CN101448789A - Soluble adenylate cyclase inhibitors - Google Patents
Soluble adenylate cyclase inhibitors Download PDFInfo
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- CN101448789A CN101448789A CNA2007800187317A CN200780018731A CN101448789A CN 101448789 A CN101448789 A CN 101448789A CN A2007800187317 A CNA2007800187317 A CN A2007800187317A CN 200780018731 A CN200780018731 A CN 200780018731A CN 101448789 A CN101448789 A CN 101448789A
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to compounds of general formula (I), to their production and to their use as a medicament.
Description
The present invention relates to the inhibitor and the production thereof of soluble adenylate cyclase and be used to produce the purposes of contraception with medicine.
There is a large amount of modern contraceptive devices to be used for the women at present, but seldom is useful on the method (condom and sterilization) of male contraception.Press for reliable, the new male contraception method of exploitation.By " male contraceptive pill (male pill) " cause sterile should be reversible, and should be effective equally with the existing method that is used for the women.Sterile should comparatively fast the generation, and should continue the long as far as possible time.This contraceptive device should not have side effect, and preparation can be non-hormonal and hormonal.Possible point of penetration is to be adjusted in the enzyme that plays an important role in the ovum fertilization: the activity of soluble adenylate cyclase (sAC).This kind of enzyme is mainly expressed in the testis stem cell and is present in the mature sperm.
In 1999, author Levin and Buck be purifying and cloned the isoform of sAC (Proc.Natl.Acad.Sci.USA 96 (1): 79-84) from rat testicle successfully.
The recombinant rat enzyme can be stimulated by supercarbonate.Utilized antibody to prove that the catalytic domain of described enzyme is positioned testis, sperm, kidney and choroid plexus.These openly are the themes of application WO 01/85753, and it is authorized to (US6544768) in the U.S..
WO01/21829 (Conti etc.) requires isolating polynucleotide sequence, isolating sAC polypeptide and the pilot system of patent protection coding people sAC isoform, utilizes them be able to differentiate and suppresses the active material of sAC.Following possibility is disclosed: utilize these materials to realize that the reversibility of motile sperm counting reduces, and they are as the purposes of the method for control male fertility.
John Herr working group proof is separated from sperm and sign people sAC isoform.WO02/20745 also requires patent protection to be used to differentiate the expression of mediator sAC or the pilot system of active material except the nucleic acid that requires patent protection coding sAC.For example, these compounds may optionally suppress the activity of sAC, thereby make the sperm forfeiture make the ability of ovum fertilization.Therefore, these sAC inhibitor may be used as non-hormonal contraceptive medicine.
But, known sAC inhibitor shows specific problem: catechol estrogen (T.Braun, Proc Soc Exp Biol Med 1990,194 (1): 58ff) and gossypol (KL Olgiati, Arch BiochemBiophys 1984,231 (2): 411ff) itself has toxicity, and neplanocin only has very faint restraining effect (MA Brown and ER Casillas, J Androl 1984,5:361ff).The more effective to a certain extent (IC of the inhibitor of described recombinant human sAC such as Zippin
50≤ 10 μ M) (people such as JH Zippin, J Cell Biol 2004,164 (4): 527ff).
In order to be provided for the method for male contraception, to quick, reversible and successfully cause the demand of sterile material increasing.
This problem solves by the compound that general formula I is provided,
Wherein use following symbol:
R
1Hydrogen, halogen, CF
3, randomly be how saturated and randomly by polysubstituted C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
2Halogen, CF
3, randomly be how saturated and randomly by polysubstituted C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
3C
6-C
12-aryl, its can be randomly with following group list or many, identical or different the replacement: halogen, randomly coverlet or polysubstituted C
1-C
6-alkyl or C
1-C
6-acyl group; Perhaps
C
6-C
12-aryl, it can replace with following group: C
1-C
6-alkoxyl group, hydroxyl, cyano group, CO
2-(C
1-C
6-alkyl), N-(C
1-C
6-alkyl)
2, CO-NR
4R
5Or CF
3C
5-C
12-heteroaryl, its can be randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, hydroxyl, cyano group, CO
2-(C
1-C
6-alkyl), N-(C
1-C
6-alkyl)
2, CO-NR
4R
5Or CF
3Perhaps
C
3-C
6-cycloalkyl, its can be randomly with following group list or many, identical or different the replacement: halogen, CF
3, hydroxyl, cyano group, CO
2-(C
1-C
6-alkyl), C
1-C
6-alkyl, C
1-C
6-acyl group, N-(C
1-C
6-alkyl)
2, CO-NR
4R
5Or C
1-C
6-alkoxyl group;
R
4Hydrogen;
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
4And R
5Form 5-8 unit ring together, described ring can comprise other heteroatoms and
R
6C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl, wherein C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, oxyethyl group, isopropoxy, chlorine, bromine, fluorine, cyano group, methylsulfonyl or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt, they overcome known defective, and show improved performance, promptly show good effectiveness, good solubility and stability.
Suppress soluble adenylate cyclase according to compound of the present invention, therefore prevent capacitation, thereby male contraception is provided.
Alkyl means the straight or branched alkyl residue in each case, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl and hexyl.
Alkoxyl group means the straight or branched alkoxy residue in each case, for example methoxyl group-, oxyethyl group-, positive propoxy-, isopropoxy-, n-butoxy-, sec-butoxy-, isobutoxy-, tert.-butoxy-, pentyloxy-, isopentyloxy-and hexyloxy-.
Acyl group means the straight or branched residue in each case, for example formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl and benzoyl.
Cycloalkyl means the mononaphthene basic ring, for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Described cycloalkyl residues can comprise one or more heteroatomss, and for example oxygen, sulphur and/or nitrogen replace carbon atom.The Heterocyclylalkyl that preferably has 3-6 annular atoms.The loop systems that can randomly comprise one or more possible two keys in the ring means for example cycloalkenyl group, for example cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and wherein coupling can occur on double-stranded and the singly-bound.
Halogen means fluorine, chlorine, bromine or iodine in each case.
Aromatic yl residue comprises 6-12 carbon atom in each case, and can for example be benzo-fused.Can mention following group as an example: phenyl, tropyl, cyclooctadiene base, indenyl, naphthyl, xenyl, fluorenyl (florenyl), anthryl etc.
The heteroaryl residue comprises 5-16 annular atoms in each case, and can comprise one or more, identical or different heteroatoms, for example the oxygen in the ring, sulphur or nitrogen replace carbon, and can be single, two or three rings, and can be again benzo-fused in each case.
Can mention as an example following:
Thienyl, furyl, pyrryl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group etc. and benzo derivative, for example benzofuryl, benzothienyl, benzoxazolyl, benzimidazolyl-, indazolyl, indyl, pseudoindoyl etc.; Or pyridazinyl, pyrimidyl, pyrazinyl, triazinyl etc. and benzo derivative, for example quinolyl, isoquinolyl etc.; Or azine group (azozinyl), indolizine base, purine radicals etc. and benzo derivative thereof; Or quinolyl, isoquinolyl, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, acridyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oxa-
Base (oxepinyl) etc.
Described heteroaryl residue can be benzo-fused in each case.For example, can mention following as 5 ring heteroaromaticss: thiophene, furans, oxazole, thiazole, imidazoles, pyrazoles and benzo derivative thereof, can mention following: pyridine, pyrimidine, triazine, quinoline, isoquinoline 99.9 and benzo derivative as 6 ring heteroaromaticss.
Heteroatoms means oxygen, nitrogen or sulphur atom.
If there is acidic functionality, then the salt of the compatible organic and mineral alkali of physiology is the salt that suits, for example easily molten basic metal and alkaline earth salt, and N-methylglucosamine, dimethyl glycosamine, ethyl glycosamine, Methionin, 1,6-hexanediamine, thanomin, glycosamine, sarkosine, serinol, trihydroxy methyl aminomethane, amino-propanediol, Sovak alkali, 1-amino-2,3, the 4-trihydroxybutane.
If there is basic functionality, then the salt of the compatible organic and mineral acid of physiology suits, and described acid is hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartrate etc. for example.
The compound of special preferred formula I, wherein said symbol has following implication:
R
1Hydrogen, halogen, CF
3, C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
2Halogen, CF
3, C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
3C
6-C
12-aryl, its can be randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3C
5-C
12-heteroaryl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3C
3-C
6-cycloalkyl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, CF
3, cyano group, C
1-C
3-alkyl, C
1-C
3-acyl group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or C
1-C
3-alkoxyl group,
R
4Hydrogen;
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
4And R
5Form 5-8 unit ring together, described ring can comprise other heteroatoms and
R
6C
1-C
6-alkyl, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl, wherein C
1-C
6-alkyl, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, oxyethyl group, isopropoxy, chlorine, bromine, fluorine, cyano group, methylsulfonyl or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
The compound of preferred formula I also, wherein said symbol has following implication:
R
1Hydrogen,
R
2C
3-C
6-cycloalkyl, C
1-C
6-alkyl, CF
3, cyano group, bromine, perhaps-OCF
3,-SO
2-CH
3Group,
R
3C
6-C
12-aryl, its can be randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3C
5-C
12-heteroaryl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3C
3-C
6-cycloalkyl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, CF
3, cyano group, C
1-C
3-alkyl, C
1-C
3-acyl group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or C
1-C
3-alkoxyl group,
R
4Hydrogen,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl
-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
6C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl, wherein C
1-C
4-
Alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, chlorine, fluorine, cyano group or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
The compound of preferred formula I also, wherein said symbol has following implication,
R
1Hydrogen,
R
2C
3-C
6-cycloalkyl, C
1-C
6-alkyl, CF
3, cyano group, bromine, perhaps contraposition-OCF
3,-SO
2-CH
3Group,
R
3C
6-C
12-aryl, its can be randomly with following group list or two, identical or different the replacement: halogen, C
1-C
3-alkyl, ethanoyl, methoxyl group, oxyethyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NHR
5Or CF
3
C
5-C
12-heteroaryl, its can be randomly with following group list or two, identical or different the replacement: chlorine and/or fluorine, C
1-C
3-alkyl, ethanoyl, methoxyl group, oxyethyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NHR
5Or CF
3C
3-C
6-cycloalkyl,
R
4Hydrogen,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
6C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl, wherein C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, chlorine, fluorine, cyano group or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
The compound of preferred formula I also, wherein said symbol has following implication:
R
1Hydrogen,
R
2The tertiary butyl, sec.-propyl, isobutyl-, sec-butyl, cyano group, bromine, perhaps contraposition-O-CF
3,-SO
2-CH
3Group,
R
3Group
R
4Hydrogen,
R
5Hydrogen or group-(CH
2)
m-N-(CH
3)
2,-(CH
2)
2-CH
3,-(CH
2)
2-NH-COCH
3,
-(CH
2)-CHCH
3-OH、-(CH
2)
2-O-CH
3、-(CH
2)
2-OH、
-CHCH
3-CH
2-OH, m=1-3 wherein,
R
6Methyl, ethyl, propyl group, 2-methoxy ethyl ,-CH
2-CF
3-,-(CH
2)
2-CF
3And benzyl,
And their isomer, diastereomer, enantiomer and salt.
The compound of preferred formula I also, wherein said symbol has following implication:
R
1Hydrogen,
R
2The tertiary butyl, sec.-propyl, isobutyl-, sec-butyl, cyano group, bromine, perhaps contraposition-O-CF
3,-SO
2-CH
3Group,
R
3Group
R
4Hydrogen,
R
5Hydrogen or group-(CH
2)-CHCH
3-OH ,-(CH
2)
2-O-CH
3,-CHCH
3-CH
2-OH,
R
6Methyl, ethyl, propyl group, 2-methoxy ethyl ,-CH
2-CF
3-,-(CH
2)
2-CF
3And benzyl,
And their isomer, diastereomer, enantiomer and salt.
Extremely preferably according to following compound of the present invention:
1. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
2. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
3. methylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
4. methylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
5. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(pyridin-4-yl) acid amides
6. benzylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
7. benzylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
8. benzylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
9. benzylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
10. 5-[(4-tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl) amino]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
11. amino 5-[(4-tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
Amino (12. ±)-5-[(4-tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
Amino (13. ±)-5-[(4-tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
14. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-(3-fluorophenyl)-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
15. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-(3-fluorophenyl)-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
16. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-(3-p-methoxy-phenyl)-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
17. methylamino 5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-(3-p-methoxy-phenyl)-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides.
The present invention also is provided for preparing the method according to the compound of general formula I of the present invention, the method is characterized in that, according to method known to those skilled in the art, makes the compound of formula II
R wherein
1, R
2, R
3And R
6Each above freely definition, and R
7Can be hydrogen or C
1-C
6-alkyl, preferred hydrogen, methyl or ethyl,
With the amine reaction of general formula III,
R wherein
4And R
5Each above freely definition,
Any required protecting group of cracking subsequently.
Work as R
7During for hydrogen, can at first react,, the carboxylic acid of general formula I I be changed into mixed acid anhydride with isobutyl chlorocarbonate for example at first by at tertiary amine for example in the presence of the triethylamine by activated acids functional group.An alkali metal salt of described mixed acid anhydride and corresponding amine be reflected at inert solvent or solvent mixture for example in tetrahydrofuran (THF), glycol dimethyl ether, dimethyl formamide, the hexamethylphosphoramide, at-20 ℃～+ 60 ℃, preferably carry out 0 ℃～30 ℃ temperature.
Further possibility is by reagent, for example the carboxylic acid of HOBt or HATU activation general formula I I.For example, acid is reflected at inert solvent with HATU's, and for example among the DMF, at the amine and the tertiary amine of the general formula III of correspondence, for example ethyl diisopropylamine exists down, and at-50～+ 60 ℃, preferred 0 ℃～30 ℃ temperature is carried out.
Work as R
6Be C
1-C
6During-alkyl, for example can also by or not by trialkylaluminium reagent, under the situation of preferred trimethyl aluminium, with corresponding amine with the direct aminolysis of this ester.
The compound that is used as the general formula I I of raw material for example can obtain by following usual manner: in nitrogen atmosphere or in hydrogen source such as the al formate, in the presence of palladium catalyst, the nitroreduction among the known K-281 IV is become amido functional group,
R wherein
7Be C
1-C
6-alkyl, preferable methyl or ethyl make the halide reaction of this amine and general formula V then in the presence of alkali such as pyridine, diisopropylethylamine, triethylamine or salt of wormwood,
R wherein
1And R
2Each above freely definition, and Hal represents halogen, preferred fluorinated thing muriate or bromide,
Form the compound of general formula VI
For example pass through iodine, NBI, NBS then, otherwise be exactly CuBr
2At the ester of 3 halogenation general formula VI, to obtain the compound of general formula VII
R wherein
1, R
2, and R
7Each above freely definition.
Subsequently, in acetone or tetrahydrofuran (THF), in the presence of alkali such as diisopropylethylamine, salt of wormwood or cesium carbonate, with the halide reaction of these esters and general formula VIII,
Wherein, R6 such as above definition, and Hal represents halogen, preferred iodide, muriate or bromide,
Form the compound of general formula I X,
Then, the ester of general formula I X and the boric acid derivatives of general formula X are carried out the catalytic reaction of Pd at 3,
R wherein
3As above definition,
If suitably, removing R
6In after the required protecting group, and if suitably, by for example carrying out saponification, change into the compound of general formula I I subsequently with sodium hydroxide solution
Perhaps, also the ester of general formula VII at first can be carried out the catalytic reaction of Pd with the boric acid derivatives of general formula X at 3,
Wherein R3 such as above definition,
Change into the compound of general formula X I,
R wherein
1, R
2, R
3And R
7Each above freely definition,
Then, be alkali for example diisopropylethylamine, salt of wormwood or cesium carbonate and in the presence of general formula VIII halid, carry out the N-alkylation step in acetone or the tetrahydrofuran (THF),
Wherein, R6 such as above definition, and Hal represents halogen, preferred iodide, muriate or bromide,
If suitably, removing R
6In after the required protecting group, and if suitably, by for example carrying out saponification, form the compound of general formula I I subsequently with sodium hydroxide solution.
Suppress soluble adenylate cyclase according to compound of the present invention, and this is that they are for example to the effect basis of male contraception.
Adenylate cyclase is the effector molecule of one of most common signal transduction pathway, and they synthesize second messenger molecule cyclic amp (cAMP) by tetra-sodium (PP) division by Triphosaden (ATP).CAMP mediation various kinds of cell is to the reaction of a large amount of neurotransmitters and hormone.Solubility, sperm-specific adenylate cyclase (sAC, people mRNA sequence (GenBank) nm_018417, people's gene ADCY X) are one of ten kinds of adenylate cyclases described in the human genome.The sAC performance is sent as an envoy to, and it is different from some specific performance properties of other adenylate cyclase.Different with all other adenylate cyclases, sAC is stimulated by the concentration of supercarbonate in the surrounding medium, rather than is stimulated by G albumen.SAC does not have any diaphragm area of striding in its aminoacid sequence, it can not be suppressed by Fu Sikelin, manganese is stronger than magnesium to its stimulation, and it only shows the sequence homology slight with other adenylate cyclase (have at the catalytic domain I of amino acid levels sAC and II and other adenylate cyclase≤26% identity).
T.Braun etc. (1975, PNAS73:1097ff) special, the manganese dependency activity of sAC in rat testicle and the sperm have been described at first.(1985, J.Biol.Chem 260 (17): show that 9699ff) the active material of sAC that stimulates in the boar semen is a supercarbonate for N.Okamura etc.Also shown and can only can in rat testicle and sperm, have been detected, and can not in other tissue, detect by the AC activity that supercarbonate stimulates.Buck and Levin group (people 1999 such as J.Buck, PNAS 96:79ff, WO01/85753) purifying sAC and order-checking from rat testicle first.(Y.Chen etc. 2000, Science289:625ff) to have proved conclusively the performance (for example ability that is stimulated by supercarbonate and magnesium) of its expection on recombinant expression protein.
Can and can infer testes specificity and sperm-specific expression (ML Sinclair etc. 2000, the Mol ReprodDevelop 56:6ff of enzyme according to sAC mRNA distribution by the active data of sAC that supercarbonate stimulates; N Okamura etc. 1985, J.Biol.Chem 260 (17): 9699ff; J.Buck etc. 1999, PNAS 96:79ff).In testis, sAC mRNA only expresses in the later stage of the gamete that forms sperm, but does not express (ML Sinclair etc. 2000, Mol Reprod Develop 56:6ff) in somatocyte.
Existing multinomial pharmaceutical research about sAC function in the mammalian sperm.Penetrate the zona pellucida of ovum at sperm, before merging with the dotter haut of ovum then, sperm function is for this reason got ready.This process, promptly capacitation is fully studied.The sperm of capacitation is characterised in that: when being stimulated aptly, and the ability (discharge lytic enzyme, it may be used for sperm and penetrate zona pellucida) of the motor pattern of its change and experience acrosomal reaction process.Capacitation takes place in vivo with external, and does not rely on magnesium hydrogen salt concentration rising (PE Visconti in the medium; GS Kopf (1998), Biol Reprod 59:1ff; E de Lamirande etc. 1997, Mol Hum Reprod 3 (3): 175ff).Capacitation can also be by adding for example two butyryl cAMP (db-cAMP) of suitable saturating film cAMP analogue and preventing the inhibitor (for example IBMX) that their are degraded and stimulated.Just recently just by the genetic defect model, promptly so-called gene is pounded out mouse and has been proved conclusively the sperm function supposed (G Esposito etc. 2004, PNAS 101 (9): 2993ff) to the dependence of sAC.The male mice that lacks the sAC gene shows the spermatogeny of normally carrying out, but they are sterile.Its sperm has movement defect, and can not make ovum fertilization.Described animal does not show any other defective or anomaly, the sAC function (people 2003 such as JH Zippin, FASEB 17:82ff) of this and other supposition) contradict.
SAC has unique sequence, and only has slight homology with other somatocyte adenylate cyclase.It is an adenylate cyclase unique in the mammalian sperm, and its activity is necessary for sperm motility and capacitation.Therefore, the important possibility of specific sAC inhibitor representative control male fertility.
Therefore, the present invention relates to contain at least a medicine as claim 1-7 claimed compounds.
The invention still further relates to purposes as claim 1-7 claimed compounds.
In order to be used as medicine according to compound of the present invention, they are changed into the form of pharmaceutical preparation, described pharmaceutical preparation also comprises except active substance and medicinal is suitable in the intestines and the organic or inorganic inert support of parenteral administration, for example water, gelatin, gum arabic, lactose, starch, Magnesium Stearate, talcum, vegetables oil, polyalkylene glycol etc.Described pharmaceutical preparation can be a solid form, for example tablet, drageeing, suppository or capsule, or liquid form, for example solution, suspensoid or emulsion.When needing, they also comprise vehicle, for example sanitas, stablizer, wetting agent or emulsifying agent; Be used to change the salt or the buffer reagent of osmotic pressure.These pharmaceutical preparations also are purposes of the present invention.
The injection liquid of the active compound in the poly-hydroxy ethoxylated castor oil or suspension, the particularly aqueous solution are particularly suitable for parenteral administration.
The surfactivity vehicle for example phosphatide of bile salt or animal or plant and their mixture and liposome or their component also can be used as carrier system.
Particularly, for example tablet, drageeing or the capsule of lactose, W-Gum or yam starch are suitable for oral to contain talcum and/or hydrocarbon carrier or tackiness agent.Can also add sweeting agent to described juice in case of necessity with liquid form such as juice administration.
For vaginal application, for example suppository is suitable and conventional.
The invention still further relates in the intestines, parenteral, vagina and Orally administered.
The dosage of active substance can become with the character of route of administration, patient age and body weight, disease to be treated and seriousness and similar factor.Per daily dose is 0.5-1000mg, and preferably 50-200mg, and described dosage can be the single dose of disposable administration, perhaps can be divided into 2 times or more times per daily dose.
According to the compound of general formula I of the present invention is the inhibitor of very good soluble adenylate cyclase.Inhibitors of soluble adenylate cyclase causes the cAMP signal suppressing.The cAMP level plays a decisive role to the control of the process that plays an important role in cell proliferation, cytodifferentiation and apoptosis.The disease that plays a decisive role of the inhibition of cAMP level wherein, for example cancer can be regulated by inhibitors of soluble adenylate cyclase.This adjusting may have prevention and therapeutic action to suffering from this sick patient.At present, increase diseases associated by radiotherapy and chemotherapy treatment with cell proliferation, as cancer.These methods are nonspecific, and the possibility of side effect is big.Therefore, it is favourable providing the novel substance that directly acts on the particular target position.The present invention relates to regulate the material of the production of cAMP by suppressing soluble adenylate cyclase.For example, can reduce or prevent unusual cell proliferation by the production of adjusting or inhibition cAMP.Can suppress soluble adenylate cyclase by using, thereby reduce cell proliferation according to material of the present invention.The present invention relates to comprise the medicine that is used for the treatment of disease of at least a compound according to general formula I and contain appropriate carrier and the medicine of vehicle.Described disease is characterised in that they are that metabolic disturbance by second messenger cAMP causes.
Can provide the method for regulating capacitation by the concentration that suppresses soluble adenylate cyclase reduction cAMP.The present invention relates to the purposes that material according to the present invention is used to reduce and/or suppress the microgamete fertility, described purposes mediates by reducing or suppressing the activity of soluble adenylate cyclase and reduce thus or suppress capacitation.
Can prevent ovum fertilization by the material that causes cAMP production to be suppressed of effective dosage.The compound that the invention still further relates to general formula I is used to produce the purposes of non-hormonal contraceptive with medicine.
If do not describe the production of initial compounds, then these compounds are known, perhaps can produce similarly with known compound or the described method of the application.The described institute of the application responds and can also or use combination technique to carry out in parallel reactor.
Can pass through ordinary method, for example crystallization process, chromatography or salt forming method are separated into enantiomer or E/Z isomer with isomer mixture.
With the method for routine, by adding equivalent or excessive alkali or acid (in case of necessity in solution) in the solution of the compound of formula I, precipitation separation or the solution of handling described formula I compound are in a usual manner produced described salt.
Production according to compound of the present invention
Following embodiment explains the production according to the compound of general formula I of the present invention, rather than will require the scope of the compound of patent protection to be restricted to these embodiment.
Compound according to general formula I of the present invention can be as following production.
Embodiment 1:5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
Will be at the 45mg in the 0.75ml dimethyl formamide at embodiment 1f) in the solution and the 40.3mg N-[(dimethylamino of acid of preparation)-1H-1,2,3-triazolo [4,5-b] pyridine-1-methylene]-N-methylmethane ammonium hexafluorophosphate N-oxide compound (HATU) and the mixing of 9.84mg4-amino tetrahydro pyran.Drip 18.0 μ l ethyl diisopropylamines at 0 ℃ then, at room temperature stirred subsequently 20 hours.Then add 25ml water, stirred 30 minutes, and suction filtration.By the residuum purifying that silica gel chromatography will so obtain, obtain the 49.7mg title compound with hexane/0-70% ethyl acetate.
NMR(300MHz，DMSO-d6)：δ＝1.22(2H)，1.26(s，9H)，1.65(2H)，3.07(3H)，3.32(2H)，3.68(2H)，3.89(1H)，6.91(1H)，6.99(1H)，7.26-7.33(4H)，7.34-7.41(5H)，7.54(2H)，11.85(1H)。
The raw material of above title compound is prepared as follows:
1a) 5-amino-1H-Ethyl indole-2-carboxylate
At first 5g5-nitro-1H-Ethyl indole-2-carboxylate is joined in 170ml methyl alcohol and the 0.5ml water, carry palladium (10%) with 6.73g ammonium formiate and 50mg charcoal and mix, refluxed 1 hour at 90 ℃.Then through diatomite (Celite) suction filtration, and use warm methanol wash.Except that after desolvating, residuum is mixed with 100ml water, and stirred 10 minutes, with precipitated solid material drying under reduced pressure, obtain the 4.12g title compound.
NMR(300MHz，DMSO-d6)：δ＝1.28(3H)，4.25(2H)，4.63(2H)，6.62-6.68(2H)，6.79(1H)，7.12(1H)，11.35(1H)，
1b) 5-(4-tert.-butylbenzene sulfonamido)-1H-Ethyl indole-2-carboxylate
Will be at the 4.12g among the 195ml DMF at embodiment 1a) in the solution of amine of preparation mix at 0 ℃ with 5.18ml ethyl diisopropylamine and 4.69g 4-tert.-butylbenzene SULPHURYL CHLORIDE, and at room temperature stirred 2 hours.Decompression removes down and desolvates, and with hexane/0-80% ethyl acetate by silica gel chromatography with the residuum purifying, obtain the 7.56g title compound.
NMR(300MHz，DMSO-d6)：δ＝1.20(9H)，1.27(3H)，4.27(2H)，6.97-7.03(2H)7.25(1H)，7.31(1H)，7.48(2H)，7.59(2H)，9.93(1H)，11.80(1H).
1c) 3-bromo-5-(4-tert.-butylbenzene sulfonamido)-1H-Ethyl indole-2-carboxylate
Will be at the 7.56g in the 217ml tetrahydrofuran (THF) at embodiment 1b) in the solution of sulfanilamide (SN) of preparation mix with the 3.36g N-bromosuccinimide, and at room temperature stirred 40 minutes.After the dilution of 300ml ethyl acetate, with the 50ml water washing once, and, use the dried over sodium sulfate organic phase with saturated sodium-chloride washed twice (each 50ml).After filtration and the concentrating under reduced pressure, the residuum that recrystallization so obtains from hexane/ethyl acetate obtains the 8.11g title compound.
NMR(300MHz，DMSO-d6)：δ＝1.20(9H)，1.30(3H)，4.31(2H)，7.08-7.15(2H)，7.33(1H)，7.50(2H)，7.60(2H)，10.08(1H)，12.16(1H).
1d) 3-bromo-5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-the 1H-Ethyl indole-2-carboxylate
Will be at the 1g in the 10ml acetone at embodiment 1c) in the suspension of bromide of preparation mix with 375mg salt of wormwood and 0.13ml methyl iodide, and at room temperature stirred 24 hours.Mixture with the dilution of 300ml ethyl acetate, is used the 50ml water washing once, and with the washing of 50ml saturated nacl aqueous solution once.With dried over sodium sulfate and filtration, concentrating under reduced pressure then.The residuum purifying of hexane/ethyl acetate by pressing chromatography so to obtain in the silica gel with 7:3 obtains the 670mg title compound.NMR(300MHz，DMSO-d6)：δ＝1.27(9H)，1.32(3H)，3.14(3H)，4.34(2H)，6.92(1H)，7.08(1H)，7.39(1H)，7.41(2H)，7.56(2H)，12.33(1H)。
1e) 5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-3-phenyl-1H-Ethyl indole-2-carboxylate
Will be at the 666mg in the mixture of 25.5ml ethanol and 25.5ml toluene at embodiment 1d) in solution and the 239mg phenyl-boron dihydroxide of ester of preparation and 3.37ml1M aqueous sodium carbonate and 160mg lithium chloride mix.Add after the 125mg tetrakis triphenylphosphine palladium, with reaction mixture refluxed 20 hours.After being cooled to room temperature, through diatomite suction filtration reaction mixture, and with ethyl acetate washing and filtering residuum.Wash the organic phase that so obtains with 10ml saturated sodium bicarbonate and saturated nacl aqueous solution, and use dried over sodium sulfate.Behind the concentrating under reduced pressure, by the residuum purifying that silica gel chromatography will so obtain, obtain the 626mg title compound with hexane/0-60% ethyl acetate.
NMR(300MHz，DMSO-d6)：δ＝1.13(3H)，1.27(9H)，3.06(3H)，4.18(2H)，6.90(1H)，7.07(1H)，7.25-7.7.36(5H)，7.39(2H)，7.43(1H)，7.55(2H)，10.24(1H)。
1f) 5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-3-phenyl-1H-Indoline-2-carboxylic acid
Will be at the 600mg in the 14.5ml ethanol at embodiment 1e) in the ester of preparation mix with 905mg sodium hydroxide with 7.25ml alcoholic acid mixture, and at room temperature stirred 20 hours.Then, with mixture with the dilution of 100ml water and use 50% sulfuric acid acidation.Filtering-depositing is also dry, obtains the 205mg title compound, and it is further reaction without being further purified.
NMR(300MHz，DMSO-d6)：δ＝1.26(9H)，3.06(3H)，6.88(1H)，7.04(1H)，7.24-7.35(5H)，7.36-7.43(3H)，7.55(2H)，11.94(1H)，12.93(1H)。
Embodiment 2:5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-morpholine-4-base ethyl) acid amides
With 45mg embodiment 1f) acid and 12.8 μ l2-(morpholine-4-yl) ethamine repeat embodiment 1, obtain the 36.2mg title compound.
NMR(300MHz，DMSO-d6)：δ＝1.27(9H)，2.18(4H)，2.25(2H)，3.06(3H)，3.25(2H)，3.38(4H)，6.85(1H)，6.98(1H)，7.27-7.42(9H)，7.55(2H)，11.85(1H)。
Embodiment 3:(±)-5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
With 45mg embodiment 1f) acid and 7.75 μ l2-amino-1-propyl alcohol repeat embodiment 1, obtain the 42.6mg title compound.
NMR(300MHz，DMSO-d6)：δ＝0.94(3H)，1.26(9H)，3.07(3H)，3.13-3.30(2H)，3.89(1H)，4.62(1H)，6.89(1H)，6.96(1H)，6.99(1H)，7.26-7.41(8H)，7.54(2H)，11.83(1H)。
Embodiment 4:(±)-5-[(4-tert.-butylbenzene alkylsulfonyl) methylamino]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
With 45mg embodiment 1f) acid and 7.31mg 1-amino-2-propyl alcohol repeat embodiment 1, obtain the 45.4mg title compound.
NMR(300MHz，DMSO-d6)：δ＝0.91(3H)，1.27(9H)，3.00-3.17(2H)，3.06(3H)，3.58(1H)，4.59(1H)，6.87(1H)，6.99(1H)，7.15(1H)，7.26-7.41(8H)，7.54(2H)，11.84(1H)。
Biological Examples:
Embodiment 1:sAC measures
In suitable Laemmli buffer system Laemmli, solubility sperm-specific adenylate cyclase enzyme catalysis Triphosaden (ATP) is to the conversion of cyclic amp (cAMP) and tetra-sodium.The free cAMP that will so produce then is used for the competitive assay technology, europium kryptofix 222 Eu[K in this technology] the anti-cAMP antibody of mark (anti-cAMP-Eu[K]-AB) be prevented from combining of allophycocyanin-1 molecule with the modification of cAMP molecule marker.Under the situation that does not have Exogenous cAMP, after the 335nm place excites, at anti-cAMP-Eu[K]-there is FRET (fluorescence resonance energy transfer) (FRET) between AB (FRET donor) and the cAMP-XL665 molecule (FRET acceptor).Based on FRET acceptor XL665 emission (665nm and 620nm), this method is quantitative, time-resolved.The minimizing of signal (is determined as WellRatio; Calculate by following formula: [(E665nm/E620nm) x 10000]) may be owing to the existence of cAMP, and therefore owing to the activity of sAC.At first, at 384 hole test panel (polystyrene; 384, the mid-1.5 μ l substances (in 30%DMSO) in every hole NV), and 30%DMSO is only arranged in solvent control.Apply then the rare sAC enzyme solution of 10 μ l (at 300mM NaCl, the enzyme stock solution in 10% glycerine; PH7.6; Enzyme intermediate product and final diluent be 1:10 a), and b) 1:2000, all exist: 1.0mM MnCl
20.2%BSA; 50mM Tris is in water, pH7.5).(200 μ M ATP are at H by adding 5 μ l ATP substrate solutions
2Among the O) the beginning enzyme reaction, and after incubation (under the room temperature 25 minutes) by adding 5 μ l stop solutions (200 μ M EDTA are in PBS) stopped reaction.At last, totally be 91.5 μ l by adding that 70 μ lPBS are adjusted to the entire reaction thing.
Then, 8 μ l are detected hole (the measurement flat board: polystyrene that liquid 1 places 384 hole measurement flat boards; 384, SV-black; Detect liquid 1:50 μ l cAMP-XL665; The 950 μ l damping fluid of regenerating; 2200ul PBS; CAMP-XL665: the explanation according to Cis bio Kit:#62AMPPEC is passed through 5ml H
2O is added to freeze-drying prods and prepares; Store: aliquots containig, at-80 ℃).Then, 3 μ l among the 91.5 μ l are added in the hole of corresponding test panel.At last, add 8 μ l detect liquid 2 (detect the anti-cAMP-Eu[K of liquid 2:50 μ l]-AB; The 950 μ l damping fluid of regenerating; 2200 μ l PBS; Anti-cAMP-Eu[K]-AB: according to the explanation preparation of Cis bioKit:#62AMPPEC; Store: aliquots containig, at-80 ℃).
At room temperature after the incubation 90 minutes, measure HTRF result with Packard Discovery or RubiStar HTRF surveying instrument and (postpone: 50 μ s again; Integral time: 400 μ s).
Embodiment 2. is separation of human sperm and capacitation from seminal fluid
2.1. separated sperm
Purifying is from people's sperm of seminal fluid in based on the double-deck gradient system of silica gel particle (trade(brand)name: Percoll or ISolate).
With every part of seminal fluid, 2.5ml (the ＂ 90%ISolate lower layer ＂ of the lower floor of preheating, available from Irvine) place 15ml centrifuge tube (taper shape, plastics), use upper strata (the ＂ 50%ISolateupper layer ＂ of 2.5ml preheating carefully, available from Irvine) cover, and in water-bath at 37 ℃ of maintenance＜1h.Cover gradient carefully with normal (aspect seminal fluid quantity, mobility and the liquefaction) seminal fluid of maximum 3ml.Under 1000xg and room temperature, carry out the sperm sedimentation and continue 25 minutes.Use glass capillary, move to just above spermatium two-layer by suction.Be elutriation ISolate gradient, be transferred to and contain 12ml mHTF nutrient solution (4mM NaHCO being suspended in spermatium among about 200 μ l respectively
30.01%BSA; 37 ℃) the 15ml plastics tubing in, and with sperm sedimentation 20 minutes under 1000xg.By suction nutrient solution is moved to just above spermatium, and with mHTF nutrient solution (4mM NaHCO
30.01%BSA; 37 ℃) be adjusted to 1000 μ l.Measure sperm quantity with the Neubauer counter, then,, use mHTF nutrient solution (4mM NaHCO in case of necessity for capacitation subsequently
30.01%BSA; 37 ℃) it is adjusted to 4 x 10
6Sperm/150 μ l.
2.2. capacitation
If the testing experiment material is to the influence of acrosomal reaction, must be with sperm with substances preincubation.This preincubation promptly realizes the presaturation of combining site in the sperm for allowing substances to penetrate into sperm before capacitation begins, and is necessary, particularly is difficult for passing under the situation of film at this material.It is that necessary Another reason is because the lipid of BSA height in conjunction with the increase of BSA concentration in the capacitation process that is caused, may cause the reduction of the effective concentration of substances in the sample.
Substances is dissolved in DMSO, and with mHTF nutrient solution (4mM NaHCO
30.01%BSA; 37 ℃) dilution is 0.5% thereby make the DMSO concentration of DMS in 400 final μ l capacitation samples.In each case, with transfer pipet 150 μ l sperm suspensions are added in the solution of substances of 150 μ l said temperatures control, then 37 ℃ of preincubation 15 minutes.Capacitation is by adding 100 μ l mHTF nutrient solution (88mM NaHCO
34%BSA; 37 ℃) start.In 400 final μ l capacitation samples, the concentration of sperm is 10 x 10
6/ ml, the concentration of supercarbonate is 4mM, and BSA concentration is 1%.At 37 ℃, capacitation was carried out in heating container 3 hours.
For stopping capacitation, (400 μ l respectively) are transferred to fully respectively and contain 1.5ml mHTF (4mM NaHCO with sample
337 ℃) the 15ml sample tube in, under 1000xg centrifugal 5 minutes, and remove supernatant liquor.This step is removed amounts of protein and substances.
Embodiment 3. flow cytometry methods are measured acrosomal reaction
3.1. start acrosomal reaction by handling, and carry out synchronous CD46-FITC dyeing with ionophore
Trigger acrosome reaction of spermatozoa (AR) by sperm with combining of zona pellucida (ZP).This reaction discharges enzyme from acrosome, can make sperm penetrate ZP and arrive ovum.In AR, meromixis takes place in the plasma membrane of sperm and outer acrosome film (OAM).During end, the sperm head still is subjected to the restriction of inner acrosomal membrane (IAM).Only in IAM, can detect CD46 antigen.
External acrosomal reaction only can with suitable concentration on the capacitation sperm, rather than the calcium ion carrier A 23187 that is subjected on the sperm that substances suppresses of capacitation sperm or its capacitation is not induced.By the anti-CD46 antibody (available from Pharmingen) of FITC mark being added the method for IAM, can separate by the sperm zone that sperm that acrosomal reaction takes place and acrosome is complete, the IAM of the sperm that acrosome is complete is exposure in flow cytometer.By using only to having the cell of defective dna film, promptly dead cell carries out painted DNA staining agent second pyridine homodimer (EhD) and carries out simultaneously dyeing, the Necrospermia and the sperm zone of living can be separated.
Because as if be used to cause the ionophore diluent of AR very unstable, and must mix with the CD46-FITC solution that is used for simultaneously dyeing, so this ionophore diluent can not prepare before on-test, but must be in the process of preparing of handling the capacitation sample.
Spermatium is resuspended in the residuum of supernatant liquor, and goes up with 450 μ lmHTF (4mM NaHCO in water-bath (37 ℃)
30.01%BSA; 37 ℃) dilution.The sperm-suspension of 100 μ l aliquots containigs is transferred to the sample-FACS flowtube (in water-bath) of preparation by transfer pipet.With transfer pipet the solution that 150 μ l contain the anti-CD46 antibody of ionophore and FITC mark is added to sperm.At mHTF (4mM NaHCO
30.01%BSA; 37 ℃) in, ultimate density is: the anti-CD46 antibody 1:125 of ionophore 800nm and dilution.With wherein sperm incubation 30 minutes, the lucifuge protection placed 37 ℃ of water-baths.
Add 3.5ml PBS[0.1%BSA]/sample, stop incubation, to descend centrifugal 5 minutes at 700xg (room temperature) then, supernatant liquor is removed in suction subsequently.After centrifugal, sample placed on the hot-plate be incubated, until test.
3.2.EhD dyeing (sperm of the generation acrosomal reaction of/work dead) in order to distinguish
After suction is removed, with the EhD solution of 500 μ l prepared fresh (150nm EhD is at PBS[w/o BSA] in; 37 ℃) be added in each spermatium.Use flow cytometer (BD FacsCalibur) working sample then.Measurement is carried out at laser excitation wavelength 488nm place, and each the measurement detected 10000 sperms.Measure generation acrosomal reaction sperm at the 530nm place by the CD46-FITC in the FL-1 strainer.Measure Necrospermia at the 634nm place by the dyeing of the EhD-DNA in the FL-2 strainer.Correspondingly will measure passage and carry out each other compensation in advance.
3.3 estimate
The sperm of selecting in to SSC-H (lateral scattering) Dot blot at FSC-H (forward scatter) is the unusual cell mass of homogeneous.Owing to use Two Colour Fluorescence dyeing, by the quadrant analytical method, at FL-1 (EhD; X-axis) in FL-2 (FITC-CD46, the Y-axis) Dot blot, uses from FSC the sperm group of selecting the SSC Dot blot is estimated.
| Quadrant in the FL-1vs.FL-2 Dot blot | Dyeing | Analyze | |
| Q1＝UL | Upper left | EhD only | Dead, the sperm of acrosomal reaction does not take place |
| Q2＝UR | Upper right | EhD and FITC-CD46 | Dead, the sperm of generation acrosomal reaction |
| Q3＝LL | The lower-left | Be unstained | Live, the sperm of acrosomal reaction does not take place |
| Q4＝LR | The bottom right | FITC-CD46 only | Live, the sperm of acrosomal reaction takes place |
Induce sperm % that acrosomal reaction takes place (=＂ IAR[%] ＂) for calculating, only fetch sperm alive from Q3 and Q4, and set them add up to 100%.Following then calculating IAR:
Acrosomal reaction (=＂ SAR[%] ＂) spontaneously takes place not adding in the part sperm under the ionophoric situation.Therefore, always contrast test to not adding ionophoric sperm through same treatment.The compute classes of SAR is similar to the calculating of IAR.Reality is calculated as following difference: ARIC=IAR-SAR by ionophore inductive acrosomal reaction (=＂ ARIC[%] ＂).
For of the influence (be determined as sperm ability to ionophore inductive acrosomal reaction) of our inhibitor of subsequent analysis to the capacitation of sAC adjusting, will contrast in positive capacitation (=with containing 25mMNaHCO
3The mHTF nutrient solution; The percentage of the sperm of the generation acrosomal reaction 1% the BSA incubation that does not contain substances) is made as=and 100%.The sperm that has added substances is defined as relative value to this maximum acrosomal reaction to the ability of acrosomal reaction.
The material that uses
People's TF (available from Irvine Scientific) of mHTF=improvement, Dulbeccos ' s phosphate buffered saline (available from Gibco) (contains
1g/LD-glucose, the 36mg/L Sodium.alpha.-ketopropionate, w/o is phenol red, w/o NaHCO
3); Bovine serum albumin, Fraction V (available from Fluka); Anhydrous dimethyl sulphoxide (DMSO) (available from Merck);
7.5% sodium hydrogen carbonate solution (893mM) (available from Irvine Scientific); Isolate-Gradient (available from Irvine Scientific); Ionophore-A23187 free acid (available from Calbiochem); Second pyridine homodimer (EhD) (available from Molecular Probe), mouse anti human CD46:FITC (available from Pharmingen).
Reference:
J.W.Carver-Ward，Human Reproduction Vol.11，No.9，pp：1923 ff，1996 High fertilization prediction by flow cytometric analysis of the CD46antigen on the inner acrosomal membrane of spermatozoa
O.J.D`Cruz，G.G.Haas，Fertility and Sterility Vol.65，No.4，pp：843ff，1996 Fluorescence-labeled fucolectins are superior markers for flowcytometric quantitation of the sperm acrosome reaction
E.Nieschlag，H.M.Behre，Andrology，Springer Verlag 1996
Embodiment:
Can find out from this table, with IC50The inhibitory action aspect to soluble adenylate cyclase of expression, compound according to the present invention show than the high about 10 times activity of known catechol estrogen (OH-estradiol). Catechol estrogen is poisonous, and therefore compound according to the present invention is much better than known compound. High about 10 times of the effectiveness of the compound that also provides than Zippin according to compound of the present invention.
Claims (18)
1, the compound of general formula (I),
Wherein use following symbol
R
1Hydrogen, halogen, CF
3, randomly be how saturated and randomly by polysubstituted C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps
Alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
2Halogen, CF
3, randomly be how saturated and randomly by polysubstituted C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps
Alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
3C
6-C
12-aryl, its can be randomly with following group list or many, identical or different the replacement: halogen, randomly coverlet or polysubstituted C
1-C
6-alkyl or C
1-C
6-acyl group; Perhaps
C
6-C
12-aryl, it can replace with following group: C
1-C
6-alkoxyl group, hydroxyl, cyano group, CO
2-(C
1-C
6-alkyl), N-(C
1-C
6-alkyl)
2, CO-NR
4R
5Or CF
3
C
5-C
12-heteroaryl, its can be randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, hydroxyl, cyano group, CO
2-(C
1-C
6-alkyl), N-(C
1-C
6-alkyl)
2, CO-NR
4R
5Or CF
3
Perhaps
C
3-C
6-cycloalkyl, its can be randomly with following group list or many, identical or different the replacement: halogen, CF
3, hydroxyl, cyano group, CO
2-(C
1-C
6-alkyl), C
1-C
6-alkyl, C
1-C
6-acyl group, N-(C
1-C
6-alkyl)
2, CO-NR
4R
5Or C
1-C
6-alkoxyl group,
R
4Hydrogen;
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group, N-C
1-C
6-alkyl-C
1-C
6-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
4And R
5Form 5-8 unit ring together, described ring can comprise other heteroatoms and
R
6C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl, wherein C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, oxyethyl group, isopropoxy, chlorine, bromine, fluorine, cyano group, methylsulfonyl or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
2, as the desired compound of claim 1, wherein said symbol has following implication:
R
1Hydrogen, halogen, CF
3, C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps
Alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
2Halogen, CF
3, C
3-C
6-cycloalkyl; Perhaps
C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl, C
1-C
6-aryl-C
1-C
6-alkyl or CF
3Group, wherein C
1-C
6-alkyl, C
1-C
6-aryl, C
1-C
6-acyl group, halo-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-alkyl, C
1-C
6-alkyl-C
1-C
6-acyl group, C
1-C
6-acyl group-C
1-C
6-acyl group, C
1-C
6-alkyl-C
1-C
6-aryl or C
1-C
6-aryl-C
1-C
6-alkyl can randomly insert single or multiple, identical or different oxygen, sulphur or nitrogen; Perhaps
Alkylsulfonyl-C
1-C
6-alkyl, sulphonamide or cyano group,
R
3C
6-C
12-aryl, its can be randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3
C
5-C
12-heteroaryl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3
C
3-C
6-cycloalkyl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, CF
3, cyano group, C
1-C
3-alkyl, C
1-C
3-acyl group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or C
1-C
3-alkoxyl group,
R
4Hydrogen;
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
4And R
5Form 5-8 unit ring together, described ring can comprise other heteroatoms and
R
6C
1-C
6-alkyl, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl, wherein C
1-C
6-alkyl, C
1-C
6-alkyl ring-C
3-C
6-alkyl, C
1-C
6-alkyl-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, oxyethyl group, isopropoxy, chlorine, bromine, fluorine, cyano group, methylsulfonyl or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
3, the desired compound of claim 1-2, wherein said symbol has following implication:
R
1Hydrogen,
R
2C
3-C
6-cycloalkyl, C
1-C
6-alkyl, CF
3, cyano group, bromine, perhaps-OCF
3,-SO
2-CH
3Group,
R
3C
6-C
12-aryl, its can be randomly with following group list or many, identical or different the replacement: halogen, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3
C
5-C
12-heteroaryl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, C
1-C
6-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or CF
3
C
3-C
6-cycloalkyl, its can be randomly with following group list or many, identical or different the replacement: chlorine and/or fluorine, CF
3, cyano group, C
1-C
3-alkyl, C
1-C
3-acyl group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NR
4R
5Or C
1-C
3-alkoxyl group,
R
4Hydrogen,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
6C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl, wherein C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, chlorine, fluorine, cyano group or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
4, the desired compound of claim 1-3, wherein said symbol has following implication:
R
1Hydrogen,
R
2C
3-C
6-cycloalkyl, C
1-C
6-alkyl, CF
3, cyano group, bromine, perhaps contraposition-OCF
3,-SO
2-CH
3Group,
R
3C
6-C
12-aryl, its can be randomly with following group list or two, identical or different the replacement: halogen, C
1-C
3-alkyl, ethanoyl, methoxyl group, oxyethyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NHR
5Or CF
3
C
5-C
12-heteroaryl, its can be randomly with following group list or two, identical or different the replacement: chlorine and/or fluorine, C
1-C
3-alkyl, ethanoyl, methoxyl group, oxyethyl group, cyano group, hydroxyl, N-(CH
3)
2, CO
2-(C
1-C
3-alkyl), CO-NHR
5Or CF
3
C
3-C
6-cycloalkyl,
R
4Hydrogen,
R
5Hydrogen;
C
1-C
6-alkyl-C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
6-alkyl, C
1-C
6-acyl group, C
1-C
6-alkoxyl group or CF
3
C
3-C
6-cycloalkyl, it is randomly with following group list or many, identical or different the replacement: C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group or CF
3
C
6-C
12-aryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
C
5-C
12-heteroaryl, it is randomly with following group list or many, identical or different the replacement: halogen, C
1-C
3-alkyl, C
1-C
3-acyl group, C
1-C
3-alkoxyl group, N-C
1-C
3-alkyl-C
1-C
3-alkyl, CF
3Or cyano group; Perhaps
The C that can replace arbitrarily
1-C
6-alkyl,
R
6C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl, wherein C
1-C
4-alkyl, CH
2-ring-C
3-C
6-alkyl, CH
2-C
6-C
12-aryl can be randomly with following group list or many, identical or different the replacement: hydroxyl, methoxyl group, chlorine, fluorine, cyano group or amino-sulfonyl,
And their isomer, diastereomer, enantiomer and salt.
5, the desired compound of claim 1-4, wherein said symbol has following implication:
R
1Hydrogen,
R
2The tertiary butyl, sec.-propyl, isobutyl-, sec-butyl, cyano group, bromine, perhaps contraposition-O-CF
3,-SO
2-CH
3Group,
R
3Group
R
4Hydrogen,
R
5Hydrogen or group-(CH
2)
m-N-(CH
3)
2,-(CH
2)
2-CH
3,-(CH
2)
2-NH-COCH
3,-(CH
2)-CHCH
3-OH ,-(CH
2)
2-O-CH
3,-(CH
2)
2-OH ,-CHCH
3-CH
2-OH, m=1-3 wherein,
R
6Methyl, ethyl, propyl group, 2-methoxy ethyl ,-CH
2-CF
3-,-(CH
2)
2-CF
3And benzyl,
And their isomer, diastereomer, enantiomer and salt.
6, the desired compound of claim 1-5, wherein said symbol has following implication:
R
1Hydrogen,
R
2The tertiary butyl, sec.-propyl, isobutyl-, sec-butyl, cyano group, bromine, perhaps contraposition-O-CF
3,-SO
2-CH
3Group,
R
3Group
R
4Hydrogen,
R
5Hydrogen or group-(CH
2)-CHCH
3-OH ,-(CH
2)
2-O-CH
3,-CHCH
3-CH
2-OH,
R
6Methyl, ethyl, propyl group, 2-methoxy ethyl ,-CH
2-CF
3-,-(CH
2)
2-CF
3And benzyl,
And their isomer, diastereomer, enantiomer and salt.
7, the desired compound of claim 1-6, it is selected from following compound:
1.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
2.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
3. methylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
4. methylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
5.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(pyridin-4-yl) acid amides
6.5-[(4-the benzylamino tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
7.5-[(4-the benzylamino tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
8. benzylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
9. benzylamino (±)-5-[(4-tert.-butylbenzene alkylsulfonyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
10.5-[(4-the amino tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
11.5-[(4-the amino tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
Amino (12. ±)-5-[(4-tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxyl-1-methylethyl) acid amides
Amino (13. ±)-5-[(4-tert.-butylbenzene alkylsulfonyl)-(2-methoxy ethyl)]-3-phenyl-1H-Indoline-2-carboxylic acid-(2-hydroxypropyl) acid amides
14.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-(3-fluorophenyl)-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
15.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-(3-fluorophenyl)-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides
16.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-(3-p-methoxy-phenyl)-1H-Indoline-2-carboxylic acid-(tetrahydropyran-4-base) acid amides
17.5-[(4-the methylamino tert.-butylbenzene alkylsulfonyl)]-3-(3-p-methoxy-phenyl)-1H-Indoline-2-carboxylic acid (2-morpholine-4-base ethyl) acid amides.
8, the medicine that contains the desired compound of at least a claim 1-7.
9, the desired medicine of claim 8, it contains the compound of the general formula 1 of effective dose.
10, be used to produce the compound of the desired general formula 1 of claim 1-7 of medicine.
11, the desired medicine of claim 10 that is used for the treatment of disease.
12, the desired medicine of claim 11, wherein said disease is caused by the cAMP metabolic disturbance.
13, be used to the desired medicine of claim 10 of practising contraception.
14, be used to suppress the desired medicine of claim 10 of soluble adenylate cyclase.
15, contain the desired medicine of claim 10-14 that is fit to carrier and vehicle.
16, the purposes of the compound of the desired general formula 1 of claim 1-7, its be used in the intestines, parenteral, vagina and Orally administered pharmaceutical dosage forms.
17, the method for the compound of preparation general formula (I) is characterized in that, makes the compound of formula II
R wherein
1, R
2, R
3And R
6Each above freely definition, and R
7Can be hydrogen or C
1-C
6-alkyl, in this case, preferred hydrogen, and C wherein
1-C
6-alkyl preferable methyl or ethyl,
With the amine reaction of general formula III,
After any required protecting group of cracking, form the compound of described general formula (I).
18, the intermediate product of general formula (II)
R wherein
1, R
2, R
3And R
6Each above freely definition, and R
7Can be hydrogen or C
1-C
6-alkyl;
The perhaps intermediate product of general formula (VII)
R wherein
1, R
2And R
7Each above freely definition;
The perhaps intermediate product of general formula (IX)
R wherein
1, R
2, R
6And R
7Each above freely definition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006014320.5 | 2006-03-23 | ||
| DE102006014320A DE102006014320B4 (en) | 2006-03-23 | 2006-03-23 | Inhibitors of the soluble adenylate class |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101448789A true CN101448789A (en) | 2009-06-03 |
Family
ID=38229991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800187317A Pending CN101448789A (en) | 2006-03-23 | 2007-03-22 | Soluble adenylate cyclase inhibitors |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP2001847A2 (en) |
| JP (1) | JP2009531319A (en) |
| KR (1) | KR20090007351A (en) |
| CN (1) | CN101448789A (en) |
| AR (1) | AR063661A1 (en) |
| CA (1) | CA2646650A1 (en) |
| DE (1) | DE102006014320B4 (en) |
| DO (1) | DOP2007000059A (en) |
| PE (1) | PE20080012A1 (en) |
| TW (1) | TW200815347A (en) |
| UY (1) | UY30236A1 (en) |
| WO (1) | WO2007107385A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108096244A (en) * | 2018-01-25 | 2018-06-01 | 昆明医科大学 | The new application of 1- hydrogen -2- indolones -3- benzyls/substituted benzyl -3- formic ether compounds |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2036906A1 (en) * | 2007-09-05 | 2009-03-18 | Bayer Schering Pharma Aktiengesellschaft | Azaindoles as inhibitors of soluble adenylate cyclase |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7442805B2 (en) * | 2003-09-25 | 2008-10-28 | Wyeth | Substituted sulfonamide-indoles |
| AU2005265270B2 (en) * | 2004-06-22 | 2011-09-22 | Vertex Pharmaceuticals Incorporated | Heterocyclic derivatives for modulation of calcium channels |
| DE102004047272A1 (en) * | 2004-09-24 | 2006-04-06 | Schering Ag | Inhibitors of soluble adenylate cyclase |
-
2006
- 2006-03-23 DE DE102006014320A patent/DE102006014320B4/en not_active Expired - Fee Related
-
2007
- 2007-03-22 WO PCT/EP2007/002708 patent/WO2007107385A2/en active Application Filing
- 2007-03-22 KR KR1020087025818A patent/KR20090007351A/en not_active Application Discontinuation
- 2007-03-22 EP EP07723654A patent/EP2001847A2/en not_active Withdrawn
- 2007-03-22 CN CNA2007800187317A patent/CN101448789A/en active Pending
- 2007-03-22 CA CA002646650A patent/CA2646650A1/en not_active Abandoned
- 2007-03-22 JP JP2009500787A patent/JP2009531319A/en active Pending
- 2007-03-23 PE PE2007000335A patent/PE20080012A1/en not_active Application Discontinuation
- 2007-03-23 AR ARP070101194A patent/AR063661A1/en unknown
- 2007-03-23 UY UY30236A patent/UY30236A1/en not_active Application Discontinuation
- 2007-03-23 TW TW096110185A patent/TW200815347A/en unknown
- 2007-03-23 DO DO2007000059A patent/DOP2007000059A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108096244A (en) * | 2018-01-25 | 2018-06-01 | 昆明医科大学 | The new application of 1- hydrogen -2- indolones -3- benzyls/substituted benzyl -3- formic ether compounds |
| CN108096244B (en) * | 2018-01-25 | 2020-11-24 | 昆明医科大学 | Application of 1-hydrogen-2-indolone-3-benzyl/substituted benzyl-3-formate compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| PE20080012A1 (en) | 2008-04-03 |
| KR20090007351A (en) | 2009-01-16 |
| JP2009531319A (en) | 2009-09-03 |
| DOP2007000059A (en) | 2007-09-30 |
| CA2646650A1 (en) | 2007-09-27 |
| WO2007107385A2 (en) | 2007-09-27 |
| EP2001847A2 (en) | 2008-12-17 |
| TW200815347A (en) | 2008-04-01 |
| DE102006014320A1 (en) | 2007-09-27 |
| AR063661A1 (en) | 2009-02-11 |
| DE102006014320B4 (en) | 2009-01-22 |
| UY30236A1 (en) | 2007-10-31 |
| WO2007107385A3 (en) | 2007-11-29 |
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