CN112724052B - GPR101 protein receptor inhibitor and preparation and application thereof - Google Patents
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Abstract
The invention provides a GPR101 protein receptor inhibitor and preparation and application thereof, and particularly provides a compound shown as a formula I in the specification, or a pharmaceutically acceptable salt thereof. The compound has excellent GPR101 protein inhibition activity.
Description
Technical Field
The invention relates to the field of small molecule protein inhibitors, and particularly provides preparation and application of a compound with a GPR101 protein regulation effect.
Background
G protein-coupled receptors (GPCRs) are seven transmembrane domain cell surface receptors coupled to G proteins. GPCRs mediate diverse sensory and physiological responses by sensing stimuli including light, odor, hormones, neurotransmitters, chemokines, small lipid molecules, and nucleotides.
GPR101 protein, GPCR (orphan G protein-coupled receptor), is highly expressed in the hypothalamus and is predicted to bind to Gs, which is a potent activator of adenylate cyclase. The GPR101 protein is encoded by the gene GPR101, approximately 800 GPCR genes are present in the human genome, and more than half of the GPCR genes are predicted to encode sensory receptors such as olfactory, visual, and taste receptors (bjarnadott et al, 2006). The remaining 350 GPCRs have important physiological roles in embryonic development, behavior, mood, cognition, regulation of blood pressure, heart rate and digestive processes, regulation of the immune system and inflammation, maintenance of homeostasis, and growth and metastasis of cancer (Filmore 2004, overturnton et al, 2006). GPCRs are associated with many diseases and are targets for approximately 40% of all prescription drugs (Filmore 2004).
In view of the above, there is an urgent need in the art for the development of novel GPR101 protein receptor inhibitors.
Disclosure of Invention
The invention aims to provide a novel GPR101 protein receptor inhibitor.
In a first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R1selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
Raselected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl;
Rbselected from the group consisting of: c (O) OR, C (O) NHR, wherein R is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl;
R2and R3Each independently one or more groups selected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl; or two R on adjacent carbon atoms2And R3Together with the carbon atom to which they are attached, substituted or notSubstituted C6-C10An aryl group;
or said R1And R2Together with the intervening atoms, form a substituted or unsubstituted 5-6 membered heteroaryl, or a substituted or unsubstituted 5-6 membered heterocyclyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
In another preferred embodiment, R1Selected from the group consisting of: H. substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C4 cycloalkyl;
Raselected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C4 alkyl;
Rbselected from the group consisting of: c (O) OR, C (O) NHR, wherein R is selected from the group consisting of: substituted or unsubstituted C1-C4 alkyl;
R2and R3Each independently one or more groups selected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl; or two R on adjacent carbon atoms2And R3Together with the carbon atom to which they are attached form C6-C10An aryl group;
or said R1And R2Together with the intervening atoms, form a 5-6 membered heteroaryl, or a 5-6 membered heterocyclyl.
In another preferred embodiment, the compound of formula I has the structure shown in formula II below:
wherein the content of the first and second substances,
Raselected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl;
Rbselected from the group consisting of: c (O) OR, C (O) NHR, wherein R is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl;
R2and R3Each independently one or more groups selected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl.
In another preferred embodiment, the compound of formula I has the structure shown in formula III below:
wherein the content of the first and second substances,
Raselected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl;
Rbselected from the group consisting of: c (O) OR, C (O) NHR, wherein R is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl;
R2and R3Each independently one or more groups selected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl.
In another preferred embodiment, R1Selected from the group consisting of: H. methyl, ethyl, cyclopropyl;
Raselected from the group consisting of: H. f, Cl, hydroxy, methyl, isopropyl;
Rbselected from the group consisting of: c (O) OR, C (O) NHR, wherein R is selected from the group consisting of: substituted or unsubstituted C1-C4 alkyl;
R2and R3Each independently one or more groups selected from the group consisting of: H. methyl and trifluoromethyl.
In another preferred embodiment, the compound of formula I is selected from the group consisting of:
in a second aspect of the invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) a pharmaceutically acceptable carrier.
In a third aspect of the present invention, there is provided a use of the compound according to the first aspect of the present invention or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition according to the second aspect of the present invention, for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of a disease associated with the activity or expression level of a GPR101 protein receptor.
In another preferred embodiment, the disease is selected from the group consisting of: diseases related to excessive secretion of auxin, diseases related to pituitary hyperplasia and diseases related to excessive secretion of prolactin.
In another preferred embodiment, the disease is selected from the group consisting of: acromegaly, gigantism, cushing's disease, dwarfism, short stature, hypopituitarism, low levels of pituitary hormone secretion.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted long-term and intensive studies to design and synthesize a novel class of GPR101 protein receptor inhibitors. On this basis, the inventors have completed the present invention.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C8Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. E.g. C2-C6Alkenyl means a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C2-C6Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term "C3-C8Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C1-C8Alkoxy "means a straight or branched chain alkoxy group having 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless otherwise specified, the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio.
A compound of formula I
The invention provides a compound shown as the following formula I, or a pharmaceutically acceptable salt thereof:
wherein the content of the first and second substances,
R1selected from the group consisting of: H. substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl;
Raselected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl;
Rbselected from the group consisting of: c (O) OR, C (O) NHR, wherein R is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl;
R2and R3Each independently one or more groups selected from the group consisting of: H. halogen, hydroxy, substituted or unsubstituted C1-C6 alkyl; or two R on adjacent carbon atoms2And R3Together with the carbon atom to which they are attached form a substituted or unsubstituted C6-C10An aryl group;
or said R1And R2Together with the intervening atoms, form a substituted or unsubstituted 5-6 membered heteroaryl, or a substituted or unsubstituted 5-6 membered heterocyclyl;
unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl.
Preferred compounds of formula I are the specific compounds shown in the examples of this application.
Preparation of Compounds of formula I
The present invention also provides a process for the preparation of a compound according to the first aspect of the invention, comprising the steps of: in a suitable solvent, compound 1 undergoes a substitution reaction with compound 2 to give compound 3.
Pharmaceutical compositions and methods of administration
The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound as a main active ingredient are useful for the prevention and/or treatment of diseases (e.g., cancer) associated with the GPR101 signaling pathway, because the compound of the present invention has excellent inhibitory activity against GPR 101.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When administered in combination, the pharmaceutical composition further comprises one or more other pharmaceutically acceptable compounds. One or more of the other pharmaceutically acceptable compounds may be administered simultaneously, separately or sequentially with a compound of the invention.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 20 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
3- ((4-isopropylphenyl) sulfonamido) -4-methylbenzoic acid methyl ester
Methyl 3-amino-4-methylbenzoate (51mg, 0.31mmol), 4-isopropylbenzenesulfonyl chloride (100mg, 0.46mmol) and trimethylamine (0.1mL, 0.69mmol) in CH2Cl2The mixture in (5mL) was stirred for 1 h. The reaction was diluted with water (10mL) and the mixture was diluted with CH2Cl2(20mL × 2) extraction. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (21mg, yield 20%) as a white solid. ESI MS (M + H)+348.5；1H NMR(CDCl3,400MHz)δ7.73(d,J＝7.0Hz,2H),7.60(d,J＝7.0Hz,2H),7.10-7.30(m,3H),3.80(s,3H),2.80-2.95(m,1H),2.10(s,3H),1.20(d,J＝6.8Hz)。
Example 2
N, 4-dimethyl-3- ((4-methylphenyl) sulfonamide) benzamide
The title compound was synthesized according to example 1 by substituting 3-amino-N, 4-dimethylbenzamide for the amine and 4-methylbenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+319.5；1H NMR(CDCl3,400MHz)δ7.70(d,J＝7.0Hz,2H),7.10-7.40(m,5H),2.80(s,3H),2.40(s,3H),2.10(s,3H).
Example 3
3- ((N, 4-dimethylphenyl) sulfonamide) -N, 4-dimethylbenzamide
The title compound was synthesized according to example 1 by substituting N, 4-dimethyl-3- (methylamino) benzamide for the amine and 4-methylbenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+333.5；1H NMR(CDCl3,400MHz)δ7.10-7.40(m,7H),3.20(s,3H),2.80(s,3H),2.40(s,3H),2.10(s,3H).
Example 4
Methyl 3- ((N-ethyl-4-methylphenyl) sulfonamide) -4-benzoic acid methyl ester
The title compound was synthesized according to example 1 by substituting methyl 3- (ethylamino) -4-benzoate for the amine and 4-methylbenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+348.5；1HNMR(CDCl3,400MHz)δ7.30-7.40(m,5H),7.10-7.20(m,2H),3.90(s,3H),3.10-3.20(m,2H),2.50(s,3H),2.10(s,3H),1.10(t,J＝8.0Hz,3H).
Example 5
Methyl 3- ((N, 5-dimethylpyridine) -2-sulfonylamino) -4-benzoic acid methyl ester
The title compound was synthesized according to example 1 by substituting methyl 4-methyl-3- (methylamino) benzoate for the amine and 5-methylpyridine-2-sulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+335.5；1H NMR(CDCl3,400MHz)δ8.60(s,1H),8.00(d,J＝7.5Hz,1H),7.80(d,J＝7.5Hz,1H),7.30-7.40(m,1H),7.10-7.20(m,2H),3.90(s,3H),3.20(S,3H),2.20(s,3H),2.10(s,3H).
Example 6
Methyl 7-methyl-1-tolyl-1H-indole-4-carboxylate
The title compound was synthesized according to example 1 by replacing the amine with methyl 7-methyl-1H-indole-4-carboxylate, the base with cesium carbonate, and the sulfonyl chloride with 4-methylbenzenesulfonyl chloride. ESI MS (M + H)+344.5；1H NMR(CDCl3,400MHz)δ7.30-7.60(m,6H),6.40(s,1H),3.90(s,3H),2.40(s,3H),1.90(s,3H).
Example 7
Methyl 3- ((4-methylphenyl) sulfonamide) -1-naphthoate
The title compound was synthesized according to example 1 by substituting methyl 3-amino-1-naphthoate for the amine and 4-methylbenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+356.5；1H NMR(CDCl3,400MHz)δ8.70(d,J＝8.0Hz,1H),8.13(s,1H),7.95(d,J＝8.0Hz,1H),7.20-7.70(m,6H),6.90(s,1H),3.90(s,1H),2.40(s,3H).
Example 8
Methyl 3- (phenylsulfonamido) -2- (trifluoromethyl) benzoate
The title compound was synthesized according to example 1 by substituting methyl 3-amino-2- (trifluoromethyl) benzoate for the amine and benzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+360.5；1H NMR(CDCl3,400MHz)δ7.50-7.70(m,5H),7.10-7.20(m,2H),6.90(d,J＝7.8Hz,1H),3.90(s,3H).
Example 9
Methyl 3-methyl-4- ((4-methylphenyl) sulfonamide) benzoate
The title compound was synthesized according to example 1 by replacing the amine with methyl 4-amino-3-benzoate and the sulfonyl chloride with benzenesulfonyl chloride. ESI MS (M + H)+320.5；1H NMR(CDCl3,400MHz)δ7.50-7.70(m,4H),7.34(m,2H),6.90(d,J＝7.8Hz,1H),3.90(s,3H),2.43(s,3H),2.12(s,3H).
Example 10
N, 3-dimethyl-4- ((4-methylphenyl) sulfonamide) benzamide
The title compound was synthesized according to example 1 by replacing the amine with methyl 4-amino-3-benzoate and the sulfonyl chloride with benzenesulfonyl chloride. ESI MS (M + H)+319.5；1H NMR(CDCl3,400MHz)δ7.60-7.70(m,3H),7.30-7.50(m,3H),6.90(d,J＝7.8Hz,1H),2.80(s,3H),2.43(s,3H),2.12(s,3H).
Example 11
Methyl 3- ((3-fluoro-4-methylphenyl) sulfonamide) -4-benzoate
The title compound was synthesized according to example 1 by substituting methyl 3-amino-4-benzoate for the amine and 3-fluoro-4-methylbenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+338.4；1H NMR(CDCl3,400MHz)δ7.70-7.80(m,1H),7.20-7.40(m,4H),7.10-7.15(m,1H),3.90(s,3H),2.30(s,3H),2.10(s,3H).
Example 12
Methyl 3- ((N-cyclopropyl-4-methylphenyl) sulfonamide) -4-benzoic acid methyl ester
The title compound was synthesized according to example 1 by replacing the amine with methyl 3- (cyclopropylamino) -4-benzoate and the sulfonyl chloride with methyl benzenesulfonyl chloride. ESI MS (M + H)+360.4；1H NMR(CDCl3,400MHz)δ7.30-7.50(m,5H),7.10-7.20(m,2H),3.90(s,3H),2.40(s,3H),2.20-2.30(m,1H),2.10(s,3H),0.70-0.80(m,2H),0.40-0.50(m,2H).
Example 13
Methyl 3- ((4-hydroxyphenyl) sulfonylamino) -4-benzoic acid methyl ester
The title compound was synthesized according to example 1 by substituting methyl 3-amino-4-benzoate for the amine and 4-hydroxybenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+322.4；1H NMR(CDCl3,400MHz)δ7.50(d,J＝8.0Hz,2H),7.20-7.40(m,2H),7.00-7.10(m,3H),3.90(s,3H),2.12(s,3H).
Example 14
Methyl 3- ((2, 4-dichlorophenyl) sulfonamide) -4-benzoate
The title compound was synthesized according to example 1, substituting methyl 3-amino-4-benzoate for amine and substituting 2, 4-dichlorobenzenesulfonyl chloride for sulfonyl chloride. ESI MS (M + H)+374.0；1H NMR(CDCl3,400MHz)δ7.90(s,1H),7.50-7.70(m,2H),7.10-7.30(m,3H),3.90(s,3H),2.10(s,3H).
Example 15
Methyl 3- ((4-chloro-2-methylphenyl) sulfonamide) -4-benzoic acid methyl ester
The title compound was synthesized according to example 1 by substituting methyl 3-amino-4-benzoate for the amine and 4-chloro-2-methylbenzenesulfonyl chloride for the sulfonyl chloride. ESI MS (M + H)+354.9；1H NMR(CDCl3,400MHz)δ7.50-7.70(m,3H),7.10-7.30(m,3H),3.90(s,3H),2.65(s,3H),2.12(s,3H).
Bioassay examplesgpr 101 tagno analysis
For GPR101 TANGO assay, TANGO cells were plated in 96 well cell culture plates overnight at a density of 10000 cells/well in DMEM supplemented with 10% FBS. On the following day (day 2), the compounds tested were preincubated with cells for 1 hour, then GPCR 101 agonist was added to each well, and the cells were incubated for an additional 48 hours. Fluorescence of the TANGO cells was observed using a plate reader (Infinite 200, Tecan) and the IC50 was calculated.
The results are shown in the following table, when IC50Below 100nM, the activity range is denoted A. When measured IC50At 100 and 500nM, the activity range is recorded as B; when IC50The activity range was recorded at 500-1000nM, C. When IC50Above 1000nM, an activity range D was recorded.
The results show that the compounds of the present invention have excellent half-inhibitory activity against GPR 101.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (5)
1. A compound, or a pharmaceutically acceptable salt thereof, as shown below:
2. a pharmaceutical composition comprising (1) a compound of claim 1, or a pharmaceutically acceptable salt thereof; (2) a pharmaceutically acceptable carrier.
3. Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for the preparation of a pharmaceutical composition for the prevention and/or treatment of a disease associated with the activity or expression level of the GPR101 protein receptor.
4. The use according to claim 3, wherein the disease is selected from the group consisting of: diseases related to excessive secretion of auxin, diseases related to pituitary hyperplasia and diseases related to excessive secretion of prolactin.
5. The use according to claim 3, wherein the disease is selected from the group consisting of: acromegaly, gigantism, cushing's disease, dwarfism, hypopituitarism, and low levels of pituitary hormone secretion.
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| CN1211991A (en) * | 1995-12-22 | 1999-03-24 | 诺沃挪第克公司 | Compounds with growth hormone releasing properties |
| CN102083312A (en) * | 2008-05-06 | 2011-06-01 | 葛兰素史密丝克莱恩有限责任公司 | Benzene sulfonamide thiazole and oxazole compounds |
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| CN1211991A (en) * | 1995-12-22 | 1999-03-24 | 诺沃挪第克公司 | Compounds with growth hormone releasing properties |
| CN102083312A (en) * | 2008-05-06 | 2011-06-01 | 葛兰素史密丝克莱恩有限责任公司 | Benzene sulfonamide thiazole and oxazole compounds |
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