compounds of this invention and one or more aforesaid compounds and choose any one kind of them or each suitable combination of multiple other medicines activeconstituents all is regarded as being included in the scope that the present invention protects.
The effect of following test compounds:
The biological test model:
Subtract the appetite effect with female NMRI mouse test.After the fasting 24 hours, test product by gavage.Animal is raised separately, freely drinks water and enriching milk was provided after giving described product in 30 minutes.Measure the enriching milk consumption per half an hour, METHOD FOR CONTINUOUS DETERMINATION 7 hours, the general health situation of observing animal.With the control animal of the milk consumption measured and vehicle treatment relatively.
Table 1: by comparing with control animal, the minimizing of treatment animal accumulation milk consumption is measured subtracts the appetite effect
| Embodiment | Oral dosage [mg/kg] | Number of animals/treatment animal accumulation milk consumption N/[ml] | Number of animals/control animal accumulation milk consumption N/[ml] | The % that the minimizing of accumulation milk consumption is equivalent to contrast |
| 2 | 50 | 10/4.90 | 10/5.48 | 11 |
Can find out obviously that by table 1 formula I compound exhibits has the good appetite effect that subtracts and also therefore is highly suitable for as diet pill.
Embodiment described below and preparation method are used to illustrate the present invention and unrestricted the present invention.
General method
Employed parent material is purchased in chemical preparations supplier such as Aldrich, Acros, Sigma, Fluka, Nova Biochem, Advanced Chemtech, Bachem, Lancaster and other companies in synthetic.
In building-up process, the functional group of employed amino acid derivative protects to prevent that side reaction takes place in coupling step by protecting group.The example and the application thereof of suitable protecting group are described in ThePeptides, supra,, the 9th volume, Udenfriend and Meienhofer (editor) 1987 (being incorporated herein by reference) in 1981.
The compounds of this invention is by using general solid phase synthesis process preparation.For example, described method is described in the Solid Phase Peptide Synthesis (Freeman﹠amp of Steward and Young; Co., SanFrancisco 1969) (being incorporated herein by reference).
Unless otherwise indicated, described compound usefulness TentaGel HL12019 resin (RappPolymere, T ü bingen) is synthetic.The obtainable polymkeric substance in this commercial channel contains the bromine acetal and connects base.This kind coupling can be passed through Vojkovsky, T. wait the people at J.Org.Chem.1998,63, among the 3162-3163 and Patek, M. at Combinatorial Chemistry 2000, London, the general method of describing among the 11.-14.7.2000 introduce all types of hydroxyl-TentaGel (being incorporated herein for reference).
In the first step is synthetic (general synthetic schemes is seen synthetic schemes 1), at high temperature, in DMSO, replace bromine in the bromine acetal bonds with amine.The amino acid of Fmoc-protection is coupled on the secondary amine that is created in thus on the polymkeric substance.This coupling is carried out with DIC/HOAt or HATU/DIEA in DMF usually.This coupling at room temperature (RT) was carried out 16 hours or was carried out under 55 ℃ 4-5 hour.The DMF solution of eliminating available 50% piperidines of protection of Fmoc base carries out (5+15 minute).Thereby can by remove volume that the optical density of protection back measuring solution in 302nm place measures the amount of the Fmoc that discharges, washings and synthetic in the weight mensuration replacement situation of used polymkeric substance; this can be according to Krchnak, and V. etc. carry out in method described in the Collect.Czech.Chem.Commun.53 (1988) 2542 (being incorporated herein by reference).
Then, the structural free amine group that will be connected with solid phase is coupled on the Fmoc-Beta-alanine (or beta-amino acids of Fmoc-a-amino acid or replacement).This coupling in DMF, is used N usually in the presence of HOBt, N '-DIC (DIC) carries out.Whether monitor this coupling by ninhydrin reaction complete.
The protection of elimination Fmoc base was carried out 5+15 minute with the DMF solution of 50% piperidines.Discharge Fmoc amount by remove the optical density of protection back solution at 302nm, synthetic in the volume of employed washings and the flow measurement of polymkeric substance.
Then, the structural free amine group that will be connected with solid phase is in DCM or acetonitrile, with the suitable SULPHURYL CHLORIDE/DIEA sulfonylation of 2 equivalents.Whether monitor this sulfonylation by ninhydrin reaction complete.
The straight chain compound precursor is after the combination on the polymkeric substance is finished, in succession with DMF and DCM or THF washing solid phase and vacuum-drying.
Needed compound is with formic acid cyclisation cracking at room temperature 18-24 hour, or carries out under 50 ℃ 6 hours or undertaken by the combination of two kinds of conditions.Filter polymkeric substance and with DCM or formic acid washing.Washings is incorporated in the formic acid solution.Evaporate this solution.Resistates is dissolved in the mixture of water and acetonitrile and lyophilize.
The exsiccant compound is by the HPLC purifying, with the 0.1%TFA aqueous solution-acetonitrile (ACN) wash-out of suitable gradient.After collection contains the peak of required synthetic product, with the solution lyophilize of compound.In order to determine synthetic correct compound, described compound is analyzed with electrospray ionization mass spectrum (LC/MS) and/or NMR and is carried out qualitative test.
In HPLC analyzes, utilization contains YMC ODS-AM 4.6 * 250mm post (S-5 (5 μ m), YMC, Inc.Wilmington, NC, USA) Beckman HPLC system (comprise solvent plenum system 126, program detection device module 166 and automatic sampler 507e and by the data station control of GoldNouveau software is housed), analysis of compounds sample under 230nm.In this device, flow velocity is that 1ml/min and eluent are the water/0.1%TFA damping fluid and the ACN (HPL level) of gradient.
Synthetic schemes 1:
Compound also can be in solution, according to described similar method preparation of synthesizing (synthetic schemes 2) on resin.Replace functional resin, in the first step, can be with 2-bromo-1,1-diethoxyethane and primary amine reaction.
Synthetic schemes 2:
According to the similar method of solid phase synthesis, with the reaction of resulting product and amino acid.Replace Fmoc, can will introduce the allyloxy carbonyl protecting group (Aloc) of (Aloc-Cl, triethylamine) and elimination (Pd (PPh3) 4, dimethyl barbituric acid) by the currently known methods described in the document as amino acid whose amino protecting group.
The aminocarboxylic acid and the SULPHURYL CHLORIDE that will contain radicals R 4 are reacted in the presence of triethylamine.(EDC HOBt) is coupled to the free carboxy acid by on the unhindered amina of eliminating the acquisition of Aloc base by the carbodiimide method.
The acid cyclisation and the ensuing further functionalization of the straight chain precursor that obtains with this method are carried out with above-mentioned similar method.
For purified product, with the sample dissolution of lyophilize crude product in the mixture of the 0.1%TFA aqueous solution and 10-50% acetonitrile or be dissolved in the acetate.This compound solution is usually by being connected to ACRODISC 13 CR PTFE 0.45 μ m strainer (Gelman Sciences; Ann Arbor, MI, USA) syringe filtering on.The filtrate of the compound of appropriate volume is expelled on the half preparation C18 post (YMC ODS-AM, S-5 (5 μ m), 20 * 150mm, YMC, Inc., Wilmington, NC, USA).The flow velocity of the water of gradient/0.1%TFA damping fluid and ACN (HPL level) eluent is by Beckman SYSTEM GOLD HPLC (Gold system, programmable solvent module 126 and programmable detector module 166 are by SYSTEM GOLD software control) keep.By the UV detector 230 or the wash-out of 280nm monitoring compound.Determine the peak of institute's synthetic compound by LC/MS after, collect compound, lyophilize is also carried out the biology test.
Behind the purifying, obtain containing the trifluoroacetate of the compound of basic group.The hydrochloride of these compounds can be by handling the trifluoroacetate preparation of compound with excessive HCl/ diox.Behind the evaporating solvent, with the hydrochloride of compound with ether sedimentation and pass through filtering separation.
Can adopt PE Sciex API 150EX and Sciex MassChrom software to carry out LC/MS in the ES+ mode, Gilson 215 liquid processors, two Shimadzu LC-10AD liquid modules, a Shimadzu SPD-10A monitor, Keystone Betasil C-18 post (a 2 * 30mm wherein are housed, 3 μ m, acetonitrile/water/0.1%TFA gradient flow velocity is 0.7ml/min).
In NMR analyzed, sample was at DMSO-d
6(Aldrich) measure with Bruker Avance DPX300 in.
Abbreviation
Unless otherwise indicated, the abbreviation in the following example has following meanings:
The ACN=acetonitrile
The Aloc=allyloxy carbonyl
The DIC=DIC
EDC=1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
FMOC=9-fluorenyl methoxy carbonyl
DCE=1, the 2-ethylene dichloride
The DIEA=diisopropyl ethyl amine
NaBH
3The CN=sodium cyanoborohydride
DMAP=N, the N-dimethyl aminopyridine
DMF=N, dinethylformamide
The THF=tetrahydrofuran (THF)
The DIC=DIC
The DMSO=dimethyl sulfoxide (DMSO)
The DCM=methylene dichloride
The HOBt=1-hydroxybenzotriazole
HOAt=1-hydroxyl-7-azepine benzotriazole
HATU=dimethylamino ([1,2,3] triazolo [4,5-b] pyridin-3-yl oxygen base) methylene radical dimethyl-ammonium hexafluorophosphate
HOAc=acetate
The Et3N=triethylamine
HCl=hydrochloric acid
The HBr=Hydrogen bromide
The HPLC=high performance liquid chromatography
The following example is explained the present invention in more detailed mode, but the present invention is not limited to product and specific embodiments described in the embodiment.
Embodiment 1
6-(4-benzyl chloride base)-1-(2,4 dichloro benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
0.5g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine (reagent 1), and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-4-chlorophenylalanine (reagent 2) (3 equivalent) is coupled on the secondary amine of polymkeric substance with HOAt (3 equivalent) and DIC (3 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture is at room temperature placed and is spent the night.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: 0.2M) of DIC (3 equivalent) coupling with Fmoc-Beta-alanine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with DCM washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with 1.5 equivalent 2,4 dichloro benzene SULPHURYL CHLORIDE (reagent 3) and the acetonitrile solution of 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with DCM washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 16 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=543.06 (calculated value, single isotropic substance); Measured value (M+H)
+: 544.3.
Embodiment 2
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
0.3g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine (reagent 1), and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-(S)-4-chlorophenylalanine (reagent 2) (3 equivalent) is coupled on the secondary amine of polymkeric substance with HATU (3 equivalent) and DIEA (9 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture was placed 4 hours down at 55 ℃.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-Beta-alanine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with DCM washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides (reagent 3) and the acetonitrile solution of 3 equivalent DIEA with DMF washing 5 times.Then with the DMF washing, with THF washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 16 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=539.10 (calculated value, single isotropic substance); Measured value (M+H)
+: 540.3.
Embodiment 3
6-benzyl-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
0.3g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine, and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-(S)-4-phenylalanine (3 equivalent) is coupled on the secondary amine of polymkeric substance with HATU (3 equivalent) and DIEA (9 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture was placed 4 hours down at 55 ℃.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-Beta-alanine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with DCM washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with the acetonitrile solution of 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides and 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with THF washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 16 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=505.14 (calculated value, single isotropic substance); Measured value (M+H)
+: 506.3.
Embodiment 4
1-(5-chloro-2-anisole alkylsulfonyl)-6-(3, the 4-dichloro benzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
0.3g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine, and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
With Fmoc-(S)-3,4-dichlorobenzene L-Ala (3 equivalent) is coupled on the secondary amine of polymkeric substance with HATU (3 equivalent) and DIEA (9 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture was placed 4 hours down at 55 ℃.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-Beta-alanine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with DCM washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with the acetonitrile solution of 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides and 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with THF washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 16 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=573.07 (calculated value, single isotropic substance); Measured value (M+H)
+: 574.3.
Embodiment 5
8-allyl group-1-(naphthalene-2-alkylsulfonyl)-6-(4-nitrobenzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone structure:
0.3g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M allyl amines, and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-(S)-4-oil of mirbane L-Ala (3 equivalent) is coupled on the secondary amine of polymkeric substance with HATU (3 equivalent) and DIEA (9 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture was placed 4 hours down at 55 ℃.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-Beta-alanine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with DCM washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with the acetonitrile solution of 1.5 equivalent 2-naphthyl SULPHURYL CHLORIDE and 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with THF washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 16 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=534.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 535.3.
Embodiment 6
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-3-hydroxyl-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
0.5g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine, and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-4-chlorophenylalanine (3 equivalent) is coupled on the secondary amine of polymkeric substance with HOAt (3 equivalent) and DIC (3 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture is at room temperature placed and is spent the night.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-isoserine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with DCM washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with the DCM solution of 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides and 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with DCM washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 16 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=555.10 (calculated value, single isotropic substance); Measured value (M+H)
+: 556.3.
Embodiment 7
5-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-7-sec.-propyl imidazolidine is [1,2-a] pyrazine-3 also, the 6-diketone
Structure:
0.3g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine, and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-4-chlorophenylalanine (3 equivalent) is coupled on the secondary amine of polymkeric substance with HOAt (3 equivalent) and DIC (3 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture is at room temperature placed and is spent the night.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-glycine (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with acetonitrile washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with the acetonitrile solution of 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides and 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with DCM washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 24 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=525.09 (calculated value, single isotropic substance); Measured value (M+H)
+: 526.3.
Embodiment 8
5-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-7-sec.-propyl-2-methyl imidazolidine is [1,2-a] pyrazine-3 also, the 6-diketone
Structure:
0.3g TentaGel HL12019 (the bromine acetal connects base, S=0.5mmol/g, RappPolymere, T ü bingen) is washed with DMSO.The DMSO solution that adds 20 equivalent 2M isopropylamine, and this mixture kept 15 hours in 60 ℃ of encloses containers.Polymkeric substance washs 7 times with DMF.
Fmoc-4-chlorophenylalanine (3 equivalent) is coupled on the secondary amine of polymkeric substance with HOAt (3 equivalent) and DIC (3 equivalent) in DMF.Ultimate density is 0.2-0.3M.Reaction mixture is at room temperature placed and is spent the night.Polymkeric substance washs 6 times with DMF.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
In DMF, use HOBt (3 equivalent) and at least 4 hours (ultimate densities: about 0.2M) of DIC (3 equivalent) coupling with Fmoc-(R)-L-Ala (3 equivalent) then.The Fmoc protecting group is removed (5+15 minute) with the DMF solution of 50% piperidines.
Polymkeric substance with acetonitrile washing 4 times, mixes (ultimate density: 0.1-0.15M), at room temperature react 5 hour with the acetonitrile solution of 1.5 equivalent 2-methoxyl group-5-chlorobenzene sulfonyl chlorides and 3 equivalent DIEA with DMF washing 5 times.Then with DMF washing 5 times, with DCM washing 5 times and vacuum-drying.
In the cyclisation cracking process, the exsiccant polymkeric substance is mixed also jolting at room temperature 24 hours with 10ml formic acid.Filter polymkeric substance and wash with DCM.The filtrate that vacuum-evaporation merges.Dissolving crude product is also lyophilize in the mixture of acetonitrile and water.By obtaining pure title compound behind the HPLC purifying.This example is used the system and method for describing in " general method ".MW=539.10 (calculated value, single isotropic substance); Measured value (M+H)
+: 540.3.
Embodiment 9
1-(5-chloro-2-anisole alkylsulfonyl)-6-cyclohexyl methyl-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 9 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-Cyclohexylalanine
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=511.19 (calculated value, single isotropic substance); Measured value (M+H)
+: 512.3.
Embodiment 10
1-(5-chloro-2-anisole alkylsulfonyl)-6-cyclohexyl-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 10 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-Cyclohexylglycine
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=497.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 498.3.
Embodiment 11
1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-6-styroyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 11 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-hyperphenylalaninemia
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=519.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 520.3.
Embodiment 12
1-(5-chloro-2-anisole alkylsulfonyl)-6-indane-1-base-8-sec.-propyl-hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 12 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-indanyl glycine
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=531.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 532.3.
Embodiment 13
1-(5-chloro-2-anisole alkylsulfonyl)-6-[2-(4-hydroxy phenyl) ethyl]-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 13 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
The high tyrosine of reagent 2:Fmoc-
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=535.15 (calculated value, single isotropic substance); Measured value (M+H)
+: 536.3.
Embodiment 14
8-sec.-propyl-6-(4-methoxy-benzyl)-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 14 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-O-methyltyrosine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=515.21 (calculated value, single isotropic substance); Measured value (M+H)
+: 516.3.
Embodiment 15
6-(4-luorobenzyl)-8-sec.-propyl-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 15 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-fluorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=503.19 (calculated value, single isotropic substance); Measured value (M+H)
+: 504.3.
Embodiment 16
8-sec.-propyl-1-(2-methoxyl group-5-Methyl benzenesulfonyl base)-6-(4-methyl-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 16 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-methylbenzene L-Ala
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=499.21 (calculated value, single isotropic substance); Measured value (M+H)
+: 500.3.
Embodiment 17
6-(4-bromobenzyl)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 17 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-bromophenyl alanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=583.05 (calculated value, single isotropic substance); Measured value (M+H)
+: 584.3.
Embodiment 18
1-(5-chloro-2-anisole alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 18 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-fluorophenylalanine
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=523.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 524.3.
Embodiment 19
1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-6-(4-methyl-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 19 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-methylbenzene L-Ala
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=519.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 520.3.
Embodiment 20
1-(4-bromo-2-ethylbenzene alkylsulfonyl)-8-sec.-propyl-6-(4-methoxy-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 20 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-O-methyltyrosine
Reagent 3:2-ethyl-4-bromobenzene sulfonyl chloride
MW=577.12 (calculated value, single isotropic substance); Measured value (M+H)
+: 578.3.
Embodiment 21
6-(4-bromobenzyl)-1-(4-bromo-2-ethylbenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 21 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-bromophenyl alanine
Reagent 3:2-ethyl-4-bromobenzene sulfonyl chloride
MW=625.02 (calculated value, single isotropic substance); Measured value (M+H)
+: 626.4.
Embodiment 22
1-(4-bromo-2-ethylbenzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 22 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-fluorophenylalanine
Reagent 3:2-ethyl-4-bromobenzene sulfonyl chloride
MW=565.10 (calculated value, single isotropic substance); Measured value (M+H)
+: 566.3.
Embodiment 23
1-(4-bromo-2-ethylbenzene alkylsulfonyl)-8-sec.-propyl-6-(4-methyl-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 23 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-methylbenzene L-Ala
Reagent 3:2-ethyl-4-bromobenzene sulfonyl chloride
MW=561.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 562.3.
Embodiment 24
8-sec.-propyl-6-(4-methoxy-benzyl)-1-(3-trifluoromethyl benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 24 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-O-methyltyrosine
Reagent 3:3-trifluoromethyl benzene sulfonyl chloride
MW=539.17 (calculated value, single isotropic substance); Measured value (M+H)
+: 540.3.
Embodiment 25
6-(4-bromobenzyl)-8-sec.-propyl-1-(3-trifluoromethyl benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 25 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-bromophenyl alanine
Reagent 3:3-trifluoromethyl benzene sulfonyl chloride
MW=587.07 (calculated value, single isotropic substance); Measured value (M+H)
+: 588.3.
Embodiment 26
6-(4-luorobenzyl)-8-sec.-propyl-1-(3-trifluoromethyl benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 26 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-fluorophenylalanine
Reagent 3:3-trifluoromethyl benzene sulfonyl chloride
MW=527.15 (calculated value, single isotropic substance); Measured value (M+H)
+: 528.3.
Embodiment 27
8-sec.-propyl-6-(4-methyl-benzyl)-1-(3-trifluoromethyl benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 27 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-methylbenzene L-Ala
Reagent 3:3-trifluoromethyl benzene sulfonyl chloride
MW=523.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 524.3.
Embodiment 28
1-(2,5-dimethyl benzene alkylsulfonyl)-8-sec.-propyl-6-(4-methoxy-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 28 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-O-methyltyrosine
Reagent 3:2,5-dimethyl benzene SULPHURYL CHLORIDE
MW=499.21 (calculated value, single isotropic substance); Measured value (M+H)
+: 500.3.
Embodiment 29
6-(4-bromobenzyl)-1-(2,5-dimethyl benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 29 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-bromophenyl alanine
Reagent 3:2,5-dimethyl benzene SULPHURYL CHLORIDE
MW=547.11 (calculated value, single isotropic substance); Measured value (M+H)
+: 548.3.
Embodiment 30
1-(2,5-dimethyl benzene alkylsulfonyl)-6-(4-luorobenzyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 30 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-fluorophenylalanine
Reagent 3:2,5-dimethyl benzene SULPHURYL CHLORIDE
MW=487.19 (calculated value, single isotropic substance); Measured value (M+H)
+: 488.3.
Embodiment 31
1-(2,5-dimethyl benzene alkylsulfonyl)-8-sec.-propyl-6-(4-methyl-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 31 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-methylbenzene L-Ala
Reagent 3:2,5-dimethyl benzene SULPHURYL CHLORIDE
MW=483.22 (calculated value, single isotropic substance); Measured value (M+H)
+: 484.3.
Embodiment 32
6-(4-benzyl chloride base)-1-(4-chloro-2,5-dimethyl benzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 32 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:4-chloro-2,5-dimethyl benzene SULPHURYL CHLORIDE
MW=537.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 538.3.
Embodiment 33
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-oil of mirbane alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 33 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-nitrobenzene sulfonyl chloride
MW=520.12 (calculated value, single isotropic substance); Measured value (M+H)
+: 521.3.
Embodiment 34
6-(4-benzyl chloride base)-1-(2,4-two chloro-5-Methyl benzenesulfonyl bases)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 34 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2,4-two chloro-5-Methyl benzenesulfonyl chlorine
MW=557.07 (calculated value, single isotropic substance); Measured value (M+H)
+: 558.3.
Embodiment 35
6-(4-benzyl chloride base)-1-(2-chloro-4-trifluoromethyl benzenesulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 35 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-chloro-4-trifluoromethyl benzene sulfonyl chloride
MW=557.08 (calculated value, single isotropic substance); Measured value (M+H)
+: 578.3.
Embodiment 36
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-methyl-5-nitro benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 36 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methyl-5-nitro benzene sulfonyl chloride
MW=534.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 535.3.
Embodiment 37
1-(4-bromo-2-trifluoromethoxy benzenesulfonyl)-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 37 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:4-bromo-2-trifluoromethoxy benzene sulfonyl chloride
MW=637.03 (calculated value, single isotropic substance); Measured value (M+H)
+: 638.4.
Embodiment 38
6-(1-benzyl-1H-imidazol-4 yl methyl)-1-(4-bromo-2-ethylbenzene alkylsulfonyl)-8-(2-pyridin-4-yl-ethyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 38 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1:2-(4-pyridyl) ethylamine
Reagent 2:Fmoc-Histidine (benzyl)
Reagent 3:4-bromo-2-ethylbenzene SULPHURYL CHLORIDE
MW=690.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 691.4.
Embodiment 39
1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-6-(4-nitrobenzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 39 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-oil of mirbane L-Ala
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=550-13 (calculated value, single isotropic substance); Measured value (M+H)
+: 551.3.
Embodiment 40
6-(4-benzyl chloride base)-8-sec.-propyl-1-(naphthalene-2-alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone structure:
The method of compound among the embodiment 40 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-naphthyl SULPHURYL CHLORIDE
MW=525.15 (calculated value, single isotropic substance); Measured value (M+H)
+: 526.3.
Embodiment 41
6-(3, the 4-dichloro benzyl)-8-sec.-propyl-1-(naphthalene-2-alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 41 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-3,4-dichlorobenzene L-Ala
Reagent 3:2-naphthyl SULPHURYL CHLORIDE
MW=559.11 (calculated value, single isotropic substance); Measured value (M+H)
+: 560.3.
Embodiment 42
6-(3, the 4-dichloro benzyl)-1-(3,4-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 42 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-3,4-dichlorobenzene L-Ala
Reagent 3:3,4-dimethoxy benzene sulfonyl chloride
MW=569.12 (calculated value, single isotropic substance); Measured value (M+H)
+: 570.3.
Embodiment 43
8-allyl group-1-(4-bromo-2-ethylbenzene alkylsulfonyl)-6-(4-benzyl chloride base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 43 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: allyl amine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-ethyl-4-bromobenzene sulfonyl chloride
MW=579.06 (calculated value, single isotropic substance); Measured value (M+H)
+: 580.3.
Embodiment 44
8-allyl group-1-(4-bromo-2-ethylbenzene alkylsulfonyl)-6-(4-nitrobenzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 44 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: allyl amine
Reagent 2:Fmoc-4-oil of mirbane L-Ala
Reagent 3:2-ethyl-4-bromobenzene sulfonyl chloride
MW=590.08 (calculated value, single isotropic substance); Measured value (M+H)
+: 591.3.
Embodiment 45
8-allyl group-1-(5-chloro-2-anisole alkylsulfonyl)-6-(3, the 4-dichloro benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 45 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: allyl amine
Reagent 2:Fmoc-3,4-dichlorobenzene L-Ala
Reagent 3:5-chloro-2-anisole SULPHURYL CHLORIDE
MW=571.05 (calculated value, single isotropic substance); Measured value (M+H)
+: 572.3.
Embodiment 46
8-allyl group-1-(naphthalene-2-alkylsulfonyl)-6-(4-nitrobenzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 46 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: allyl amine
Reagent 2:Fmoc-4-oil of mirbane L-Ala
Reagent 3:2-naphthyl SULPHURYL CHLORIDE
MW=534.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 535.3.
Embodiment 47
1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-6-pyridin-4-yl methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 47 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-pyridyl L-Ala
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=506.14 (calculated value, single isotropic substance); Measured value (M+H)
+: 507.3.
Embodiment 48
1-(5-bromo-2-anisole alkylsulfonyl)-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 48 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:5-bromo-2-anisole SULPHURYL CHLORIDE
MW=583.05 (calculated value, single isotropic substance); Measured value (M+H)
+: 584.3.
Embodiment 49
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 49 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=519.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 520.3.
Embodiment 50
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-trifluoromethoxy benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 50 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-trifluoromethoxy benzene sulfonyl chloride
MW=559.12 (calculated value, single isotropic substance); Measured value (M+H)
+: 560.3.
Embodiment 51
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-methylsulfonyl benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 51 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methyl sulphonyl benzene sulfonyl chloride
MW=553.11 (calculated value, single isotropic substance); Measured value (M+H)
+: 554.3.
Embodiment 52
3-[6-(4-benzyl chloride base)-8-sec.-propyl-4,7-dioxo hexahydropyrazine is [1,2-a] pyrimidine-1-alkylsulfonyl also] the benzonitrile structure:
The method of compound among the embodiment 52 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:3-cyano group benzene sulfonyl chloride
MW=500.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 501.3.
Embodiment 53
6-(4-benzyl chloride base)-8-sec.-propyl-1-(3-trifluoromethyl benzenesulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 53 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:3-trifluoromethyl benzene sulfonyl chloride
MW=543.12 (calculated value, single isotropic substance); Measured value (M+H)
+: 544.3.
Embodiment 54
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2,4,6-trichlorobenzene alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 54 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2,4,6-trichlorobenzene SULPHURYL CHLORIDE
MW=577.02 (calculated value, single isotropic substance); Measured value (M+H)
+: 578.3.
Embodiment 55
6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 55 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2,5-dimethoxy benzene sulfonyl chloride
MW=535.15 (calculated value, single isotropic substance); Measured value (M+H)
+: 536.3.
Embodiment 56
6-(4-benzyl chloride base)-1-(2,5-dichlorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 56 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2, the 5-two chloro phenylsulfonyl chloride
MW=543.06 (calculated value, single isotropic substance); Measured value (M+H)
+: 544.3.
Embodiment 57
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-4,7-dioxo octahydro pyrazine is [1,2-a] pyrimidine-2-allyl formiate also
Structure:
The method of compound among the embodiment 57 by describing among the embodiment 1, utilize following reagent synthetic through following change:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
After this step and after eliminating the Fmoc protection, under identical condition, use the allylic step of coupling Fmoc-Asp (OH)-O-to replace the step of coupling Fmoc-Beta-alanine in embodiment 1 method.After eliminating the Fmoc protection, synthetic with reagent 3 continuation according to the method for embodiment 1.
Reagent 3:5-chloro-2-anisole SULPHURYL CHLORIDE
MW=623.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 624.4.
Embodiment 58
1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-6-(4-methoxy-benzyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 58 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-O-methyltyrosine
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=535.15 (calculated value, single isotropic substance); Measured value (M+H)
+: 536.3.
Embodiment 59
2-(the amino butyl of 4-)-6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 59 by describing among the embodiment 1, utilize following reagent synthetic through following change:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
After this step and after eliminating the Fmoc protection, under identical condition, use the step of coupling Fmoc-β-high-lysine (Boc) to replace the step of coupling Fmoc-Beta-alanine in embodiment 1 method.After eliminating the Fmoc protection, synthetic with reagent 3 continuation according to the method for embodiment 1.
Reagent 3:5-chloro-2-anisole SULPHURYL CHLORIDE
MW=610.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 611.4.
Embodiment 60
6-(4-benzyl chloride base)-8-ethyl-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 60 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: ethylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=505.14 (calculated value, single isotropic substance); Measured value (M+H)
+: 506.3.
Embodiment 61
6-(4-benzyl chloride base)-1-(2-methoxyl group-5-Methyl benzenesulfonyl base)-8-methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 61 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: methylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=491.13 (calculated value, single isotropic substance); Measured value (M+H)
+: 492.3.
Embodiment 62
6-(4-benzyl chloride base)-8-isobutyl--1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 62 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isobutylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=533.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 534.3.
Embodiment 63
6-(4-benzyl chloride base)-8-isobutyl--1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 63 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1:2-butylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=533.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 534.3.
Embodiment 64
1-(5-chloro-2-anisole alkylsulfonyl)-8-sec.-propyl-6-pyridin-3-yl methyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 64 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-3-pyridyl L-Ala
Reagent 3:5-chloro-2-anisole SULPHURYL CHLORIDE
MW=506.14 (calculated value, single isotropic substance); Measured value (M+H)
+: 507.3.
Embodiment 65
6-(4-benzyl chloride base)-8-cyclopropyl-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 65 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: cyclopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=517.14 (calculated value, single isotropic substance); Measured value (M+H)
+: 518.3.
Embodiment 66
6-(4-benzyl chloride base)-8-cyclopentyl-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 66 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: cyclopentyl amine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=545.18 (calculated value, single isotropic substance); Measured value (M+H)
+: 546.3.
Embodiment 67
6-(4-benzyl chloride base)-1-(2-methoxyl group-5-Methyl benzenesulfonyl base)-8-propyl group hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 67 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: n-propyl amine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=519.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 520.3.
Embodiment 68
8-allyl group-6-(4-benzyl chloride base)-1-(2-methoxyl group-5-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 68 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: allyl amine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-Methyl benzenesulfonyl chlorine
MW=517.14 (calculated value, single isotropic substance); Measured value (M+H)
+: 518.2.
Embodiment 69
1-(5-bromo-2-anisole alkylsulfonyl)-6-(4-benzyl chloride base)-8-ethyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 69 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: ethylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-bromobenzene sulfonyl chloride
MW=569.04 (calculated value, single isotropic substance); Measured value (M+H)
+: 570.3.
Embodiment 70
6-(4-benzyl chloride base)-1-(5-chloro-2-anisole alkylsulfonyl)-8-ethyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 70 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: ethylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-5-chlorobenzene sulfonyl chloride
MW=525.09 (calculated value, single isotropic substance); Measured value (M+H)
+: 526.3.
Embodiment 71
1-(4-bromo-2-ethylbenzene alkylsulfonyl)-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 71 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:5-bromo-2-ethylbenzene SULPHURYL CHLORIDE
MW=581.08 (calculated value, single isotropic substance); Measured value (M+H)
+: 582.3.
Embodiment 72
6-(4-benzyl chloride base)-1-(2,5-dimethyl benzene alkylsulfonyl)-8-ethyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 72 by describing among the embodiment 2, utilize following reagent synthetic:
Reagent 1: ethylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2,5-dimethyl benzene SULPHURYL CHLORIDE
MW=489.15 (calculated value, single isotropic substance); Measured value (M+H)
+: 490.3.
Embodiment 73
2-chloro-5-[6-(4-benzyl chloride base)-8-sec.-propyl-4,7-dioxo hexahydropyrazine is [1,2-a] pyrimidine-1-alkylsulfonyl also] benzsulfamide
Structure:
The method of compound among the embodiment 73 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:4-chloro-2-sulfuryl amino benzene sulfonyl chloride
MW=588.07 (calculated value, single isotropic substance); Measured value (M+H)
+: 589.3.
Embodiment 74
6-(4-benzyl chloride base)-1-(2,4-two chloro-6-Methyl benzenesulfonyl bases)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 74 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methyl-4, the 6-two chloro phenylsulfonyl chloride
MW=557.08 (calculated value, single isotropic substance); Measured value (M+H)
+: 558.3.
Embodiment 75
6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-methoxyl group-4-Methyl benzenesulfonyl base) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
The method of compound among the embodiment 75 by describing among the embodiment 1, utilize following reagent synthetic:
Reagent 1: isopropylamine
Reagent 2:Fmoc-4-chlorophenylalanine
Reagent 3:2-methoxyl group-4-Methyl benzenesulfonyl chlorine
MW=519.16 (calculated value, single isotropic substance); Measured value (M+H)
+: 520.3.
Embodiment 76
6-(4-benzyl chloride base)-8-sec.-propyl-1-(4-anisole alkylsulfonyl) hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-anisole sulfuryl amino) propionyl amino] propionic acid amide
52mg EDC, 45mg HOBt and 100 μ l N-ethylmorpholines are added in the 1ml DMF solution of 124mg 3-(4-anisole sulfuryl amino) propionic acid.To the 1ml DMF solution that wherein drips 100mg 2-amino-3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl propionic acid amide, and with this mixture stirring 12 hours.Filtering reacting solution mixes with ethyl acetate, extracts with 5% sodium bicarbonate aqueous solution and sodium chloride aqueous solution then.With the dry organic phase of Chromabond XTR, concentrating under reduced pressure separates resistates (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90) by HPLC then.Obtain needed product, MW=598.16 (calculated value); Measured value (M-C
2H
6O+H)
+: 552.1.
B) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(4-anisole alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
With 167mg 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-anisole sulfuryl amino) propionyl amino] solution of propionic acid amide in 3ml formic acid at room temperature stirred 12 hours.The concentrating under reduced pressure reaction soln separates resistates (KnauerEurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20 → 10/90) by HPLC.Obtain needed product, MW=506.02 (calculated value); Measured value (M+H)
+: 506.34.
Embodiment 77
1-(4-chlorobenzene alkylsulfonyl)-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(4-chlorobenzene sulfuryl amino) propionic acid.Obtain needed product, MW=602.58 (calculated value); Measured value (M-C
2H
6O+H)
+: 556.1.
B) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(4-chlorobenzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-chlorobenzene sulfuryl amino) propionyl amino]-propionic acid amide begins to synthesize.Obtain needed product, MW=510.44 (calculated value); Measured value (M+H)
+: 510.30.
Embodiment 78
6-(4-benzyl chloride base)-1-(3,4-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(3,4-dimethoxy benzene sulfuryl amino) propionic acid
With 3.8g 3, the drips of solution of 4-dimethoxy benzene sulfonyl chloride in the 5ml diox is added in the 20ml 1N NaOH solution of 1.5g 3-alanine.Stirred this mixture 12 hours, and controlled pH (pH＞7) simultaneously, make pH be lower than 7, use the dichloromethane extraction reaction soln then by adding citric acid.The organic phase dried over mgso, concentrating under reduced pressure and in ensuing reactions steps without being further purified direct use.Obtain needed product, MW=289.31 (calculated value); Measured value (M+H)
+: 290.1.
B) 3-(3, the 4-Dimethoxyphenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(3,4-dimethoxy benzene sulfuryl amino) propionic acid.Obtain needed product, MW=628.19 (calculated value); Measured value (M+H)
+: 582.3.
C) 6-(4-benzyl chloride base)-1-(3,4-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(3, the 4-Dimethoxyphenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=536.05 (calculated value); Measured value (M+H)
+: 536.36.
Embodiment 79
1-(3-chlorobenzene alkylsulfonyl)-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(2-chlorobenzene sulfuryl amino) propionic acid
According to embodiment 78a) similar method, begin to synthesize with the 2-chlorobenzene sulfonyl chloride.Obtain needed product, MW=263.70 (calculated value); Measured value (M+H)
+: 264.05.
B) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(2-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(2-chlorobenzene sulfuryl amino) propionic acid.Obtain needed product, MW=602.58 (calculated value); Measured value (M-C
2H
6O+H)
+: 556.7.
C) 1-(3-chlorobenzene alkylsulfonyl)-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(2-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=510.44 (calculated value); Measured value (M+H)
+: 510.10.
Embodiment 80
6-(4-benzyl chloride base)-1-(4-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-fluorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 78a) similar method, begin to synthesize with 3-(4-fluorobenzene sulfuryl amino) propionic acid.Obtain needed product, MW=586.13 (calculated value); Measured value (M-C
2H
6O+H)
+: 540.7.
B) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(4-fluorobenzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-fluorobenzene sulfuryl amino)-propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=493.99 (calculated value); Measured value (M+H)
+: 494.13.
Embodiment 81
6-(4-benzyl chloride base)-1-(2,5-dimethoxy benzenesulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(2,5-dimethoxy benzene sulfuryl amino) propionic acid
According to embodiment 78a) similar method, with 2,5-dimethoxy benzene sulfonyl chloride begins to synthesize.Obtain needed product, MW=289.31 (calculated value); Measured value (M+H)
+: 290.1.
B) 3-(2, the 5-Dimethoxyphenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(2,5-dimethoxy benzene sulfuryl amino) propionic acid.Obtain needed product, MW=628.19 (calculated value); Measured value (M-C
2H
6O+H)
+: 582.7.
C) 6-(4-benzyl chloride base)-1-(2,5-dimethoxy-benzenesulfonyl)-8-sec.-propyl hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(2, the 5-Dimethoxyphenyl)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(4-chlorobenzene sulfuryl amino) propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=536.05 (calculated value); Measured value (M+H)
+: 536.16.
Embodiment 82
6-(4-benzyl chloride base)-1-(3-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(3-fluorobenzene sulfuryl amino) propionic acid
According to embodiment 78a) similar method, begin to synthesize with 3-fluorobenzene SULPHURYL CHLORIDE.Obtain needed product, MW=247.25 (calculated value); Measured value (M+H)
+: 248.05.
B) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(3-fluorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(3-fluorobenzene sulfuryl amino) propionic acid.Obtain needed product, MW=586.13 (calculated value); Measured value (M-C
2H
6O+H)
+: 540.7.
C) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(3-fluorobenzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(3-fluorobenzene sulfuryl amino) propionyl amino]-propionic acid amide begins to synthesize.Obtain needed product, MW=493.99 (calculated value); Measured value (M+H)
+: 494.25.
Embodiment 83
1-benzenesulfonyl-6-(4-benzyl chloride base)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(benzenesulfonyl amino) propionyl amino] propionic acid amide
According to embodiment 78a) similar method, begin to synthesize with 3-(benzenesulfonyl amino) propionic acid.Obtain needed product, MW=568.13 (calculated value); Measured value (M-C
2H
6O+H)
+: 522.7.
B) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(benzenesulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(benzenesulfonyl amino) propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=475.99 (calculated value); Measured value (M+H)
+: 476.14.
Embodiment 84
6-(4-benzyl chloride base)-1-(2-fluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(2-fluorobenzene sulfuryl amino) propionic acid
According to embodiment 78a) similar method, begin to synthesize with 2-fluorobenzene SULPHURYL CHLORIDE.Obtain needed product, MW=247.25 (calculated value); Measured value (M+H)
+: 248.05.
B) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(2-fluorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(2-fluorobenzene sulfuryl amino) propionic acid.Obtain needed product, MW=586.13 (calculated value); Measured value (M-C
2H
6O+H)
+: 540.7.
C) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(2-fluorobenzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(2-fluorobenzene sulfuryl amino) propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=493.99 (calculated value); Measured value (M+H)
+: 494.13.
Embodiment 85
6-(4-benzyl chloride base)-1-(2,4 difluorobenzene alkylsulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(2,4 difluorobenzene sulfuryl amino) propionic acid
According to embodiment 78a) similar method, begin to synthesize with the 2,4 difluorobenzene SULPHURYL CHLORIDE.Obtain needed product, MW=265.25 (calculated value); Measured value (M+H)
+: 266.05.
B) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(2,4 difluorobenzene sulfuryl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(2,4 difluorobenzene sulfuryl amino) propionic acid.Obtain needed product, MW=604.13 (calculated value); Measured value (M-C
2H
6O+H)
+: 558.7.
C) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(2,4 difluorobenzene alkylsulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(2,4 difluorobenzene sulfuryl amino)-propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=511.99 (calculated value); Measured value (M+H)
+: 512.12.
Embodiment 86
6-(4-benzyl chloride base)-1-(3,4-difluoro benzenesulfonyl)-8-sec.-propyl hexahydropyrazine is [1,2-a] pyrimidine-4 also, the 7-diketone
Structure:
A) 3-(3,4-difluoro benzenesulfonyl amino) propionic acid
According to embodiment 78a) similar method, with 3,4-two fluoro-benzene sulfonyl chlorides begin to synthesize.Obtain needed product, MW=265.25 (calculated value); Measured value (M+H)
+: 266.05.
B) 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(3,4-difluoro benzenesulfonyl amino) propionyl amino] propionic acid amide
According to embodiment 76a) similar method, begin to synthesize with 3-(3,4-difluoro benzenesulfonyl amino) propionic acid.Obtain needed product, MW=604.13 (calculated value); Measured value (M+H)
+: 558.7.
C) 6-(4-benzyl chloride base)-8-sec.-propyl-1-(3,4-difluoro benzenesulfonyl) hexahydropyrazine [1,2-a] pyrimidine-4 also, the 7-diketone
According to embodiment 76b) similar method, with 3-(4-chloro-phenyl-)-N-(2,2-diethoxy ethyl)-N-sec.-propyl-2-[3-(3,4-difluoro benzenesulfonyl amino)-propionyl amino] propionic acid amide begins to synthesize.Obtain needed product, MW=511.99 (calculated value); Measured value (M+H)
+: 512.12.
Claims (17)
1, formula I compound and physiology thereof the salt that can tolerate,
Wherein the implication of each symbol is
That A represents to contain the heteroatomic 3-12 unit of one or more N of being selected from, O and S is single-, two-or spiral shell two rings, and described 3-12 unit ring can contain other substituting group 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 are H, (C independently of one another
1-C
6)-alkyl, heterocycle;
N is 0,1;
M is 0,1,2,3,4,5,6;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-and heterocycle, wherein alkylidene group can be replaced by F;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or loop systems can be substituted maximum 3 times of base replacement, and described substituting group is selected from 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 is H, F, Cl, Br, I, OH, CF
3, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, CON (R11) (R12), N (R13) (R14), (C
1-C
6)-alkyl-N (R13) (R14), COOH, COO-(C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, CO-N ((C
1-C
6)-alkyl)
2, heterocycle, wherein heterocycle cannot be by the nitrogen-atoms combination;
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-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
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-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
2, the salt that can tolerate on the formula I compound of claim 1 and the physiology thereof, wherein the implication of each symbol is
A for the heteroatomic 3-12 unit that can contain one or more N of being selected from, O and S single-, two-or spiral shell two rings, and described 3-12 unit ring can contain other substituting group 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 are H, (C independently of one another
1-C
6)-alkyl, heterocycle;
M is 1;
N is 0,1;
R1 is R8, (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9, (SO
2)-R8, (SO
2)-(C
1-C
6)-alkylidene group-R8, (SO
2)-(C
2-C
6)-alkylene group-R9, (C=O)-R8, (C=O)-(C
1-C
6)-alkylidene group-R8, (C=O) NH-R8, (C=O)-(C
2-C
6)-alkylene group-R9, (C=O)-NH-(C
1-C
6)-alkylidene group-R8, (C=O)-NH-(C
2-C
6)-alkylene group-R9, COO-R8, COO-(C
1-C
6)-alkylidene group-R8, COO-(C
2-C
6)-alkylene group-R9, alkynylene-R9, (C
1-C
4-alkyl)-heterocycle;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or loop systems can be substituted maximum 3 times of base replacement, and described substituting group is selected from 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 is H, F, Cl, Br, I, OH, CF
3, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-aryl, S-aryl, CON (R11) (R12), N (R13) (R14), (C
1-C
6)-alkyl-N (R13) (R14), COOH, COO-(C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, CO-N ((C
1-C
6)-alkyl)
2, heterocycle, wherein heterocycle cannot be by the nitrogen-atoms combination;
R3, R4, R5 are H, F, Cl, Br, I, OH, CF independently of one another
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
0-C
8)-alkylidene group-aryl, O-(C
0-C
8)-alkylidene group-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
R6 is H, F, Cl, Br, I, OH, CF
3, NO
2, CN, OCF
3, O-(C
1-C
6)-alkyl, O-(C
1-C
4)-alkoxyl group-(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 group, O-(C
3-C
8)-cycloalkenyl group, (C
2-C
6)-alkynyl, aryl, O-aryl, (C
1-C
8)-alkylidene group-aryl, O-(C
1-C
8)-alkylidene group-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
3, the salt that can tolerate on claim 1 or 2 described formula I compounds and the physiology thereof, wherein the implication of each symbol is
A is an aryl, and wherein aryl rings can be substituted the base replacement, and described substituting group is selected from 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 are H, (C independently of one another
1-C
6)-alkyl;
M is 1;
R1 is (C
1-C
6)-alkylidene group-R8, (C
2-C
6)-alkylene group-R9;
R8, R9 are H, F, Cl, Br, I, OH, CF independently of one another
3, aryl, heterocycle, (C
3-C
8)-cycloalkyl, wherein ring or loop systems can be substituted maximum 3 times of base replacement, and described substituting group is selected from 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 is H, F, Cl, Br, I, OH, CF
3, CN, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, N (R13) be OH, (C (R14)
1-C
6)-alkyl-N (R13) (R14);
R3 is H;
R4, R5 are H, F, Cl, Br, OH, CF independently of one another
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
4, the salt that can tolerate on one or multinomial described compound and the physiology thereof among the claim 1-3, wherein the implication of each symbol is
A is an aryl, and wherein aryl rings can be substituted the base replacement, and described substituting group is selected from 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 are H, (C independently of one another
1-C
6)-alkyl;
M is 1;
N is 0,1;
R1 is (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl;
R2 is H, OH, (C
1-C
6)-alkyl, COO-(C
2-C
6)-alkenyl, (C
1-C
6)-alkyl-N (R13) (R14);
R3 is H;
R4 is F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R5 is H, F, Cl, Br, OH, CF
3, OCF
3, O-(C
1-C
6)-alkyl, (C
1-C
6)-alkyl;
R6 is H.
5, as one or multinomial described compound among the claim 1-4 of medicine.
6, the medicine that contains among one or more claims 1-4 one or multinomial described compound.
7, contain among one or more claims 1-4 one or multinomial described compound and one or more subtract the medicine of appetite activeconstituents.
8, the medicine that contains among one or more claims 1-4 one or multinomial described compound and one or more statinses.
9, the medicine that claim 6 is described, wherein said other activeconstituents comprises one or more antidiabetic medicines, blood-sugar decreasing active, the HMGCoA reductase inhibitor, cholesterol absorption inhibitor, the PPAR gamma agonist, the PPAR alfa agonists, PPAR α/gamma agonist, fibrate, the MTP inhibitor, the bile acide absorption inhibitor, the CETP inhibitor, the polymer bile acid adsorbent, the ldl receptor inductor, the ACAT inhibitor, antioxidant, the lipoprotein lipase inhibitor, ATP-Citrate trianion lyase inhibitors, inhibitor for squalene synthetic enzyme, lipoprotein (a) antagonist, lipase inhibitor, insulin type, sulfonylurea, biguanides, the meglitinide class, thiazolidinediones, alpha-glucosidase inhibitor, act on the activeconstituents of the ATP-dependency potassium channel of β cell, the CART agonist, the NPY agonist, the MC4 agonist, increase food factor agonist, the H3 agonist, the TNF agonist, the CRF agonist, CRF BP antagonist, agonist can be decided in excellent Lip river, β 3 agonists, MSH (melanocyte-stimulation hormone) agonist, the CCK agonist, serotonin reuptake inhibitor, mixed type serotonin energy and norepinephrine energy compound, the 5HT agonist, the bombesin agonist, the sweet third plain antagonist, tethelin, tethelin-release compound, the TRH agonist, uncoupling protein 2 or 3 conditioning agents, the leptin agonist, DA agonist (bromocriptine, Doprexin), lipase/amylase inhibitor, the PPAR conditioning agent, RXR conditioning agent or TR-beta-agonists or Amphetamine.
10, subtracting the appetite activeconstituents with at least a other unites as one or multinomial described compound among the claim 1-4 of prevention or treatment of obesity medicine.
11, subtracting the appetite activeconstituents with at least a other unites as one or multinomial described compound among the claim 1-4 of prevention or treatment type ii diabetes medicine.
12, a kind of preparation contains among one or more claims 1-4 the method for the medicine of or multinomial described compound, and this method comprises mixes activeconstituents and this mixture is converted into a kind of suitable form of medication with pharmaceutically acceptable carrier.
13, one or the application of multinomial described compound in preparation Mammals diet pill among the claim 1-4.
14, one or multinomial described compound are used for preventing or treating the application of fat medicine among the claim 1-4 in preparation.
15, one or multinomial described compound are used for preventing or treating the application of the medicine of type ii diabetes among the claim 1-4 in preparation.
16, one or multinomial described compound are used for preventing or treating the application of the medicine of metabolism syndrome among the claim 1-4 in preparation.
17, one or multinomial described compound are used for the treatment of application in the medicine of women and male sexual disorder in preparation among the claim 1-4.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10305885.0 | 2003-02-13 | ||
| DE10305885A DE10305885A1 (en) | 2003-02-13 | 2003-02-13 | 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 |
| DE10349672.6 | 2003-10-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1751046A true CN1751046A (en) | 2006-03-22 |
| CN100363364C CN100363364C (en) | 2008-01-23 |
Family
ID=32747777
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800039186A Pending CN1747955A (en) | 2003-02-13 | 2004-01-29 | Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments |
| CNB2004800042121A Expired - Fee Related CN100363364C (en) | 2003-02-13 | 2004-01-29 | Substituted hexahydropyrazino(1,2-a)pyrimidin-4,7-dion derivatives, method for the production and use thereof as medicaments |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800039186A Pending CN1747955A (en) | 2003-02-13 | 2004-01-29 | Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN1747955A (en) |
| DE (1) | DE10305885A1 (en) |
| ZA (2) | ZA200505419B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5545573B2 (en) * | 2008-10-14 | 2014-07-09 | 株式会社 ＰＲＩＳＭ ＢｉｏＬａｂ | Alpha helix mimetics and related methods |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6184223B1 (en) * | 1995-10-27 | 2001-02-06 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
| US6013458A (en) * | 1995-10-27 | 2000-01-11 | Molecumetics, Ltd. | Reverse-turn mimetics and methods relating thereto |
| US6294525B1 (en) * | 1999-09-01 | 2001-09-25 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
-
2003
- 2003-02-13 DE DE10305885A patent/DE10305885A1/en not_active Withdrawn
-
2004
- 2004-01-29 CN CNA2004800039186A patent/CN1747955A/en active Pending
- 2004-01-29 CN CNB2004800042121A patent/CN100363364C/en not_active Expired - Fee Related
-
2005
- 2005-07-05 ZA ZA200505419A patent/ZA200505419B/en unknown
- 2005-07-05 ZA ZA200505420A patent/ZA200505420B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200505420B (en) | 2006-07-26 |
| CN1747955A (en) | 2006-03-15 |
| DE10305885A1 (en) | 2004-08-26 |
| ZA200505419B (en) | 2006-03-29 |
| CN100363364C (en) | 2008-01-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1993364A (en) | Hexahydro-pyrazino[1,2-a]pyrimidine-4,7-dione derivatives substituted with amino acids | |
| CN1171889C (en) | Heteroalkylamino-substituted bicyclic nitrogen heterocycles as inhibitors of P38 protein kinase | |
| CN100351253C (en) | Pyrrolo [2,3-d] pyrimidine compounds as immunosuppressive agents | |
| CN1555260A (en) | Aminoalkyl-substituted aromatic bicyclic compounds, methods for their preparation and their use as pharmaceuticals | |
| CN1290847C (en) | Aza-arylpiperazines | |
| CN1277828C (en) | Piperzine devivs. | |
| CN1324015C (en) | Pyridine and pyrimidine derivatives | |
| CN1192773C (en) | Cyclic amine CCR3 antagonisis | |
| CN1486302A (en) | Abca-1 elevating compounds against coronary artery disease or atherosclerosis | |
| CN1500081A (en) | Thiohydantonins and use thereof for treating diabetes | |
| CN1703397A (en) | Sulfonylamino-acetic acid derivatives and their use as orexin receptor antagonists | |
| CN1633294A (en) | 2,4,5-trisubstituded thiazolyl derivatives and their antiinflammatory activity | |
| CN1741999A (en) | Pyridazinone derivatives as GSK-3beta inhibitors | |
| CN1659156A (en) | Novel guanidinobenzamides | |
| CN1934105A (en) | Aryl-substituted heterocycles, process for their preparation and their use as medicaments | |
| CN1337953A (en) | New thryoid receptor ligands and process II | |
| CN1761671A (en) | 4-aminothieno [2,3-d] pyrimidine-6-carbonitrile derivatives as PDE7 inhibitors | |
| CN1556705A (en) | 7,8,9,10-tetrahydro-6H-azepino, 6,7,8,9-tetrahydro-pyrido and 2,3-dihydro-2H-pyrrolo[2,1-b]-quinazolinone derivatives | |
| CN1578781A (en) | 1,8 naphthyridine derivatives and their use to treat diabetes and related disorders | |
| CN101048180A (en) | Solid formulation with improved solubility and stability, and method for producing said formulation | |
| CN1260345A (en) | Hydrazide compound, its preparing method and medicine compositions thereof | |
| CN1159292C (en) | Aryl substituted cyclic amines as selective dopamine D3 ligands | |
| CN1934090A (en) | Substituted n-cyclohexyl imidazolinones having an mch-modulatory effect | |
| CN1960726A (en) | Composition comprising a jnk inhibitor and cyclosporin | |
| CN1674899A (en) | Use of IkappaB-kinase inhibitors in pain therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1085208 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080123 Termination date: 20100129 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1085208 Country of ref document: HK |