CN111606914B - [ pyrrolo-furan ] -spiro-indenone compound, pharmaceutical composition and application - Google Patents

[ pyrrolo-furan ] -spiro-indenone compound, pharmaceutical composition and application Download PDF

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CN111606914B
CN111606914B CN201910133443.0A CN201910133443A CN111606914B CN 111606914 B CN111606914 B CN 111606914B CN 201910133443 A CN201910133443 A CN 201910133443A CN 111606914 B CN111606914 B CN 111606914B
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左之利
汪亮亮
翁智颖
徐国伟
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Kunming Institute of Botany of CAS
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Abstract

The invention relates to [ pyrrolo-furan]-spiro indanone compound, pharmaceutical composition and application. The structural general formula of the compound is as follows:
Figure DDA0001976181570000011
R 1 is one of the following groups: tolyl, a first saturated alicyclic group, a first chain hydrocarbon group, phenylalkyl, naphthyl, biphenyl, pyridyl, diazophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, halophenyl, halogen,
Figure DDA0001976181570000012
Haloalkyl, alkoxy, alkoxycarbonyl,
Figure DDA0001976181570000013
An alkylamino group,
Figure DDA0001976181570000014
sulfonyl and amido. R 2 Is one of the following groups: a second saturated alicyclic hydrocarbon group, a second chain hydrocarbon group, a halogenated phenyl group, a diaza-phenyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thienyl group, a thiazolyl group,
Figure DDA0001976181570000015
Haloalkyl, alkoxy, alkoxycarbonyl. R 3 Is a group ofFirstly, the method comprises the following steps:
Figure DDA0001976181570000016
Figure DDA0001976181570000017
the compound is used for preparing 2-type adenylate cyclase agonists and medicines for treating 2-type adenylate cyclase related diseases.

Description

[ pyrrolo-furan ] -spiro-indanone compound, pharmaceutical composition and application
Technical Field
The invention relates to the technical field of medicines, in particular to a [ pyrrolo-furan ] -spiro-indanone compound, a pharmaceutical composition and application thereof.
Background
Adenylate cyclase is (Adenylyl cyclase, AC) a key signal molecule downstream of G protein-Coupled Receptors (GPCRs); insulin, epinephrine and other proteins and catecholamines hormones all need to be transmitted by an adenylate cyclase system to play a role; adenylate cyclase is the ultimate effector enzyme of many cell transmembrane signal transduction. Adenylate cyclase catalyzes Adenosine Triphosphate (ATP) to remove pyrophosphate, and Cyclic Adenosine monophosphate (cAMP) is synthesized. Cyclic adenosine monophosphate is an important second messenger in the intracellular signal transduction process, can activate Protein Kinase A (PKA) to regulate the activity of various downstream proteins (including transcription factors), and influences various biological processes such as cell proliferation, differentiation and apoptosis so as to regulate cell response. It has been found that adenylate cyclase expressed in mammalian cells has a total of 9 transmembrane subtypes (AC 1-AC 9) and one soluble subtype (AC 10), and the distribution, activity and expression level of each subtype is inconsistent in different tissues and cells, so that cyclic adenosine monophosphate signaling pathways have different regulatory mechanisms and are involved in different physiological processes.
Adenylate cyclase type 2 (AC 2) is widely distributed in tissues such as brain, lung, skeletal muscle, heart, etc. The related research reports that: adenylyl cyclase type 2 may be involved in skeletal muscle physiology, pulmonary diseases, neuroendocrine tumors, colorectal cancer, etc. Relevant studies have shown that: the type 2 adenylate cyclase coding gene polymorphism is related to neuropsychiatric diseases and pulmonary diseases. At present, due to the lack of pharmacological studies of gene knockout or overexpression of type 2 adenylate cyclase in mouse models, more physiological and pharmacological functions thereof have not been discovered yet. Type 2 adenylate cyclase belongs to the type of adenylate cyclase activated by G protein beta gamma subunit, and the activation of type 2 adenylate cyclase can be realized by stimulation of endogenous substance G-protein alpha subunit and Protein Kinase C (PKC).
In the prior art, the compound Forskolin (FSK) and its derivatives (as shown in the following structure) are the only small molecular agonists of adenylate cyclase. Wherein, the structures of the forskolin and the derivatives thereof are as follows:
Figure GDA0003946434630000021
however, forskolin and its derivatives have activation effects on 8 transmembrane subtypes of adenylate cyclase (AC 1-AC 8) except adenylate cyclase 9 (AC 9); the forskolin and the derivatives thereof have no subtype selectivity on 9 adenylate cyclase transmembrane subtypes, can not individually activate a specific type of adenylate cyclase transmembrane subtype, and can not selectively and efficiently activate type 2 adenylate cyclase. In addition, there has not been any report in the prior art that other compounds can selectively activate adenylyl cyclase type 2.
Disclosure of Invention
In view of the above, the present invention provides a [ pyrrolo-furan ] -spirocyclic indanone compound, a pharmaceutical composition and an application thereof, and mainly aims to design and synthesize a compound represented by formula (I), wherein the compound is used for preparing 2-type adenylate cyclase (AC 2) agonists and medicines for treating diseases (neuropsychiatric diseases, pulmonary diseases, tracheal diseases and bronchial diseases) related to 2-type adenylate cyclase.
In order to achieve the purpose, the invention mainly provides the following technical scheme:
in one aspect, an embodiment of the present invention provides a [ pyrrolofuran ] -spirocyclic indanone compound, which is characterized in that the structural general formula is shown in formula (I):
Figure GDA0003946434630000031
wherein R is 1 Is one of the following groups: tolyl, a first saturated alicyclic hydrocarbon group, a first chain hydrocarbon group, phenylalkyl, naphthyl, biphenyl, pyridyl, diazophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, halophenyl, halogen, hydrogen, haloalkyl, alkoxy, alkoxycarbonyl, amino, alkylamino, nitro, hydroxyl, carboxyl, sulfonyl, amide;
wherein R is 2 Is one of the following groups: a second saturated alicyclic hydrocarbon group, a second chain hydrocarbon group, a halogenated phenyl group, a diazophenyl group, a furyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thienyl group, a thiazolyl group, hydrogen, a halogenated alkyl group, an alkoxy group, and an alkoxycarbonyl group;
wherein R is 3 Is one of the following groups: hydrogen
Figure GDA0003946434630000032
Methyl radical
Figure GDA0003946434630000033
Methoxy radical
Figure GDA0003946434630000034
Halogen element
Figure GDA0003946434630000035
Hydroxy radical
Figure GDA0003946434630000036
Amino group
Figure GDA0003946434630000037
Nitro radical
Figure GDA0003946434630000038
Carboxylic acid groups
Figure GDA0003946434630000039
Figure GDA00039464346300000310
Cyano radical
Figure GDA00039464346300000311
Sulfonic acid group
Figure GDA00039464346300000312
The purpose of the invention and the technical problem to be solved can be further realized by adopting the following technical measures.
Preferably, the tolyl group is selected from
Figure GDA00039464346300000313
Preferably, the first saturated alicyclic hydrocarbon group is selected from
Figure GDA00039464346300000314
Preferably, the first chain hydrocarbon group is selected from one of the following groups:
Figure GDA00039464346300000315
Figure GDA00039464346300000316
preferably, the phenylalkyl is selected from
Figure GDA00039464346300000317
Preferably, the naphthyl group is selected from
Figure GDA00039464346300000318
It is preferable thatThe biphenyl group is selected from
Figure GDA00039464346300000319
Preferably, the second saturated alicyclic hydrocarbon group is one of the following groups:
Figure GDA00039464346300000320
Figure GDA00039464346300000321
preferably, the second chain hydrocarbon group is selected from one of the following groups:
Figure GDA0003946434630000041
preferably, the diazepine group is one of the following groups:
Figure GDA0003946434630000042
Figure GDA0003946434630000043
preferably, the halophenyl group is preferably
Figure GDA0003946434630000044
Preferably, the pyridyl is one of the following groups:
Figure GDA0003946434630000045
preferably, the furyl group is
Figure GDA0003946434630000046
Preferably, the pyrrolyl group is one of the following groups:
Figure GDA0003946434630000047
preferably, the pyrazolyl group is one of the following groups:
Figure GDA0003946434630000048
preferably, the imidazolyl group is one of the following groups:
Figure GDA0003946434630000049
preferably, thienyl is
Figure GDA00039464346300000410
Preferably, thiazolyl is one of the following groups:
Figure GDA00039464346300000411
preferably, the [ pyrrolofuran ] -spirocyclic indanone compound is any one of the following compounds:
Figure GDA00039464346300000412
Figure GDA0003946434630000051
in another aspect, the present invention provides a method for preparing [ pyrrolofuran ] -spirocyclic indanones, wherein the chemical reaction equation is as follows:
Figure GDA0003946434630000052
preferably, the preparation method comprises the following steps: aldehyde is reacted by a one-pot process
Figure GDA0003946434630000053
N-substituted maleimides
Figure GDA0003946434630000061
Diazo(s) to nitrogen
Figure GDA0003946434630000062
Adding a molecular sieve MS and a catalyst rhodium diacetate into a 1, 2-tetrachloroethane solution to obtain a reaction system; filling inert gas into the reaction system for protection, and reacting for a set time at a set reaction temperature to obtain a product mixture; filtering, drying, concentrating and purifying the product mixture to obtain the [ pyrrolo-furan]-spirocyclic indanones.
Preferably, the aldehyde is reacted with
Figure GDA0003946434630000063
N-substituted maleimides
Figure GDA0003946434630000064
Diazo
Figure GDA0003946434630000065
The equivalent ratio of (2-4) to 1, and the total equivalent number is 5-9; the dosage of the 1, 2-tetrachloroethane solution is 5-15 mL; the dosage of the molecular sieve is 400-800 mg; the dosage of the catalyst rhodium diacetate is 1-15mg. Preferably, the molecular sieve is selected from
Figure GDA0003946434630000066
And (3) a molecular sieve. Preferably, the reaction temperature is 80-120 ℃ and the reaction time is 2-3 hours. Preferably, the product mixture is sequentially subjected to diatomite filtration treatment, anhydrous sodium sulfate drying treatment, reduced pressure concentration treatment and column chromatography purification treatment to obtain the [ pyrrolo-furan]-spirocyclic indanones.
In another aspect, the [ pyrrolo-furan ] -spiro-indanone compound is applied to preparation of the 2-type adenylate cyclase agonist.
The application of the [ pyrrolo-furan ] -spiro-indanone compound in preparing medicaments for treating diseases related to 2-type adenylate cyclase; the diseases related to type 2 adenylate cyclase include neuropsychiatric diseases, pulmonary diseases, tracheal diseases and bronchial diseases.
In yet another aspect, embodiments of the present invention further provide a pharmaceutical composition, wherein the pharmaceutical composition includes: the [ pyrrolo-furan ] -spiro-indenone compound and at least one pharmaceutically acceptable auxiliary material.
Preferably, the pharmaceutical composition is for the preparation of an adenylate cyclase type 2 agonist.
Preferably, the pharmaceutical composition is used for the preparation of a medicament for the treatment of a disease associated with adenylyl cyclase 2; the diseases related to type 2 adenylate cyclase include neuropsychiatric diseases, pulmonary diseases, tracheal diseases and bronchial diseases.
Compared with the prior art, the [ pyrrolo-furan ] -spiro-indanone compound, the pharmaceutical composition and the application have at least the following beneficial effects:
the invention provides the [ pyrrolo-furan ] -spiro-indanone compound with the structure shown in the formula (I) for the first time, and the compound has the advantages of novel structure, easy chemical synthesis, low cost and small side effect. Meanwhile, the compound designed by the invention is not only a high-efficiency activator of the type 2 adenylate cyclase except for Forskolin (FSK), but also can selectively activate the type 2 adenylate cyclase, and has no obvious activation or no activation to other transmembrane subtypes of the adenylate cyclase. Therefore, the compounds of the invention have the application as or for preparing 2-type adenylate cyclase (AC 2) agonists and therapeutic drugs for diseases related to 2-type adenylate cyclase (neuropsychiatric diseases, pulmonary diseases, tracheal diseases and bronchial diseases).
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to make the technical solutions of the present invention practical in accordance with the contents of the specification, the following detailed description is given of preferred embodiments of the present invention with reference to the accompanying drawings.
Drawings
FIG. 1 is a graph of primary screening signals of agonistic action of Compound 1 of the present invention on human embryonic kidney HEK293+ hAC1, hAC2, hAC4, hAC5, hAC8 cells, respectively;
FIG. 2 is a graph showing the effect of Compound 1 on the agonism of human embryonic kidney HEK293+ hAC2 cells.
Detailed Description
To further explain the technical means and effects of the present invention adopted to achieve the predetermined object, the following detailed description of the embodiments, structures, features and effects according to the present invention will be made with reference to the accompanying drawings and preferred embodiments. In the following description, different "one embodiment" or "an embodiment" refers to not necessarily the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
Example 1
The present embodiment provides a [ pyrrolo-furan ] -spiro-indenone compound, whose structural general formula is shown in formula (I):
Figure GDA0003946434630000071
wherein R is 1 Is one of the following groups: tolyl radical (preferred)
Figure GDA0003946434630000081
) The first saturated alicyclic hydrocarbon group (preferably)
Figure GDA0003946434630000082
) First chain hydrocarbon group (preferably one of the following groups:
Figure GDA0003946434630000083
Figure GDA0003946434630000084
) Phenylalkyl (preferred is
Figure GDA0003946434630000085
) Naphthyl (preferred)
Figure GDA0003946434630000086
) Biphenyl group (preferably)
Figure GDA0003946434630000087
) Pyridyl (in particular one of the following groups:
Figure GDA0003946434630000088
Figure GDA0003946434630000089
) Diazophenyl (preferably one of the following groups:
Figure GDA00039464346300000810
Figure GDA00039464346300000811
) Furyl group
Figure GDA00039464346300000812
Pyrrolyl (in particular one of the following groups:
Figure GDA00039464346300000813
) Pyrazolyl (in particular one of the following groups:
Figure GDA00039464346300000814
) Imidazolyl (specifically, one of the following groups:
Figure GDA00039464346300000815
Figure GDA00039464346300000816
) Thienyl, a
Figure GDA00039464346300000817
Thiazolyl (in particular one of the following groups:
Figure GDA00039464346300000818
) Halogenated phenyl, halogen
Figure GDA00039464346300000819
Hydrogen
Figure GDA00039464346300000820
Haloalkyl, alkoxy, alkoxycarbonyl, amino, alkylamino, nitro, hydroxyl, carboxyl, sulfonyl, amide.
Preferably, R 1 Is one of the following groups:
Figure GDA0003946434630000091
wherein R is 2 Is one of the following groups: a second saturated alicyclic hydrocarbon group (preferably one of the following groups:
Figure GDA0003946434630000092
) A second chain hydrocarbon group (preferably one of the following:
Figure GDA0003946434630000093
Figure GDA0003946434630000094
) Halogenophenyl (preferably
Figure GDA0003946434630000095
) Diazophenyl (preferably one of the following groups:
Figure GDA0003946434630000096
) Furyl group
Figure GDA0003946434630000101
Pyrrolyl (in particular one of the following groups:
Figure GDA0003946434630000102
Figure GDA0003946434630000103
) Pyrazolyl (in particular one of the following groups:
Figure GDA0003946434630000104
) Imidazolyl (specificallyOne of the following groups:
Figure GDA0003946434630000105
) Thienyl, a
Figure GDA0003946434630000106
Figure GDA0003946434630000107
Thiazolyl (in particular one of the following groups:
Figure GDA0003946434630000108
) Hydrogen, haloalkyl, alkoxy, alkoxycarbonyl.
Preferably, R 2 Is one of the following groups:
Figure GDA0003946434630000109
wherein R is 3 Is one of the following groups: hydrogen
Figure GDA0003946434630000111
Methyl radical
Figure GDA0003946434630000112
Methoxy radical
Figure GDA0003946434630000113
Halogen element
Figure GDA0003946434630000114
Hydroxy radical
Figure GDA0003946434630000115
Amino group
Figure GDA0003946434630000116
Nitro radical
Figure GDA0003946434630000117
Carboxylic acid groups
Figure GDA0003946434630000118
Cyano radical
Figure GDA0003946434630000119
Sulfonic acid group
Figure GDA00039464346300001110
R 3 Is a substituent at any position on the benzene ring.
In addition, this embodiment also provides a method for preparing [ pyrrolo-furan ] -spiro-indanone compounds, wherein the chemical reaction equation is as follows:
Figure GDA00039464346300001111
the preparation method comprises the following specific steps: aldehyde is prepared by a three-component one-pot method
Figure GDA00039464346300001112
N-substituted maleimides
Figure GDA00039464346300001113
Diazo(s) to nitrogen
Figure GDA00039464346300001114
The three compounds were added to 5-15mL of a 1,1, 2-tetrachloroethane solution at an equivalent ratio of 4
Figure GDA00039464346300001115
Molecular sieve and 0.2 equivalent catalyst of rhodium diacetate, the system is filled with argon for protection, and the reaction is carried out for 2 to 3 hours at the temperature of 80 ℃. After the reaction of the raw materials is completed, after the mixture (i.e., product mixture) obtained after the reaction is cooled, the mixture is filtered through kieselguhr, dried through anhydrous sodium sulfate, concentrated under reduced pressure, and purified through column chromatography to obtain the compound shown in the general formula (I).
Example 2
Based on example 1, this example lists the preparation method and the structure determination data of 20 [ pyrrolo-furan ] -spiro-indanones compounds. The method comprises the following specific steps:
1. compound 1
When R in formula (I) 1 Is composed of
Figure GDA00039464346300001116
R 2 Is composed of
Figure GDA00039464346300001117
R 3 When the compound is H, the obtained compound is a compound 1; the structural formula is as follows:
Figure GDA00039464346300001118
the preparation method of the compound 1 comprises the following steps:
Figure GDA0003946434630000121
the preparation method comprises the following specific steps: 2-diazo-1, 3-indandione (100mg, 0.58mmol), p-tolualdehyde (279mg, 2.32mmol), N-o-chlorophenylmaleimide (482mg, 2.32mmol), rhodium diacetate (2.57mg, 0.006mmol) and 500mg of powder
Figure GDA0003946434630000122
Adding a molecular sieve into 7mL of 1, 2-tetrachloroethane, reacting the system at 80 ℃ for 2-3 hours under the protection of argon, and completely reacting the raw materials to obtain a mixture. After the mixture was cooled, the mixture was subjected to celite filtration, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography purification to give compound 1 as a white powdery solid in 65.66% yield.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.10-8.06(m,2H),7.97-7.95(m,2H),7.54-7.35(m,6H),7.18-7.16(m,2H),6.12(d,J＝7.40Hz,1H),4.11(dd,J＝7.40,8.36Hz,1H),3.93(d,J＝8.36Hz,1H),2.32(s,3H)ppm.EI-MS calc.for C 27 H 18 ClNO 5 :471；Found:471(M).
2. compound 2
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000123
R 2 Is composed of
Figure GDA0003946434630000124
R 3 When the compound is H, the obtained compound is a compound 2; the structural formula is as follows:
Figure GDA0003946434630000125
the preparation method of the compound 2 comprises the following steps:
Figure GDA0003946434630000126
the preparation method comprises the following specific steps: the preparation steps of the compound 2 are similar to those of the compound 1, and the compound 2 can be obtained by only replacing p-tolualdehyde which is a raw material in the preparation steps of the compound 1 with cyclopropyl formaldehyde, wherein the yield is 55.67%.
The structure determination data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05-8.01(m,2H),7.97-7.93(m,2H),7.65-7.63(m,1H),7.53-7.51(m,1H),7.47-7.42(m,2H),4.26(dd,J＝6.52,9.04Hz,1H),3.87(dd,J＝8.32,14.92,1H),1.39(m,1H),0.75(m,2H),0.48(m,2H)ppm.EI-MS calc.for C 23 H 16 ClNO 5 :421；Found:421(M).
3. compound 3
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000131
R 2 Is composed of
Figure GDA0003946434630000132
R 3 When the compound is H, the obtained compound is a compound 3; the structural formula is as follows:
Figure GDA0003946434630000133
the preparation method of the compound 3 comprises the following steps:
Figure GDA0003946434630000134
the preparation method comprises the following specific steps: the preparation procedure of compound 3 is similar to that of compound 1, and compound 3 can be obtained by only replacing p-tolualdehyde, which is the raw material in the preparation procedure of compound 1, with isobutyraldehyde, with a yield of 63.37%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.06-8.01(m,2H),7.97-7.91(m,2H),7.68(dd,J＝1.60,7.72Hz,1H),7.52-7.39(m,3H),4.54(dd,J＝5.76,10.28Hz,1H),3.91-3.88(m,1H),3.83(d,J＝8.04,1H),2.37-2.27(m,1H),1.21(d,J＝6.60Hz,1H),1.04(d,J＝6.48Hz,1H)ppm.EI-MS calc.for C 23 H 18 ClNO 5 :423；Found:423(M).
4. compound 4
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000141
R 2 Is composed of
Figure GDA0003946434630000142
R 3 When the compound is H, the obtained compound is a compound 4; the structural formula is as follows:
Figure GDA0003946434630000143
the preparation method of the compound 4 comprises the following steps:
Figure GDA0003946434630000144
the preparation method comprises the following specific steps: the preparation step of the compound 4 is similar to that of the compound 1, and the compound 4 is obtained by only replacing p-tolualdehyde which is a raw material in the preparation step of the compound 1 with cyclohexyl formaldehyde, wherein the yield is 58.74%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05-8.03(m,2H),7.96-7.93(m,2H),7.71(dd,J＝1.44,7.64Hz,1H),7.52-7.39(m,3H),4.60(dd,J＝5.72,10.24Hz,1H),3.92-3.88(m,1H),3.81(d,J＝8.04,1H),2.25(d,J＝11.73,1H),2.11-1.96(m,2H),1.76-1.66(m,4H),1.42-0.83(m,6H)ppm.EI-MS calc.for C 26 H 22 ClNO 5 :463；Found:463(M).
5. compound 5
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000145
R 2 Is composed of
Figure GDA0003946434630000146
R 3 When the compound is H, the obtained compound is a compound 5; the structural formula is as follows:
Figure GDA0003946434630000147
the preparation method of the compound 5 comprises the following steps:
Figure GDA0003946434630000151
the preparation method comprises the following specific steps: the preparation of compound 5 was carried out in a similar manner to that of compound 1, except that p-tolualdehyde, which is a raw material in the preparation of compound 1, was replaced with 3-methyl-2-butenal to obtain compound 5 in a yield of 52.64%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.06-8.02(m,2H),7.97-7.91(m,2H),7.67(dd,J＝1.54,7.62Hz,1H),7.53-7.40(m,3H),2.75-5.71(m,1H),3.92-3.88(m,1H),5.65-5.63(m,1H),3.86-3.85(m,2H),1.81(s,6H)ppm.EI-MS calc.for C 24 H 18 ClNO 5 :435；Found:435(M).
6. compound 6
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000152
R 2 Is composed of
Figure GDA0003946434630000153
R 3 When H, the resulting compound is compound 6; the structural formula is as follows:
Figure GDA0003946434630000154
the preparation method of the compound 6 comprises the following steps:
Figure GDA0003946434630000155
the preparation method comprises the following specific steps: the preparation process of compound 6 was similar to that of compound 1 except that p-tolualdehyde, which is the starting material in the preparation process of compound 1, was replaced with n-butyraldehyde to obtain compound 6 in a yield of 61.33%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05-8.03(m,2H),7.97-7.91(m,2H),7.67(dd,J＝1.64,7.60Hz,1H),7.53-7.40(m,3H),5.00-4.95(m,1H),3.84-3.83(m,2H),2.08-1.99(m,1H),1.92-1.82(m,1H),1.61-1.52(m,2H),0.97(t,J＝7.36Hz,3H)ppm.EI-MS calc.for C 23 H 18 ClNO 5 :423；Found:423(M).
7. compound 7
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000161
R 2 Is composed of
Figure GDA0003946434630000162
R 3 When the compound is H, the obtained compound is a compound 7; the structural formula is as follows:
Figure GDA0003946434630000163
the preparation method of the compound 7 comprises the following steps:
Figure GDA0003946434630000164
the preparation method comprises the following specific steps: the preparation of compound 7 was carried out in a similar manner to that of compound 1, except that p-tolualdehyde, which is a raw material in the preparation of compound 1, was replaced with 2-ethyl-2-butenal to obtain compound 7 in a yield of 59.15%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05-8.03(m,2H),7.97-7.92(m,2H),7.50-7.38(m,4H),5.70(t,J＝7.32Hz,1H),5.48(d,J＝7.45Hz,1H),3.99-3.95(m,1H),3.37-2.28(m,1H),2.10-1.98(m,3H),1.41-1.32(m,2H),1.08-1.03(m,3H),0.87(t,J＝7.36Hz,3H)ppm.EI-MS calc.for C 27 H 24 ClNO 5 :477；Found:477(M).
8. compound 8
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000165
R 2 Is composed of
Figure GDA0003946434630000166
R 3 When the compound is H, the obtained compound is a compound 8; the structural formula is as follows:
Figure GDA0003946434630000171
the preparation method of the compound 8 comprises the following steps:
Figure GDA0003946434630000172
the preparation method comprises the following specific steps: the preparation process of the compound 8 is similar to that of the compound 1, and the compound 8 is obtained by replacing p-tolualdehyde, which is a raw material in the preparation process of the compound 1, with 2-ethyl-2-butenal, with a yield of 63.24%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05-8.03(m,2H),7.97-7.92(m,2H),7.63-7.61(m,1H),7.52-7.40(m,3H),4.90(dd,J＝5.64,13.16Hz,1H),3.85-3.84(m,2H),2.15-2.04(m,1H),1.97-1.86(m,1H),1.12(t,J＝7.38Hz,3H)ppm.EI-MS calc.for C 22 H 16 ClNO 5 :409；Found:409(M).
9. compound 9
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000173
R 2 Is composed of
Figure GDA0003946434630000174
R 3 When the compound is H, the obtained compound is a compound 9; the structural formula is as follows:
Figure GDA0003946434630000175
the preparation method of the compound 9 comprises the following steps:
Figure GDA0003946434630000181
the preparation method comprises the following specific steps: the preparation of compound 9 was carried out in a similar manner to that of compound 1, except that p-tolualdehyde, which is the starting material in the preparation of compound 1, was replaced with phenylacetaldehyde to obtain compound 9 in a yield of 52.19%.
The structure determination data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.05-8.01(m,2H),7.96-7.90(m,2H),7.20-7.69(m,1H),7.55-7.42(m,3H),7.39-7.19(m,5H),5.25-5.20(m,1H),3.92-3.83(m,2H),3.52(dd,J＝5.32,14.60Hz,1H),3.17(dd,J＝7.98,14.70Hz,1H)ppm.EI-MS calc.for C 27 H 18 ClNO 5 :471；Found:471(M).
10. compound 10
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000182
R 2 Is composed of
Figure GDA0003946434630000183
R 3 When the compound is H, the obtained compound is a compound 10; the structural formula is as follows:
Figure GDA0003946434630000184
compound 10 was prepared as follows:
Figure GDA0003946434630000185
the preparation method comprises the following specific steps: the preparation process of the compound 10 is similar to that of the compound 1, and the compound 10 is obtained by replacing p-tolualdehyde which is a raw material in the preparation process of the compound 1 with phenylpropyl aldehyde, wherein the yield is 50.63%.
The structure determination data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.06-8.04(m,2H),7.98-7.92(m,2H),7.64-7.61(m,1H),7.52-7.39(m,3H),7.29-7.17(m,5H),5.00-4.94(m,1H),3.84-3.83(m,2H),2.86(t,J＝7.76Hz,2H),2.42-2.31(m,1H),2.29-2.18(m,1H)ppm.EI-MS calc.for C 28 H 20 ClNO 5 :485；Found:485(M).
11. compound 11
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000191
R 2 Is composed of
Figure GDA0003946434630000192
R 3 When the compound is H, the obtained compound is a compound 11; the structural formula is as follows：
Figure GDA0003946434630000193
Compound 11 was prepared as follows:
Figure GDA0003946434630000194
the preparation method comprises the following specific steps: the preparation process of the compound 11 is similar to that of the compound 1, and the compound 11 is obtained by replacing p-tolualdehyde, which is a raw material in the preparation process of the compound 1, with 2-naphthaldehyde, with a yield of 48.32%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.15-8.13(m,1H),8.07-7.83(m,8H),7.75-7.71(m,1H),7.55-7.42(m,5H),6.07(d,J＝6.72Hz,1H),4.35(d,J＝10.39Hz,1H),4.06(dd,J＝6.84,10.27Hz,1H)ppm.EI-MS calc.for C 30 H 18 ClNO 5 :533；Found:533(M).
12. compound 12
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000195
R 2 Is composed of
Figure GDA0003946434630000196
R 3 When the compound is H, the obtained compound is a compound 12; the structural formula is as follows:
Figure GDA0003946434630000201
compound 12 was prepared as follows:
Figure GDA0003946434630000202
the preparation method comprises the following specific steps: the preparation of compound 12 was carried out in a similar manner to that of compound 1, except that p-tolualdehyde, which is the starting material in the preparation of compound 1, was replaced with 4-biphenylcarboxaldehyde to give compound 12 in a yield of 48.32%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.14-8.11(m,1H),8.06-8.04(m,1H),7.99-7.93(m,2H),7.68-7.33(m,15H),5.95(d,J＝6.80Hz,1H),4.32(d,J＝10.32Hz,1H),4.02(dd,J＝6.86,10.30Hz,1H)ppm.EI-MS calc.for C 32 H 20 ClNO 5 :533；Found:533(M).
13. compound 13
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000203
R 2 Is composed of
Figure GDA0003946434630000204
R 3 When the compound is H, the obtained compound is a compound 13; the structural formula is as follows:
Figure GDA0003946434630000205
compound 13 was prepared as follows:
Figure GDA0003946434630000211
the preparation method comprises the following specific steps: the preparation process of compound 13 is similar to that of compound 1, and compound 13 is obtained in 70.24% yield by replacing N-o-chlorophenylmaleimide as the raw material in the preparation process of compound 1 with N-cyclopentylmaleimide.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.12-8.09(m,1H),8.05-8.02(m,1H),7.98-7.93(m,2H),7.29(d,J＝7.96Hz,2H),7.18(d,J＝7.92Hz,2H),6.03(d,J＝7.92Hz,1H),4.39-4.31(m,1H),3.80(t,J＝8.16Hz,1H),3.57(d,J＝8.36Hz,1H),2.35(s,3H),2.07-2.00(m,1H),1.92-1.81(m,5H),1.55-4.521(m,2H),ppm.EI-MS calc.forC 26 H 23 NO 5 :429；Found:429(M).
14. compound 14
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000212
R 2 Is composed of
Figure GDA0003946434630000213
R 3 When H, the resulting compound is compound 14; the structural formula is as follows:
Figure GDA0003946434630000214
compound 14 was prepared as follows:
Figure GDA0003946434630000215
the preparation method comprises the following specific steps: the preparation of Compound 14 was carried out in a similar manner to that of Compound 1 except that N-o-chlorophenylmaleimide as the starting material in the preparation of Compound 1 was replaced with N-isobutylmaleimide to give Compound 14 in a yield of 74.18%.
The structure determination data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),8.05-8.03(m,1H),7.97-7.95(m,2H),7.30(d,J＝7.88Hz,2H),7.17(d,J＝7.80Hz,2H),6.08(d,J＝7.88Hz,1H),3.86(t,J＝8.12Hz,1H),3.63(d,J＝8.36Hz,1H),3.25(d,J＝7.32Hz,3H),2.35(s,3H),2.04-1.95(m,1H),0.94(dd,J＝6.64,20.48Hz,6H)ppm.EI-MS calc.for C 25 H 23 NO 5 :417；Found:417(M).
15. compound 15
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000221
R 2 Is composed of
Figure GDA0003946434630000222
R 3 When H, the resulting compound is compound 15; the structural formula is as follows:
Figure GDA0003946434630000223
compound 15 was prepared as follows:
Figure GDA0003946434630000224
the preparation method comprises the following specific steps: the preparation process of compound 15 is similar to that of compound 1, and compound 15 is obtained in 72.25% yield by replacing N-o-chlorophenylmaleimide as the raw material in the preparation process of compound 1 with N-isopropylmaleimide.
The structure determination data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),8.05-8.02(m,1H),7.98-7.93(m,2H),7.30(d,J＝7.96Hz,2H),7.18(d,J＝7.88Hz,2H),6.03(d,J＝7.84Hz,1H),4.31-4.24(m,1H),3.79(t,J＝8.12,1H),3.57(d,J＝8.36Hz,1H),2.35(s,3H),1.36(dd,J＝6.94,14.26Hz,6H)ppm.EI-MS calc.for C 24 H 21 NO 5 :403；Found:403(M).
16. compound 16
When R in the formula (I) 1 Is composed of
Figure GDA0003946434630000225
R 2 Is composed of
Figure GDA0003946434630000226
R 3 When H, the resulting compound is compound 16; the structural formula is as follows:
Figure GDA0003946434630000231
compound 16 was prepared as follows:
Figure GDA0003946434630000232
the preparation method comprises the following specific steps: the preparation process of compound 16 is similar to that of compound 1, and compound 16 can be obtained in 68.24% yield by replacing N-o-chlorophenylmaleimide as a raw material in the preparation process of compound 1 with N-tert-butylmaleimide.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),8.04-8.01(m,1H),7.97-7.92(m,2H),7.32(d,J＝7.96Hz,2H),7.18(d,J＝7.88Hz,2H),6.04(d,J＝8.00Hz,1H),3.69(t,J＝8.20,1H),3.45(d,J＝8.44Hz,1H),2.35(s,3H),1.50(s,6H)ppm.EI-MS calc.for C 25 H 23 NO 5 :417；Found:417(M).
17. compound 17
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000233
R 2 Is composed of
Figure GDA0003946434630000234
R 3 When H is obtained, the resulting compound is compound 17; the structural formula is as follows:
Figure GDA0003946434630000235
compound 17 was prepared as follows:
Figure GDA0003946434630000241
the preparation method comprises the following specific steps: the preparation process of compound 17 is similar to that of compound 1, and compound 17 is obtained in 70.56% yield by replacing N-o-chlorophenylmaleimide as the raw material in the preparation process of compound 1 with N-cyclopropylmaleimide.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),8.05-8.03(m,1H),7.98-7.93(m,2H),7.24(d,J＝8.20Hz,2H),7.18(d,J＝7.96Hz,2H),6.02(d,J＝7.92Hz,1H),3.81(t,J＝8.12,1H),3.58(d,J＝8.32Hz,1H),2.48(m,1H),2.35(s,3H),1.09-1.03(m,1H),1.00-0.86(m,2H),0.76-0.69(m,1H)ppm.EI-MS calc.for C 24 H 19 NO 5 :401；Found:401(M).
18. compound 18
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000242
R 2 Is composed of
Figure GDA0003946434630000243
R 3 When H, the resulting compound is compound 18; the structural formula is as follows:
Figure GDA0003946434630000244
compound 18 was prepared as follows:
Figure GDA0003946434630000245
the preparation method comprises the following specific steps: the preparation process of compound 18 is similar to that of compound 1, and compound 18 can be obtained in 73.63% yield by replacing N-o-chlorophenylmaleimide as the raw material in the preparation process of compound 1 with N-cyclohexylmaleimide.
The structure determination data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),8.05-8.03(m,1H),7.98-7.93(m,2H),7.29(d,J＝7.92Hz,2H),7.18(d,J＝7.84Hz,2H),6.03(d,J＝7.84Hz,1H),3.92-3.85(m,1H),3.78(t,J＝8.12,1H),3.58(d,J＝8.32Hz,1H),2.35(s,3H),2.15-1.93(m,2H),1.78-1.79(m,2H),1.68-1.59(m,3H),1.31-1.14(m,3H)ppm.EI-MS calc.for C 27 H 25 NO 5 :443；Found:443(M).
19. compound 19
Is of immediate type(I) R in (1) 1 Is composed of
Figure GDA0003946434630000251
R 2 Is composed of
Figure GDA0003946434630000252
R 3 When H, the resulting compound is compound 19; the structural formula is as follows:
Figure GDA0003946434630000253
compound 19 was prepared as follows:
Figure GDA0003946434630000254
the preparation method comprises the following specific steps: the preparation of Compound 19 was carried out in a similar manner to that of Compound 1 except that N-o-chlorophenylmaleimide as the starting material in the preparation of Compound 1 was replaced with N-methylmaleimide to give Compound 19 in a yield of 68.91%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.11-8.09(m,1H),8.06-8.04(m,1H),7.99-7.94(m,2H),7.28(d,J＝8.00Hz,2H),7.18(d,J＝7.92Hz,2H),6.04(d,J＝7.76Hz,1H),3.88(t,J＝8.00,1H),3.65(d,J＝8.20,1H),2.96(s,3H),2.35(s,3H)ppm.EI-MS calc.for C 22 H 17 NO 5 :375；Found:375(M).
20. compound 20
When R in formula (I) 1 Is composed of
Figure GDA0003946434630000255
R 2 Is composed of
Figure GDA0003946434630000256
R 3 When H, the resulting compound is compound 20; the structural formula is as follows:
Figure GDA0003946434630000261
compound 20 was prepared as follows:
Figure GDA0003946434630000262
the preparation method comprises the following specific steps: the preparation of the compound 20 was carried out in a similar manner to that of the compound 1 except that N-o-chlorophenylmaleimide as a starting material in the preparation of the compound 1 was replaced with N-cyclobutylmaleimide to obtain the compound 20 in a yield of 68.91%.
The structural determination data is as follows: 1 H NMR(400MHz,CDCl 3 )δ8.12-8.10(m,1H),8.05-8.02(m,1H),7.98-7.93(m,2H),7.29(d,J＝7.96Hz,2H),7.18(d,J＝7.88Hz,2H),6.03(d,J＝7.96Hz,1H),4.50-4.41(m,1H),3.79(t,J＝8.14,1H),3.55(d,J＝8.32Hz,1H),2.80-2.65(m,2H),2.35(s,3H),2.19-2.13(m,2H),1.86-1.63(m,2H)ppm.EI-MS calc.for C 25 H 21 NO 5 :415；Found:415(M).
example 3
This example mainly determines the agonistic action of some compounds in example 2 of the present invention on adenylate cyclase cells, so as to prove that the compounds represented by formula (I) provided by the present invention can be applied to the preparation of adenylate cyclase (AC 2) agonists and drugs for treating related diseases.
1. Laboratory instruments and materials
1.1 instruments
Figure GDA0003946434630000263
1.2 Primary Agents and drugs
(1) Part of the compound of example 2;
(2) Positive control: forskolin FSK Standard-SIGMA (HPLC > 98%);
(3) Other reagents:
Figure GDA0003946434630000271
1.3 drug formulation
FSK: the stock solution is frozen and stored in a refrigerator with the temperature of-20 ℃ by diluting the stock solution to 50mM or 10mM by DMSO, and the stock solution is diluted to the required concentration by a stimulation buffer according to the requirements of a kit when in use.
1.4 test cells
Human embryonic kidney HEK293 (hAC 1, hAC2, hAC5, hAC 8) gene stable expression cell line and control stable transformant (puro) were constructed from Shenzhen Baien vitamin science and technology Limited. HEK93+ hAC cells were grown in high sugar medium (containing glutamine) supplemented with 10% serum, 2 ug/ml Puromycin, and maintained in a 37 ℃ incubator with humidified 5% carbon dioxide air.
After treating the cells, the cells were resuspended in a prepared Stimalization buffer (HBSS 1X, HEPES 1M,250mM IBMX, BSA Stabilizer 7.5%) and adjusted to the desired cell concentration for the experiment.
2. Experimental method
2.1 construction of stably transfected cell lines
Respectively synthesizing genes hAC1-Myc, hAC2-Myc, hAC5-Myc and hAC8-Myc (with Myc-tag at the C end), constructing on a lentivirus vector pLVX-CMV-PGK-puro → enzyme digestion, sequencing identification → large-lift plasmid → transfected 293T cell packaging lentivirus → purification and titer determination of lentivirus → 3 lentiviruses respectively infect HEK293 cells → puro screens transgenic cell strains transferred with exogenous genes → 3 monoclonal pcr are respectively selected to identify HEK-293 stable transgenic strains → Qpcr detects the expression condition of target genes in the monoclonal cell strains.
2.2 preliminary screening
3 groups were set as a control group (control group), a 50. Mu.M FSK positive control group, and a 50. Mu.M primary screening group for the compounds of the present invention, and the specific procedures were as follows:
(1) Configuring a simulation buffer;
(2) Treating the cells, centrifuging, resuspending with Buffer, and adjusting the density to 5 × 10^4/ml (i.e., 500cells per well, which can be adjusted according to experiment);
(3) The primary screening was performed by diluting the drug concentration to 100. Mu.M (final concentration: 50. Mu.M) with a stimulation buffer;
(4) Taking 10 μ l of cells and drugs in Topsealtm-A-96 plate, and incubating for 30min (sealing) in 20 μ l of system;
(5) Adding 10ul Eu-cAMP tracer and 10ul ULight-anti-cAMP working solution respectively for incubation for 60min (keeping out of the sun and sealing);
(6) Fluorescence signal values (615 and 665 nm) were measured using a microplate reader and converted to cAMP concentrations by standard curve.
3. Results of the experiment
The compounds of the invention were screened for small molecule agonist high throughput using the LANCE Ultra cAMP Detection Kit and assayed for agonism on HEK293+ hAC1, hAC2, hAC5, hAC8 cells, respectively.
The data from the experimental results show (see data in fig. 1 and table 1) that the compounds designed in the examples of the present invention are agonist selective for AC2 cells, and at a final concentration of 50 μ M in the initial screening, the cAMP concentration of the compounds designed in the examples of the present invention on HEK293+ hAC2 cells is significantly increased, approaching that of the FSK positive control compound.
Table 1 shows the preliminary screening data of the partial compounds in example 2 for the agonistic effect on human embryonic kidney HEK293+ hAC2 cells
Compound (I) cAMP(nM) Percentage of efficiency
FSK (contrast) 53.35 100％
Compound 1 0.174 93.58％
Compound 3 14.52 27.21％
Compound
4 29.67 55.60％
Compound 5 23.87 44.74％
Compound
6 31.88 59.57％
Compound 7 23.76 44.53％
Compound
8 6.54 0％
Compound
10 17.07 31.99％
Compound 12 2.69 5.04％
Compound 13 34.63 64.91％
Compound 14 30.23 56.66％
Compound 15 31.49 59.02％
Compound 16 16.53 30.98％
Compound 17 37.78 70.81％
Compound 18 37.06 69.46％
Compound 19 33.06 61.96％
Example 4
This example mainly measures the agonistic activity of compound 1 on adenylyl cyclase type 2 (AC 2) cells.
1. Laboratory instruments and materials
See example 3
2. Experimental method
The signal values obtained in the preliminary screening of example 3 were compared with the intensity values obtained in the previous screening, and the number of cells used was appropriately adjusted to obtain a dose-response curve, as follows:
(1) Taking 5 μ l of 50mM mother liquor, adding 495 μ l of Buffer to dilute to 500 μ M, and then serially diluting according to protocol (1 nM-100 μ M);
(2) 10 μ l of serially diluted drug and cells were applied to Topsealtm-A-96 plates for a total of 20 μ l of system and incubated for 30min (sealed);
(3) Adding 10ul Eu-cAMP tracer and 10ul ULight-anti-cAMP working solution respectively for incubation for 60min (keeping out of the sun and sealing);
(4) Fluorescence signal values (615 and 665 nm) were measured using a microplate reader and converted to cAMP concentrations by standard curve.
3. Results of the experiment
The cAMP concentration of HEK293+ hAC2 cells under the action of the compound 1 is increased along with the increase of the compound concentration, the activation activity value EC50 of the HEK293+ hAC2 cells is 0.178 +/-0.04101 mu M, the EC50 of the corresponding FSK on the HEK293+ hAC2 cells is 2.215 +/-0.06401 mu M, and the dose-effect curve graph is shown in a figure 2.
In conclusion, the compound shown in the formula (I) provided by the invention is a high-efficiency activator of the type 2 adenylate cyclase except forskolin, can selectively activate the type 2 adenylate cyclase, and has no obvious activation or no activation to other transmembrane subtypes of the adenylate cyclase.
In addition, when the compound shown in the formula (I) provided by the invention is used as a medicine, the compound can be directly used and also can be used in the form of a pharmaceutical composition. When used as a pharmaceutical composition, the pharmaceutical composition contains 0.1-99%, preferably 0.5-90%, of the compound of formula (I), and the balance of pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable excipients (e.g., carriers or excipients) for humans and animals. Herein, a pharmaceutically acceptable adjuvant (carrier or excipient) is one or more adjuvants selected from solid, semi-solid and liquid diluents, super-fillers and pharmaceutical preparations. The medicine of the invention can be used as the 2-type adenylate cyclase agonist and the therapeutic medicine of diseases (neuropsychiatric diseases, pulmonary diseases, tracheal diseases and bronchial diseases) related to the 2-type adenylate cyclase.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are still within the scope of the technical solution of the present invention.

Claims (3)

1. The application of [ pyrrolo-furan ] -spiro-indenone compounds in the preparation of 2-type adenylate cyclase agonists or in the preparation of medicaments for treating diseases related to 2-type adenylate cyclase; wherein the structural general formula of the [ pyrrolo-furan ] -spiro-indanone compound is shown as the formula (I):
Figure FDA0003946434620000011
wherein R is 1 Is one of the following groups:
Figure FDA0003946434620000012
wherein, R2 is one of the following groups:
Figure FDA0003946434620000013
wherein R is 3 Is hydrogen
Figure FDA0003946434620000014
2. Use of [ pyrrolo-furan ] -spiroindenone compounds according to claim 1 for the preparation of adenyl cyclase type 2 agonists or for the preparation of medicaments for the treatment of adenyl cyclase type 2 related diseases, characterized in that said [ pyrrolo-furan ] -spiroindenone compounds are any one of the following compounds:
Figure FDA0003946434620000015
Figure FDA0003946434620000021
3. use of [ pyrrolo-furan ] -spirocyclic indanones according to claim 1 or 2 for the preparation of adenyl cyclase type 2 agonists or for the preparation of medicaments for the treatment of adenyl cyclase type 2 related diseases, characterized in that the adenyl cyclase type 2 related diseases are neuropsychiatric diseases, pulmonary diseases, tracheal diseases, bronchial diseases.
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