CN101511186A - Dihydropyridine compounds and compositions for headache - Google Patents

Abstract

The present invention provides methods for treating and/or preventing headache by administering to a patient a therapeutically effective amount of a 1, 2-dihydropyridine compound, and optionally a cholinesterase inhibitor and/or an anti-migraine agent. The headache may be a primary headache, such as migraine, or a secondary headache. The invention also provides combinations, commercial packages and pharmaceutical compositions comprising a therapeutically effective amount of a 1, 2-dihydropyridine compound and optionally a cholinesterase inhibitor and/or an anti-migraine agent. The 1, 2-dihydropyridine compound may be, for example, 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1, 2-dihydropyridin-2-one. The cholinesterase inhibitor may be, for example, 1-benzyl-4- ((5, 6-dimethoxy-1-indanone) -2-yl) methylpiperidine.

Description

Dihydropyridine compounds and compositions for headache

related application

This application claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 60/689,519, filed June 13, 2005, and U.S. Provisional Application No. 60/667,665, filed April 4, 2005, which are hereby incorporated The entire contents are incorporated by reference.

field of invention

The present invention provides pharmaceutical compositions containing dihydropyridine compounds and methods of using the dihydropyridine compounds in the treatment of various diseases and disorders. The dihydropyridine compounds may optionally be used in combination with other drugs used in the treatment of various diseases and disorders, such as cholinesterase inhibitors or anti-migraine agents.

Background of the invention

The pathophysiology of migraine has been described in detail. See Waeber et al., Neurology, 61 (Suppl 4): S9-S20 (2003). Although the mechanism causing migraine is still not fully understood, neurological theories of migraine have been reported. The theory is that trigeminovascular fibers projecting toward the meninges are activated during migraine, leading to release of neuropeptides and neurogenic sterile inflammation in the dura. Based on this established hyperalgesia symptoms.

There is evidence for at least 10 receptors (5-HT _1B , 5-HT _1D , 5-HT _1F , 5-HT _2B , NK-1, GABA _A , N-methyl-D-aspartate ( NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), class III metabotropic glutamate receptor, opioid μ receptor) represent potential anti-migraine agents target. Sumatriptan affects 5-HT _1B/1D/1F receptors. See Mitsikostas et al., BrainResearch Reviews, 35:20-35 (2001). The role of AMPA receptors, kainate receptors and mGluRs (metabotropic glutamate receptors) in headache has been studied. Blockade of AMPA but not kainate receptors, or activation of mGluR4 receptors, have been reported to have some role in headache treatment. See Mitsikostas et al., British Journal of Pharmacology, 127:623-630 (1999). Comparison of LY293558 (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainic acid (KA) receptor antagonist) with sumatriptan and placebo in migraine compared in preclinical models. For placebo, the effective rate of sustained response 2 hours after infusion was 25% (4 patients/16 patients); for LY293558, it was 69% (9 patients/13 patients); and for sumatriptan Said to be 87% (13 patients/15 patients). In conclusion, AMPA/GLuR5 antagonism provides a target for migraine therapy. See Ramadan et al., Cephalalgia, 21:267-272 (2001); Sang et al., Cephalalgia, 24:596-602 (2004).

There remains a need in the art for new compounds and new methods of treating diseases and disorders that are modulated to any degree by NMDA receptors, AMPA receptors and/or kainate receptors. It is with this and other important objectives that the present invention aims.

Summary of the invention

The present invention provides a method of treating and/or preventing headache (eg, migraine) in a patient in need thereof by administering a therapeutically effective amount of at least one 1,2-dihydropyridine compound, and any A therapeutically effective amount of: (i) at least one cholinesterase inhibitor, (ii) at least one anti-migraine agent or (iii) at least one cholinesterase inhibitor and at least one anti-migraine agent agent. Headaches can be primary or secondary. In one embodiment, the 1,2-dihydropyridine compound is 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine- 2-keto. In one embodiment, the cholinesterase inhibitor is donepezil. The combination of a 1,2-dihydropyridine compound and a cholinesterase inhibitor can unexpectedly produce a synergistic effect in the treatment and/or prevention of headache.

In other embodiments, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of at least one 1,2-dihydropyridine compound (e.g., 3-(2-cyanophenyl)-5-(2-pyridine base)-1-phenyl-1,2-dihydropyridin-2-one). The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one cholinesterase inhibitor (such as donepezil) and (ii) at least one 1,2-dihydropyridine compound (such as 3- (2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one). The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one anti-migraine agent and (ii) at least one 1,2-dihydropyridine compound (such as 3-(2-cyano phenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one). The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one cholinesterase inhibitor (such as donepezil); (ii) at least one 1,2-dihydropyridine compound (such as 3- (2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one); and (iii) at least one anti-migraine agent.

Brief description of the drawings

Figure 1 shows the reaction of compound A (i.e. 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one) on the same side Effect of paw withdrawal latency (withdrawal latency).

Figure 2 shows the reaction of compound A (i.e. 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one) to the opposite side Effect of paw withdrawal latency.

Detailed description of the invention

"Patient" refers to an animal, preferably a mammal, more preferably a human. The term "patient" includes both men and women; including adults, children and infants. In one embodiment, the patient may be a pet, such as a dog or cat.

"Headache" refers to primary headache and secondary sexual headache. Primary and secondary headaches can be episodic or chronic. "Episodic headaches" means that patients feel headaches 1-14 days a month. "Chronic headache" means that the patient experiences headaches 15 or more days per month. Treatment can be acute or chronic. "Acute treatment"means treating headache as needed, eg, administering to the patient a therapeutically effective amount of a compound or composition of the invention described herein upon onset of headache. "Chronic treatment" refers to the ongoing (eg, daily) treatment of headache, whether or not the patient experiences headache when administered a therapeutically effective amount of a compound or composition of the invention described herein. Headaches may cause one or more symptoms such as dizziness, nausea, vomiting, fatigue, aura, photophobia, phonophobia, and the like.

"Primary headache" includes migraine, tension headache, cluster headache, paroxysmal hemicrania, short-duration episodes due to conjunctival injection and tearing Unilateral neuralgia-like headache (SUNCT), trigeminal autonomic cephalalgia, stabbing headache, cough headache, exertional headaches, and libido Activity-related headache, hypnic headache, thunderclap headache, hemicrania continua, or new daily-persistent headache. "Secondary headache" includes headache attributable to head and/or neck trauma; headache attributable to cranial and/or carotid vascular disorders; headache attributable to nonvascular intracranial disorders; headache attributable to medications ; Headache due to drug discontinuation; Headache due to infection; Headache due to imbalance in homeostasis; Headache or facial pain due to disturbance of facial structure and/or cranial structure; or headache.

"Migraine" means a recurrent syndrome characterized by pain in the head, usually on one side of the head. Migraines are usually throbbing and moderately or severely impair or interfere with daily activities. One or more symptoms caused by migraine include dizziness, nausea, vomiting, fatigue, aura, photophobia, phonophobia, etc. Migraines can occur with or without aura. Exemplary migraines include classic migraine, common migraine, complicated migraine, menstrual migraine, premenstrual migraine, Ophthalmic migraine, ophthalmoplegic migraine, fulgurating migraine, Harris migraine, and hemiplegic migraine. Neurologic symptoms due to migraine may occur, but the latter do not follow the head pain. For example, abdominal pain and vomiting may occur, so head pain is not the only manifestation of migraine.

"Single administration" with respect to the administration of two or more compounds for the treatment and/or prevention of the diseases and disorders described herein includes, for example, sequential administration of the compounds in any order or simultaneous administration of the compounds. Simultaneous administration of the compounds means that the compounds are administered to the patient at substantially the same time or at exactly the same time, depending on the mode of administration. The sequential administration of the compounds may be in any order and without any waiting time between administrations of the compounds. Sequential administration can take into account various influencing factors: which compound should be administered first, which compound should be administered second, and how long there should be a wait between administering the compounds. For example, when two or more compounds are administered separately and sequentially, factors influencing when administering the compounds to a patient include, for example: (a) the time to achieve maximum efficacy of the administered compounds, (b) the time to achieve maximum efficacy of the administered compounds. time to least side effects, (c) dose of compound, (d) route of administration of compound, (e) disease or disorder to be treated, (f) patient to be treated, (g) in vivo relationship of administered compound, and other similar factors known in the art. The time interval between successive administrations is preferably selected such that, when comparing effects, the combination of active ingredients produces an effect greater than the sum of the effects obtained with only one active ingredient for the disease or disorder to be treated.

The term "combination" refers to the separate administration of a 1,2-dihydropyridine compound and a second active ingredient (eg, a cholinesterase inhibitor) in separate pharmaceutical compositions or preparations (eg, the first pharmaceutical composition contains 1 , 2-dihydropyridine compound, the second pharmaceutical composition contains a cholinesterase inhibitor). The pharmaceutical compositions or formulations may have the same or different modes of administration.

"Active ingredient" refers to 1,2-dihydropyridine, cholinesterase inhibitors, anti-migraine agents, and other compounds described herein that are useful in the treatment and/or prevention of a disease or disorder.

"Monotherapy" refers to therapy that uses only one active ingredient to treat and/or prevent a disease or disorder.

"Combination therapy" refers to a therapy in which two or more active ingredients are administered alone or in a pharmaceutical composition for the treatment and/or prevention of a disease.

"Therapeutically effective amount" refers to the amount of the active ingredient required for the treatment and/or prevention of diseases. When two or more active ingredients are administered for combination therapy, the term "therapeutically effective amount" refers to the amount required for each active ingredient to treat and/or prevent diseases, including, for example: (a) a therapeutically effective amount of the first an active ingredient and a therapeutically effective amount of a second active ingredient (i.e. the amount of each active ingredient used for monotherapy treatment and/or disease prevention for combination therapy); (b) a therapeutically effective amount of the first active ingredient and sub-therapeutic A second active ingredient in an amount (sub-therapeutic amount), which is effectively combined for treatment and/or prevention of disease (for example, a sub-therapeutic amount of the second active ingredient can be used in combination therapy to obtain equal to or greater than the second active ingredient ingredients if used in monotherapy); c) a sub-therapeutic amount of the first active ingredient and a therapeutically effective amount of the second active ingredient in effective combination for the treatment and/or prophylaxis of disease (e.g. may be used in combination therapy (d) subtherapeutic amounts of the first active ingredient and subtherapeutic amounts of the second Active ingredients, which are used in combination therapy for the treatment and/or prophylaxis of a disease or disorder (e.g. subtherapeutic amounts of the first active ingredient may be used in combination therapy to obtain an amount equal to or greater than that of the first active ingredient if used in monotherapy) results obtained; and sub-therapeutic amounts of the second active ingredient may be used in combination therapy to achieve results equal to or greater than those obtained with the second active ingredient if used in monotherapy). When three or more active ingredients are used in combination therapy, the same therapeutic/subtherapeutic amounts can be used. For example: (a) may be a therapeutically effective amount of all three active ingredients; (b) may be a therapeutically effective amount of two active ingredients and a subtherapeutic amount of a third active ingredient; (c) may be a therapeutically effective amount of one active ingredient and subtherapeutic amounts of the other two active ingredients; or (d) may be subtherapeutic amounts of all three active ingredients.

A "commercial package", also known as a kit, may include a combination of: (i) a first pharmaceutical composition or preparation containing a 1,2-dihydropyridine compound; (ii) a second pharmaceutical composition or preparation , which contains a second active ingredient (eg, a cholinesterase inhibitor); (iii) FDA-approved instructions for using the pharmaceutical composition or preparation to treat or prevent a disease; and (iv) optionally administering the drug combination Other materials to monitor drug levels in the body; to support patient compliance with drug therapy; or to monitor disease conditions. Commercially available packaging can supply sufficient drugs and materials for days, weeks or months. In another embodiment, a "commercial package" may include (i) a pharmaceutical composition or formulation containing both a 1,2-dihydropyridine compound and a second active ingredient (eg, a cholinesterase inhibitor); ( ii) FDA-approved instructions for using the pharmaceutical composition or preparation to treat or prevent disease; and (iii) optional other materials for administering the pharmaceutical composition or preparation (e.g., syringes, diluents, medical gloves, hand disinfectants, etc.); other materials that monitor drug levels in the body; other materials that support patient compliance with drug therapy; or other materials that monitor disease conditions. Commercially available packaging can supply sufficient drugs and materials for days, weeks or months.

；化合物

；化合物

；化合物·2H₂O；化合物·

；化合物·6H₂O等。＂化合物＂可以是本文所述的任意化合物，例如3-(2-氰基苯基)-5-(2-吡啶基)-1-苯基-1，2-二氢吡啶-2-酮。"Hydrate"refers to a compound containing water molecules of crystallization. The molecule of crystal water may be an integer of 1 or more, such as 1-10; or any fraction greater than 0 or a fraction of an integer of 1-10. For example hydrates can be expressed as compounds

; compound

; compound

; Compound · 2H ₂ O; Compound ·

; Compound · 6H ₂ O, etc. "Compound" may be any compound described herein, for example 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one.

"Pharmaceutically acceptable salts" are well known in the art and include pharmaceutically acceptable salts of inorganic acids such as hydrochloride, sulfate, hydrobromide and phosphate, and pharmaceutically acceptable salts of organic acids such as formate, ethyl salt, trifluoroacetate, methanesulfonate, besylate and toluenesulfonate. When certain substituents are specified, the compounds of the present invention can form, for example, alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; organic amine salts such as trimethylamine, triethylamine, pyridine, methyl Salts of pyridine, dicyclohexylamine or N,N'-dibenzylethylenediamine. It should be understood by those skilled in the art that the compounds of the present invention can be prepared in any other pharmaceutically acceptable salt form.

In one embodiment, the compound used in the methods and compositions described herein is a 1,2-dihydropyridine compound. The 1,2-dihydropyridine compound may be any compound known in the art. The term "1,2-dihydropyridine compounds" includes 1,2-dihydropyridine compounds, pharmaceutically acceptable salts of 1,2-dihydropyridine compounds, stereoisomers of 1,2-dihydropyridine compounds, 1 , pharmaceutically acceptable salts of stereoisomers of 2-dihydropyridine compounds, hydrates of 1,2-dihydropyridine compounds, hydrates of pharmaceutically acceptable salts of 1,2-dihydropyridine compounds, 1,2 - Stereoisomers of hydrates of dihydropyridine compounds and stereoisomers of hydrates of pharmaceutically acceptable salts of 1,2-dihydropyridine compounds.

Preferably, the 1,2-dihydropyridine compound used in the methods and compositions described herein is a compound of formula (I):

in

Q is NH, O or S;

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, halogen, C _1-6 alkyl or -XA;

X is a single bond, optionally substituted C _1-6 alkylene (alkylene), optionally substituted C _2-6 alkenylene (alkenylene), optionally substituted C _2-6 alkynylene ( alkynylene), -O-, -S-, -CO-, -SO-, -SO ₂ -, -N(R ⁶ )-, -N(R ⁷ )-CO-, -CO-N(R ⁸ ) -, -N(R ⁹ )-CH ₂ -, -CH ₂ -N(R ¹⁰ )-, -CH ₂ -CO-, -CO-CH ₂ -, -N(R ¹¹ )S(O) _m - , -S(O) _n -N(R ¹² )-, -CH ₂ -S(O) _p -, -S(O) _q -CH ₂ -, -CH ₂ -O-, -O-CH ₂ - , -N(R ¹³ )-CO-N(R ¹⁴ )- or -N(R ¹⁵ )-CS-N(R ¹⁶ )-;

R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen, C _1-6 alkyl or C _1-6 alkane base oxygen;

m, n, p and q are each independently integers 0, 1 or 2;

A is optionally substituted C _3-8 cycloalkyl, optionally substituted C _3-8 cycloalkenyl, optionally substituted 5- to 14-membered non-aromatic heterocycle, optionally substituted C _6-14 aromatic hydrocarbon rings or optionally substituted 5- to 14-membered aromatic heterocyclic rings; provided that three of R ¹ , R ² , R ³ , R ⁴ and R ⁵ are -XA; and R ¹ , the remaining 2 groups in R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen or C _1-6 alkyl.

In one embodiment, the following compounds are excluded from the scope of compounds of formula (I): (1) when Q is O; R ¹ and R ⁵ are hydrogen; and R ² , R ³ and R ⁴ are phenyl; (2) when Q is O; ^R1 and ^R4 are hydrogen; and ^R2 , ^R3 and ^R5 are phenyl; and (3) when Q is O; ^R1 and ^R2 are hydrogen; ³ , R ⁴ and R ⁵ are phenyl.

In another preferred embodiment, the 1,2-dihydropyridine compound used in the methods and compositions described herein is a compound of formula (II):

Wherein Q is NH, O or S;

X ¹ , X ² and X ³ are each independently a single bond, an optionally substituted C _1-6 alkylene group, an optionally substituted C _2-6 alkenylene group, an optionally substituted C _2-6 Alkynylene, -O-, -S-, -CO-, -SO-, -SO ₂ -, -N(R ⁶ )-, -N(R ⁷ )-CO-, -CO-N(R ⁸ )-, -N(R ⁹ )-CH ₂ -, -CH ₂ -N(R ¹⁰ )-, -CH ₂ -CO-, -CO-CH ₂ -, -N(R ¹¹ )-S(O) _m -, -S(O) _n -N(R ¹² )-, -CH ₂ -S(O) _p -, -S(O) _q -CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, -N(R ¹³ )-CO-N(R ¹⁴ )- or -N(R ¹⁵ )-CS-N(R ¹⁶ );

R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen, C _1-6 alkyl or C _1-6 alkane Oxygen;

m, n, p and q are each independently integers 0, 1 or 2;

A ¹ , A ² and A ³ are each independently optionally substituted C _3-8 cycloalkyl, optionally substituted C _3-8 cycloalkenyl, optionally substituted 5- to 14-membered non- Aromatic heterocycle, optionally substituted C _6-14 aromatic hydrocarbon ring or optionally substituted 5- to 14-membered aromatic heterocycle; and R ¹⁷ and R ¹⁸ are each independently hydrogen, halogen or C _1-6 alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X ¹ , X ² and X ³ are each independently a single bond, optionally substituted C _1-6 alkylene, optionally substituted C _2-6 alkenylene or optionally substituted C _2-6 alkynylene. Substituents can be one or more -O-, -S-, -CO-, -SO-, -SO ₂ -, -N(R ⁶ )-, -N(R ⁷ )-CO-, -CO- N(R ⁸ )-, -N(R ⁹ )-CH ₂ -, -CH ₂ -N(R ¹⁰ )-, -CH ₂ -CO-, -CO-CH ₂ -, -N(R ¹¹ )- S(O) _m -, -S(O) _n -N(R ¹² )-, -CH ₂ -S(O) _p -, -S(O) _q -CH ₂ -, -CH ₂ -O-, -O-CH ₂ -, -N(R ¹³ )-CO-N(R ¹⁴ )- and -N(R ¹⁵ )-CS-N(R ¹⁶ )-;

R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen, C _1-6 alkyl or C _1-6 alkane Alkoxy;

m, n, p and q are each independently integers 0, 1 or 2;

A ¹ , A ² and A ³ are each independently optionally substituted C _3-8 cycloalkyl, optionally substituted C _3-8 cycloalkenyl, optionally substituted 5- to 14-membered non- An aromatic heterocycle, an optionally substituted C _6-14 aromatic hydrocarbon ring, or an optionally substituted 5- to 14-membered aromatic heterocycle.

The substituting group of 1,2-dihydropyridine compound of the present invention can be one or more hydroxyl; Halogen; Nitrile; Nitro; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl[ Wherein the alkyl, alkenyl and alkynyl groups can be independently optionally substituted by one or more groups selected from the following groups: hydroxyl, nitrile, halogen, C _1-6 alkylamino, di(C _1-6 alkyl ) amino, C _2-6 alkenyl amino, two (C _2-6 alkenyl) amino, C _2-6 alkynyl amino, two (C _2-6 alkynyl) amino, NC _1-6 alkyl-NC _{2 -6} alkenylamino, NC _1-6 alkyl-NC _2-6 alkynylamino, NC _2-6 alkenyl-NC _2-6 alkynylamino, aralkyloxy, TBDMSoxy, C _1-6 Alkylsulfonylamino, C _1-6 alkylcarbonyloxy, C _2-6 alkenylcarbonyloxy, C _2-6 alkynylcarbonyloxy, NC _1-6 alkylcarbamoyl, NC _2-6 Alkenylcarbamoyl and NC _1-6 alkynylcarbamoyl]; C _1-6 alkoxy; C _2-6 alkenyloxy; C _2-6 alkynyloxy [wherein alkyloxy, alkenyl C _1-6 alkylamino, aralkyloxy and hydroxy]; C _1-6 alkyl Thio; C _2-6 alkenylthio; C _2-6 alkynylthio [wherein alkylthio, alkenylthio and alkynylthio can be independently optionally selected from one or more of the following The group substitution: hydroxyl, nitrile, halogen, C _1-6 alkylamino, aralkyloxy, TBDMSoxy, C _1-6 alkylsulfonylamino, C _1-6 alkylcarbonyloxy and C _1-6 alkylcarbamoyl]; optionally substituted carbonyl [which may be substituted by the following groups: C _1-6 alkoxy, amino, C _1-6 alkylamino, di(C _1-6 Alkyl) amino, C _2-6 alkenyl amino, two (C _2-6 alkenyl) amino, C _2-6 alkynyl amino, two (C _2-6 alkynyl) amino, NC _1-6 alkyl- NC _2-6 alkenylamino, NC _1-6 alkyl-NC _2-6 alkynylamino and NC _2-6 alkenyl-NC _2-6 alkynylamino]; optionally substituted amino [which may be replaced by one Or two groups selected from the following substitutions: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkylsulfonyl, C _2-6 alkenylsulfonyl , C _2-6 alkynylsulfonyl, C _1-6 alkylcarbonyl, C _2-6 alkenylcarbonyl and C _2-6 alkynylcarbonyl]; C _1-6 alkylsulfonyl; C _2-6 alkenyl Sulfonyl; C _2-6 alkynyl sulfinyl; C _1-6 alkyl sulfinyl; C _2-6 alkenyl sulfinyl; C _2-6 alkynyl sulfinyl; formyl; optionally substituted C _3-8 cycloalkyl; Optionally substituted C _3-8 cycloalkenyl [wherein the cycloalkyl and/or cycloalkenyl can be independently optionally substituted by one or more groups selected from the following groups: Hydroxy, halogen, nitrile, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl and aralkyl]; 5- to 14-membered non-aromatic heterocycle [which may be optionally substituted by one or more groups selected from the group consisting of: hydroxyl, Halogen, nitrile, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl and aralkyl]; C _6-14 aromatic hydrocarbon ring [it can be optionally Substituted by one or more groups selected from the group consisting of hydroxyl, halogen, nitrile, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl and aryl Alkyl]; and a 5- to 14-membered aromatic heterocyclic ring [which may be optionally substituted by one or more groups selected from the group consisting of hydroxyl, halogen, nitrile, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl and aralkyl].

In another embodiment, the present invention provides a compound of formula (II), wherein A ¹ , A ² and A ³ are each independently an optionally substituted C _3-8 cycloalkyl, an optionally substituted C _{3 -8} cycloalkenyl or an optionally substituted 5- to 14-membered non-aromatic heterocyclic ring. In another embodiment, the present invention provides a compound of formula (II), wherein A ¹ , A ² and A ³ are each independently an optionally substituted C _6-14 aromatic hydrocarbon ring or an optionally substituted 5- to 14-membered aromatic heterocycle. In another embodiment, the present invention provides a compound of formula (II), wherein A ¹ , A ² and A ³ are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, Thienyl, thiazolyl, furyl, naphthyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, Cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; any of which may optionally have a substituent . In another embodiment, the present invention provides a compound of formula (II), wherein A ¹ , A ² and A ³ are each independently selected from:

或

or

Each of these can be optionally substituted. In another embodiment, the present invention provides a compound of formula (II), wherein A ¹ , A ² and A ³ are each independently substituted with hydroxyl, halogen, amino or nitrile. In another embodiment, the present invention provides a compound of formula (II), wherein A ¹ , A ² and A ³ are each independently hydroxyl, halo, amino, nitrile or nitro. In another embodiment, the invention provides compounds of formula (II), wherein Q is oxygen.

In another embodiment, the present invention provides a compound of formula (I) or (II), wherein X ¹ , X ² and X ³ are each independently a single bond, -CH ₂ -, -CH(OH)-, - _CH2 - _CH2- , -CH=CH-, -C≡C-, -O- or -CO-. In another embodiment, the invention provides a compound of formula (I) or (II), wherein each of ^X1 , ^X2 and ^X3 is a single bond. In another embodiment, the present invention provides compounds of formula (I) or (II), wherein R ¹⁷ and R ¹⁸ are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl or isopropyl. In another embodiment, the invention provides compounds of formula (I) or (II), wherein R ¹⁷ and R ¹⁸ are each hydrogen.

For the 1,2-dihydropyridine compound of the present invention, the halogen atom means fluorine, chlorine, bromine, iodine, etc., and preferred atoms include fluorine, chlorine and bromine. For the 1,2-dihydropyridine compound of the present invention, C _1-6 alkyl refers to an alkyl group having 1-6 carbons, examples of which include linear or branched chain alkyl groups such as methyl, ethyl, normal Propyl, isopropyl, n-butyl, isobutyl, sec-butyl (1-methylpropyl), tert-butyl, isopentyl, n-pentyl, tert-amyl (1,1-dimethyl propyl), 1,2-dimethylpropyl, 2,2-dimethylpropyl (neopentyl), 1-ethylpropyl, 2-methylbutyl, n-hexyl, isohexyl, 1 , 2-dimethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2 -Trimethylpropyl, 1-ethylbutyl, 1-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl , 2,3-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, etc.

For the 1,2-dihydropyridine compound of the present invention, C _2-6 alkenyl refers to alkenyl having 2-6 carbons, examples of which include vinyl, 1-ethylvinyl (1-butene-2 -yl), allyl (2-propenyl), 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl (2-butene-2- base), 2-methyl-2-propenyl, 1-methyl-2-propenyl, 1-butenyl (1-buten-1-yl), 2-butenyl (2-butene- 1-yl), 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexadienyl, 1,6-hexadienyl and the like.

For the 1,2-dihydropyridine compound of the present invention, C _2-6 alkynyl refers to an alkynyl group having 2-6 carbons, examples of which include ethynyl, 1-propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1-ethyl-1-propynyl, 1-ethynyl-2-propynyl, 2-methyl-3-butenyl, 1-pentynyl, 1-hexynyl, 1,3-hexadiynyl, 1,6-hexadiynyl and the like.

For the 1,2-dihydropyridine compound of the present invention, C _1-6 alkyloxy refers to an alkoxy group having 1-6 carbons, examples of which include methoxy, ethoxy, n-propoxy, Isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, 1,2-dimethylpropoxy , neopentyloxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, n-hexyloxy, isohexyloxy, 1-ethyl-1-methylpropoxy , 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1,1-dimethylbutoxy , 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, 1,3-dimethylbutoxy oxy, 1-ethylbutoxy, 1-methylbutoxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, and the like.

For the 1,2-dihydropyridine compound of the present invention, C _2-6 alkynyloxy refers to an alkynyloxy group having 2-6 carbon atoms, examples of which include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy, 2-butynyloxy, 3-butynyloxy, 1-methyl-2-propynyloxy, 1-ethyl-2-propynyloxy 1-ethynyl-2-propynyloxy, 1-pentynyloxy, 1-hexynyloxy, 1,3-hexadiynyloxy, 1,6-hexadiynyloxy, etc.

For the 1,2-dihydropyridine compound of the present invention, C _2-6 alkenyloxy refers to an alkenyloxy group having 2-6 carbons, examples of which include ethyleneoxy, 1-ethylvinyloxy ( 1-buten-2-yloxy), allyloxy (2-propenyloxy), 1-propenyloxy, isopropenyloxy, 2-methyl-1-propenyloxy, 1-methyl -1-propenyloxy (2-buten-2-yloxy), 2-methyl-2-propenyloxy, 1-methyl-2-propenyloxy (1-buten-3-yloxy base), 1-butenyloxy (1-buten-1-yloxy), 2-butenyloxy (2-buten-1-yloxy), 3-butenyloxy, 1- Pentenyloxy, 1-hexenyloxy, 1,3-hexadienyloxy, 1,6-hexadienyloxy and the like.

For the 1,2-dihydropyridine compound of the present invention, C _3-8 cycloalkyl refers to a cycloalkyl group consisting of 3-8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, etc.

For the 1,2-dihydropyridine compound of the present invention, C _3-8 cycloalkenyl refers to a cycloalkenyl group consisting of 3-8 carbon atoms, examples of which include cyclopropen-1-yl, 2-cyclopropene- 1-yl, cyclobuten-1-yl, 2-cyclobuten-1-yl, 1,3-cyclobutadien-1-yl, cyclopenten-1-yl, 2-cyclopentene-1 -yl, 3-cyclopentadien-1-yl, 1,3-cyclopentadien-1-yl, 1,4-cyclopentadien-1-yl, 2,4-cyclopentadien-1- Base, cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1,3-cyclohexadien-1-yl, 1,4-cyclohexyl En-1-yl, 1,5-cyclohexadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, cyclopentene-1 - Base, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 4-cyclopenten-1-yl, 1,3-cyclopentadien-1-yl, 1,4- Cyclopentadien-1-yl, 1,5-cyclopentadien-1-yl, 1,6-cyclopentadien-1-yl, 2,4-cyclopentadien-1-yl, 2, 5-cyclopentadien-1-yl, 2,6-cyclopentadien-1-yl, 3,5-cyclopentadien-1-yl, 1,3,5-cyclopentadien-1- Base, 1,3,6-cycloheptatrien-1-yl, 1,4,6-cycloheptatrien-1-yl, 2,4,6-cycloheptatrien-1-yl, cyclooctene -1-yl, 2-cycloocten-1-yl, 3-cycloocten-1-yl, 4-cycloocten-1-yl, 1,3-cyclooctadien-1-yl, 1, 4-cyclooctadien-1-yl, 1,5-cyclooctadien-1-yl, 1,6-cyclooctadien-1-yl, 1,7-cyclooctadien-1-yl, 2,4-cyclooctadien-1-yl, 2,5-cyclooctadien-1-yl, 2,6-cyclooctadien-1-yl, 2,7-cyclooctadiene-1- Base, 3,5-cyclooctadien-1-yl, 3,6-cyclooctadien-1-yl, 1,3,5-cyclooctatrien-1-yl, 1,3,6-ring Octatrien-1-yl, 1,3,7-cyclooctatrien-1-yl, 1,4,6-cyclooctatrien-1-yl, 1,4,7-cyclooctatriene-1 -yl, 1,5,7-cyclooctatrien-1-yl, 2,4,6-cyclooctatrien-1-yl, 2,4,7-cyclooctatrien-1-yl, etc.

For the 1,2-dihydropyridine compounds of the present invention, the 5- to 14-membered non-aromatic heterocyclic ring refers to a monocyclic, bicyclic or tricyclic ring containing one or more heteroatoms selected from nitrogen, sulfur and oxygen 5- to 14-membered non-aromatic heterocycle. Specific examples thereof include pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, dihydropyridine pyryl, imidazolidinyl, oxazolidinyl, etc. In addition, non-aromatic heterocyclic rings also include groups derived from pyridone rings and non-aromatic condensed rings (eg, groups derived from phthalimide rings, succinimide rings, etc.).

For the 1,2-dihydropyridine compound of the present invention, C _6-14 aromatic hydrocarbon ring and aryl refer to aromatic hydrocarbon ring, monocyclic and fused bicyclic, tricyclic, etc. composed of 6-14 carbon atoms. Specific examples thereof include phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indathenyl, acenaphthyl, fluorenyl , phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl, benzocyclooctenyl, etc.

For the 1,2-dihydropyridine compounds of the present invention, the 5- to 14-membered aromatic heterocyclic and heteroaryl rings refer to monocyclic, bicyclic or bicyclic rings containing one or more heteroatoms selected from nitrogen, sulfur and oxygen. Cyclic or tricyclic 5- to 14-membered aromatic heterocyclic ring. Specific examples thereof include (1) nitrogen-containing aromatic heterocycles such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, Imidazolyl, benzimidazolyl, indolyl, isoindolyl, indolyl, isoprenyl, indazolyl, quinolinyl, isoquinolyl, quinazinyl, phthalazyl (phthalazyl) , naphthylidinyl (naphthylidinyl), quinoxalyl (quinoxalyl), quinazoline, cinnolinyl (cynnolinyl), pteridinyl, imidazotriazinyl, pyrazinopyridazinyl, acridyl, phenanthrene Phenanthridinyl, carbazolyl, carbazolinyl, perimidinyl, phenanthrolinyl, phenazinyl, imidazopyridinyl, imidazopyrimidinyl or pyrimidinyl Azolopyridyl; (2) sulfur-containing aromatic heterocycles, such as thienyl or benzothienyl; (3) oxygen-containing aromatic heterocycles, such as furyl, pyranyl, cyclopentapyranyl, benzene and (4) aromatic heterocycles containing two or more different heteroatoms, such as thiazolyl, isothiazolyl, benzothiazolyl, benzothiadiazolyl, phenothiazolyl, Azinyl, isoxazolyl, furazanyl, phenoxazinyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, pyrazolooxadiazolyl, imidazothiazolyl, Thienofuryl, furopyrrolyl or pyridoxadinyl.

In another embodiment, the 1,2-dihydropyridine compound used in the methods and compositions described herein is preferably a compound of formula (III):

Wherein X ¹ , X ² , X ³ , A ¹ , A ² , A ³ , R ¹⁷ and R ¹⁸ have the same meanings as in the compound of formula (II).

In another embodiment, the present invention provides a compound of formula (III), wherein A ¹ , A ² and A ³ are each independently an optionally substituted C _6-14 aromatic hydrocarbon ring or a 5- to 14-membered aromatic heterocycle. In another embodiment, the present invention provides a compound of formula (III), wherein A ¹ , A ² and A ³ are each independently phenyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, Thienyl, thiazolyl, furyl, naphthyl, quinolinyl, isoquinolyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazopyridyl, carbazolyl, Cyclopentyl, cyclohexyl, cyclohexenyl, dioxinyl, adamantyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each of which may be optionally substituted. In another embodiment, the present invention provides a compound of formula (III), wherein A ¹ , A ² and A ³ are each independently selected from:

或

or

Each of these can be optionally substituted. In another embodiment, the present invention provides a compound of formula (III), wherein the binding positions of the substituents on A ¹ , A ² and A ³ are located at the carbon atoms connected to the groups X ¹ , X ² and X ³ respectively The α-bit. In another embodiment, the invention provides compounds of formula (III), wherein X ¹ , X ² and X ³ are single bonds. In another embodiment, the invention provides compounds of formula (III), wherein R ⁷ and R ¹⁸ are hydrogen.

In one embodiment, the 1,2-dihydropyridine compound used in the methods and compositions described herein is preferably Compound A:

The IUPAC name of compound A is 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile. Compound A is also known as 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one.

In the context of the specification, the terms "compound A", "2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile" and " 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one" means including its pharmaceutically acceptable salts, its stereoisomers hydrates, pharmaceutically acceptable salts of stereoisomers thereof, hydrates thereof, hydrates of pharmaceutically acceptable salts thereof, stereoisomers of hydrates thereof, and stereoisomers of hydrates of pharmaceutically acceptable salts thereof. In another embodiment, the term "compound A", "2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile " and "3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one" are meant to include their pharmaceutically acceptable salts, their Hydrates and hydrates of their pharmaceutically acceptable salts.

In other embodiments, the 1,2-dihydropyridine compound useful in the methods and compositions of the present invention is 3-(2-cyanophenyl)-5-(2-methylsulfonylaminophenyl)- 1-phenyl-1,2-dihydropyridin-2-one; 3-(2-chloro-3-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydro Pyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyano Phenyl)-5-(2-pyridyl)-1-(3-nitrophenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-( 2-pyridyl)-1-(3-aminophenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1- (3-methylsulfonylaminophenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-methyl ylaminophenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-dimethylaminophenyl) -1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-[3-(5-methoxymethyl-2-oxazole Alkanon-3-yl)-phenyl]-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-methyl Oxycarbonylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-methylaminocarbonylphenyl) -1,2-dihydropyridin-2-one; 3-(2-cyano-3-pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2 -ketone; 3-(2-chlorophenyl)-5-(2-pyridyl)-1-(4-hydroxyphenyl)-1,2-dihydropyridin-2-one; 3-(2-chloro Phenyl)-5-(2-pyridyl)-1-(4-dimethylaminoethoxyphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl )-5-(2-pyridyl)-1-(3-formylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2- Pyridyl)-1-(3-hydroxymethylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1- (3-cyanomethylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-acetamido Methylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-methylsulfonamidomethyl Phenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-acetoxymethylphenyl)- 1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1- (4-methylthienyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(4-methylsulfonylbenzene Base)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-formylthiophen-3-yl)-1-phenyl-1,2-two Hydropyridine-2-one; 3-(2-cyanophenyl)-5-(2-diethylaminomethylthiophen-3-yl)-1-phenyl-1,2-dihydropyridine-2- Ketone; 3-(2-cyanophenyl)-5-(2-hydroxymethylthiophen-3-yl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2- Cyanophenyl)-5-(2-pyridyl)-1-benzyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl )-1-(3-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-phenyl-(2-pyridyl)-1,2- Dihydropyridine-2-one; 3-(2-cyanophenyl)-1,5-diphenyl-1,2-dihydropyridine-2-one; 3-(2-cyanophenyl)- 5-(2-methoxyphenyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(3,4-dimethoxybenzene Base)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(thiophen-3-yl)-1-phenyl-1,2- Dihydropyridine-2-one; 3-(2-cyanophenyl)-5-(2-fluorophenyl)-1-phenyl-1,2-dihydropyridine-2-one; 3-(2 -cyanophenyl)-5-(thiophen-2-yl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(3- Furfuryl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-furfuryl)-1-phenyl-1,2- Dihydropyridine-2-one; 3-(2-chlorophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one; 3-(2-methyl Oxycarbonylphenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-phenyl-5-(2-pyridyl)-1-phenyl -1,2-dihydropyridin-2-one; 3-(2-fluorophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3 -(2-chlorophenyl)-5-(2-pyridyl)-1-(3-methoxyphenyl)-1,2-dihydropyridin-2-one; 3-(2-fluoro-3- Pyridyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(4-methoxy-3-pyridyl)-5-(2- Pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-1-(3-methoxy Phenyl)-1,2-dihydropyridin-2-one; 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-1-(3-fluorophenyl)- 1,2-dihydropyridine-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(4-fluorophenyl)-1,2-dihydropyridine- 2-keto; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-fluorophenyl)-1,2-dihydropyridin-2-one; 3-(2 -cyanophenyl)-5-(2-pyridyl)-1-(4-methoxyphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)- 5-(2-pyridyl)-1-(3-methoxy-phenyl)-1,2-dihydropyridin-2-one; 3-phenyl-5-(2-pyridyl)-1- (3-fluorophenyl)-1,2-dihydropyridin-2-one; 3-(2-chlorophenyl)-5-(2-pyridyl)-1-(4-fluorophenyl)-1 , 2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(4-formylphenyl)-1,2-dihydropyridine- 2-keto; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(2-formylphenyl)-1,2-dihydropyridin-2-one; 3-( 2-cyanophenyl)-5-(2-pyridyl)-1-(3-chlorophenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)- 5-(2-pyridyl)-1-(3-methylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)- 1-(3-trifluoromethylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(thiophene- 3-yl)-1,2-dihydropyridine-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-furfuryl)-1,2- Dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(4-methylphenyl)-1,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-pyridyl)-1-(4-trifluoromethylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyano phenyl)-5-(2-pyridyl)-1-(2-methoxypyridin-5-yl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl )-5-(2-pyridyl)-1-(pyrimidin-5-yl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridine Base) -1-(3-benzyloxymethylpyridin-5-yl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl) -1-(2-Ethylthiopyridin-5-yl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1- (4-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-methoxypyridine-5 -yl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(2-chloropyridine- 5-yl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(2-fluoropyridin-5-yl)- 1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(2-methoxyphenyl)-1,2-dihydropyridine -2-one; 3-phenyl-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-chlorophenyl)- 5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one; 3-(thiophen-3-yl)-5-(2-pyridyl)-1 -(3-pyridyl)-1,2-dihydropyridin-2-one; 3-(2,6-dimethylphenyl)-5-(2-pyridyl)-1-(3-pyridyl )-1,2-dihydropyridin-2-one; 3-(2-cyanothiophen-3-yl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2- Dihydropyridin-2-one; 3-(2-fluoro-3-pyridyl)-5-(2-pyridyl)-1-(3-pyridyl)-1,2-dihydropyridin-2-one ; 3-(2-chlorophenyl)-5-(2-pyridyl)-1-(3-hydroxyphenyl)-1-,2-dihydropyridin-2-one; 3-(2-chlorobenzene Base)-5-(2-pyridyl)-1-(3-dimethylaminoethoxyphenyl)-1,2-dihydropyridin-2-one; 3-(2-chlorophenyl)- 5-(2-pyridyl)-1-(3-dimethylaminopropoxyphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2 -pyridyl)-1-(2-hydroxymethylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1 -(4-cyanomethylphenyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(2-cyano 3-(2-cyanophenyl)-5-(6-diethylaminomethyl-2-pyridyl)-1-benzene Base-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridine-2-one ; 3-(2-hydroxypyridin-6-yl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 1-(2-aminobenzothiazole- 6-yl)-3-(2-cyanophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5- (2-pyridyl)-1-(1-benzyl-1,2,3,6-tetrahydropyridin-5-yl)-1,2-dihydropyridin-2-one; 3-[2-( 5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(6-methylpyridin-2-yl)-1-phenyl-1,2-dihydropyridine-2- Ketone; 3-(2-cyanophenyl)-5-(5-methylpyridin-2-yl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyano phenyl)-5-(3-hydroxypyridin-2-yl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-1-phenyl -5-(2-thiazolyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-methoxypyridin-6-yl)-1- Phenyl-1,2-dihydropyridin-2-one; 1-(4-aminophenyl)-3-(2-cyanophenyl)-5-(2-pyridyl)-1,2-di Hydropyridine-2-one; 1-(3-aminophenyl)-3-(2-cyanophenyl)-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one; 3 -(2-cyanophenyl)-5-(2-pyridyl)-1-(2-aminotoluene-4-yl)-1,2-dihydropyridin-2-one; 3-(2-cyano phenyl)-1-[3-(dimethylaminoethoxy)phenyl]-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyano phenyl)-1-[3-(piperidineethoxy)phenyl]-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanobenzene Base)-1-[3-(pyrrolidineethoxy)phenyl]-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl) -1-[3-(Diisopropylaminoethoxy)phenyl]-5-(-2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanobenzene Base)-1-[3-(4-piperidinyl-1-oxyl)phenyl]-5-(2-pyridinyl)-1,2-dihydropyridin-2-one; 3-(2 -cyanophenyl)-1-(4-nitrophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 1-phenyl-5-(2-pyridine Base)-3-(2-thiazolyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-1-(3-pyridyl)-5-(2-pyrimidine Base)-1,2-dihydropyridin-2-one; 3-(2-fluoropyridin-3-yl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridine- 2-keto; 3-(2-cyanopyridin-3-yl)-1-phenyl-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one; 3-(2-cyano phenyl)-1-(3-nitrophenyl)-5-(2-pyrimidinyl)-1,2-dihydropyridin-2-one; 3-(2-nitrophenyl)-1- Phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-formylthiophen-3-yl)-5-(2-pyridyl)-1-benzene Base-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(2-naphthyl)-1,2-dihydropyridine -2-one; 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(1-naphthyl)-1,2-dihydropyridine- 2-keto; 5-(2-aminopyridin-6-yl)-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one; 5-(2- Bromopyridin-6-yl)-3-(2-cyanophenyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-( 2-morpholinopyridin-6-yl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-1-(3-hydroxyphenyl)- 5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-1-[3-(4-piperidinyloxy)]phenyl- 5-(2-pyridinyl)-1,2-dihydropyridin-2-one; 1-[3-(N-acetylpiperidin-4-yl-oxyl)phenyl]-3-(2- Cyanophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-1-{3-[1-(methylsulfonyl )piperidin-4-yl-oxyl]phenyl}-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 1-[3-(N-methylpiperidin-4 -yl-oxy)phenyl]-3-(2-cyanophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one; 3-(6-chloro-1H -benzimidazol-2-yl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-(2-cyanophenyl)-5-( 2-pyridyl)-1-(2-nitrotoluen (nitrotoluen)-4-yl)-1,2-dihydropyridin-2-one; 3-(2-cyanothiophen-3-yl)-5 -(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; 3-[2-(5-oxazolyl)phenyl]-1-phenyl-5-(2 -pyridyl)-1,2-dihydropyridin-2-one; 3-[2-(5-oxazolyl)thiophen-3-yl]-1-phenyl-5-(2-pyridyl)- 1,2-dihydropyridin-2-one; and 3-(2-ethoxycarbonylvinylthiophen-3-yl)-5-(2-pyridyl)-1-phenyl-1,2-dihydro Pyridin-2-one.

1,2-Dihydropyridine compounds and methods of making 1,2-dihydropyridine compounds are described in US Patent No. 6,949,571, US Publication No. 2004/0023973 and PCT Publication Nos. WO 03/047577, WO 04/009553, WO 06/004100 and WO 06/004107, the entire contents of which are hereby incorporated by reference.

-8-基)-1-丙酮、(2-[2-(1-苄基哌啶-4-基)乙基]-2，3-二氢-9-甲氧基-1H-吡咯并[3，4-b]喹啉-1-酮)等。在一实施方案中，所述胆碱酯酶抑制剂是多奈哌齐、他克林、加兰他敏或利伐斯的明。In one embodiment, the compounds used in the methods and compositions described herein are cholinesterase inhibitors. The cholinesterase inhibitor can be any one known in the art. The term "cholinesterase inhibitor" includes cholinesterase inhibitors, pharmaceutically acceptable salts of cholinesterase inhibitors, stereoisomers of alkaline esterase inhibitors and stereoisomers of cholinesterase inhibitors pharmaceutically acceptable salts. Exemplary cholinesterase inhibitors include donepezil, tacrine, physostigmine, pyridostigmine, neostigmine, rivastigmine, galantamine, citicoline, vinacridine, Perzine (such as huperzine A), metrifosate, heptastigmine, edrophonium, phenserine, tolserine, phenylnorcymserine, quinostigmine, ganstigmine, epastigmine, upreazine, 3-[1-(Benzyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepine

-8-yl)-1-propanone, (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[ 3,4-b] quinolin-1-one) and the like. In one embodiment, the cholinesterase inhibitor is donepezil, tacrine, galantamine or rivastigmine.

In one embodiment, a preferred cholinesterase inhibitor for use in the methods and compositions described herein is a compound of formula (IV):

wherein J is (a) a substituted or unsubstituted group selected from (i) phenyl, (ii) pyridyl, (iii) pyrazinyl, (iv) quinolinyl, (v) Cyclohexyl, (vi) quinoxalinyl (vii) furyl; (b) monovalent or divalent groups, wherein phenyl may have one or more substituents selected from: (i) indanyl, (ii) indanonyl, (iii) indenyl, (iv) indanonyl, (v) indanedionyl (indanedionyl), (vi) tetralone (tetralonyl), (vii) benzo ring Heptanyl (benzosuberonyl), (viii) indanolyl (indanolyl) and (ix) C ₆ H ₅ -CO-CH(CH ₃ )-; (c) a monovalent group derived from a cyclic amide compound; (d ) lower alkyl; or (e) R ²¹ -CH=CH-, wherein R ²¹ is hydrogen or lower alkoxycarbonyl; B is -(CHR ²² ) _r -, -CO-(CHR ²² ) _r -, -NR ⁴ -(CHR ²² ) _r -, -CO-NR ⁵ -(CHR ²² ) _r , -CH=CH-(CHR ²² ) _r -, -OCOO-(CHR ²² ) _r -, -OOC-NH-(CHR ²² ) _r -, -NH-CO-(CHR ²² ) _r -, -CH ₂ -CO-NH-(CHR ²² ) _r -, -(CH ₂ ) ₂ -NH-(CHR ²² ) _r , -CH( OH)-(CHR ²² ) _r -, =(CH-CH=CH) _b -, =CH-(CH ₂ ) _c -, =(CH-CH) _d =, -CO-CH=CH-CH ₂ - , -CO-CH ₂ -CH(OH)-CH ₂ -, -CH(CH ₃ )-CO-NH-CH ₂ -, -CH=CH=CO-NH-(CH ₂ ) ₂ -, -NH- , -O-, -S-, dialkylaminoalkyl-carbonyl or lower alkoxycarbonyl; ^R4 is hydrogen, lower alkyl, acyl, lower alkylsulfonyl, phenyl, substituted phenyl, benzyl or substituted benzyl; R ⁵ is hydrogen, lower alkyl or phenyl; r is 0 or an integer of 1-10; R ²² is hydrogen or methyl, so that an alkylene can have no methyl branch or have one or multiple methyl branches; b is an integer of 1-3; c is 0 or an integer of 1-9; d is 0 or an integer of 1-5; T is nitrogen or carbon; Q is nitrogen, carbon or

是单键或双键。 q is an integer of 1-3; K is hydrogen, phenyl, substituted phenyl, aralkyl, wherein phenyl may have a substituent, cinnamoyl, lower alkyl, pyridylmethyl, cycloalkylalkyl, adamantanemethyl, furylmethyl, cycloalkyl, lower alkoxycarbonyl or acyl; and

is a single or double bond.

In compounds of formula (IV), J is preferably (a) or (b), more preferably (b). In the definition of (b), monovalent groups (2), (3) and (5) and divalent groups (2) are preferred. Group (b) preferably comprises the following structural formula:

wherein t is an integer of 1-4; and each S is independently hydrogen or a substituent, such as lower alkyl having 1-6 carbon atoms or lower alkoxy having 1-6 carbon atoms. Among these substituents, methoxy is most preferred. Phenyl most preferably has 1-3 methoxy groups on it. (S) _t can form methylenedioxy or ethylenedioxy on two adjacent carbon atoms of phenyl. Among the above groups, indanonyl, indanedionyl and indenyl groups, which optionally have a substituent on the phenyl group, are most preferred.

In the definition of B, -(CHR ²² ) _r , -CO-(CHR ²² ) _r , =(CH-CH=CH) _b -, =CH-(CH ₂ ) _c - and =(CH-CH) are preferred _d = (wherein b is an integer of 1-3; c is 0 or an integer of 1-9; d is 0 or an integer of 1-5). Most preferred are the group -( ^CHR22 ) _r- , and the group =CH-( _CH2 ) _c- , wherein ^R22 is hydrogen and r is an integer 1-3. Preferred groups of B may be attached to (b) of J, especially (b)(2). The ring containing T and Q in formula (I) may be 5-, 6- or 7-membered. Preferably Q is nitrogen, T is carbon or nitrogen, and q is 2; or Q is nitrogen, T is carbon, and q is 1 or 3; or Q is carbon, T is nitrogen and q is 2. Preferably K is phenyl, aralkyl, cinnamoyl, phenylalkyl or phenylalkyl having a substituent on the phenyl.

In one embodiment, a preferred cholinesterase inhibitor for use in the methods and compositions described herein is a compound of formula (V):

Wherein ^R is (1) substituted or unsubstituted phenyl; (2) substituted or unsubstituted pyridyl; (3) substituted or unsubstituted pyrazyl (pyrazyl); (4) Substituted or unsubstituted quinolinyl; (5) substituted or unsubstituted indanyl; (6) substituted or unsubstituted cyclohexyl; (7) substituted or unsubstituted quinoxa (8) a substituted or unsubstituted furyl group; (9) a monovalent or divalent group derived from an indanone having a substituted or unsubstituted phenyl group (10) derived from a cyclic amide compound (11) lower alkyl; or (12) R ³ -CH=C-, wherein R ³ is a hydrogen atom or lower alkoxycarbonyl; X is -(CH ₂ ) _n -, -C(O )-(CH ₂ ) _n -, -N(R ⁴ )-(CH ₂ ) _n -, -C(O)-N(R ⁵ )-(CH ₂ ) _n -, -CH=CH-(CH ₂ ) _n -, -OC(O)-O-(CH ₂ ) _n -, -OC(O)-NH-(CH ₂ ) _n -, -CH=CH-CH=CO-, -NH-C(O )-(CH ₂ ) _n -, -CH ₂ -C(O)-NH-(CH ₂ ) _n -, -(CH ₂ ) ₂ -C(O)-NH-(CH ₂ ) _n -, -CH (OH)-(CH ₂ ) _n -, -C(O)-CH=CH-CH ₂ -, -C(O)-CH ₂ -CH(OH)-CH ₂ -, -CH(CH ₃ )- C(O)-NH-CH ₂ -, -CH=CH-C(O)-NH-(CH ₂ ) ₂ -, dialkylaminoalkylcarbonyl, lower alkoxycarbonyl; n is an integer 0-6; ^R is hydrogen, lower alkyl, acyl, lower alkylsulfonyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; and ^R is hydrogen, lower alkyl or phenyl; ^R2 is substituted or unsubstituted phenyl; substituted or unsubstituted aralkyl; cinnamoyl; lower alkyl; pyridylmethyl; cycloalkylalkyl; adamantylmethyl; Acylmethyl; and is a single or double bond.

For the cholinesterase inhibitors described herein, the term "lower alkyl" refers to straight or branched chain alkyl having 1 to 6 carbon atoms. Exemplary "lower alkyl" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, amyl, isopentyl, neopentyl, tert-amyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methyl-pentyl, 3- Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl-butyl, 2,3- Dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethyl propyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, etc. Lower alkyl is preferably methyl, ethyl, propyl or isopropyl; more preferably methyl.

For the cholinesterase inhibitors described herein, substituted or unsubstituted phenyl, pyridyl, pyrazinyl, quinolinyl, indanyl, cyclohexyl, quinoxalinyl and furan in the definition of ^R Examples of substituents of radicals include lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; corresponding to the above-mentioned Lower alkoxy of lower alkyl such as methoxy and ethoxy; nitro; halogen such as chlorine, fluorine and bromine; carboxyl; lower alkoxycarbonyl corresponding to the above lower alkoxy such as methoxycarbonyl , ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl and n-butoxycarbonyl; amino; lower monoalkylamino; lower dialkylamino; carbamoyl; amido groups derived from aliphatic saturated monocarboxylic acids, such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and pivalylamino; cycloalkoxycarbonyl, such as cyclohexyloxycarbonyl; lower alkylaminocarbonyl such as methylaminocarbonyl and ethylaminocarbonyl; lower alkylcarbonyloxy corresponding to the above-mentioned lower alkyl such as methylcarbonyloxy, ethylcarbonyloxy and n-propylcarbonyloxy; Halogenated lower alkyl such as trifluoromethyl; hydroxy; formyl; and lower alkoxy lower alkyl such as ethoxymethyl, methoxymethyl and methoxyethyl. "Lower alkyl" and "lower alkoxy" in the above-mentioned substituents include all groups derived from the above-mentioned groups. There may be 1, 2 or 3 substituents which may be the same or different.

For the cholinesterase inhibitors described herein, when the substituent is phenyl, the following formula falls within the range of substituted phenyl:

where G is -C(O)-, -OC(O)-, -O-, -CH ₂ -NH-C(O)-, -CH ₂ -O-, -CH ₂ -SO ₂ -, -CH (OH)- or _-CH2 -S(→O)-; E is carbon or nitrogen; and D is a substituent.

For the cholinesterase inhibitors described herein, preferred examples of substituents for phenyl (i.e., "D") include lower alkyl, lower alkoxy, nitro, halogenated lower alkyl, lower alkoxycarbonyl , formyl, hydroxy and lower alkoxy lower alkyl, halogen and benzoyl and benzylsulfonyl. There may be two or more substituents which may be the same or different. Preferable examples of the substituent of pyridyl include lower alkyl and amino and halogen. Preferable examples of the substituent of the pyrazinyl group include lower alkoxycarbonyl, carboxyl, amido, carbamoyl and cycloalkoxycarbonyl.

For the cholinesterase inhibitors described herein, as for R ¹ , said pyridyl is preferably 2-pyridyl, 3-pyridyl or 4-pyridyl; said pyrazinyl is preferably 2-pyrazinyl; The quinolinyl is preferably 2-quinolinyl or 3-quinolinyl; the quinoxalinyl is preferably 2-quinoxalinyl or 3-quinoxalinyl; and the furyl is preferably 2- furyl.

For the cholinesterase inhibitors described herein, examples of monovalent or divalent groups are derived from indanones with unsubstituted or substituted phenyl groups of (A) or (B):

Wherein m is an integer of 1-4, each A is independently hydrogen, lower alkyl, lower alkoxy, nitro, halogen, carboxyl, lower alkoxycarbonyl, amino, lower monoalkylamino, lower dialkyl Amino, carbamoyl, amido derived from aliphatic saturated monocarboxylic acid having 1-6 carbon atoms, cycloalkoxycarbonyl, lower alkylaminocarbonyl, lower alkylcarbonyloxy, halogenated lower alkyl , hydroxy, formyl or lower alkoxy lower alkyl; preferably hydrogen, lower alkyl or lower alkoxy; most preferably indanone is unsubstituted or substituted with 1-3 methoxy.

酮(tetrahydrobenzodiazepinone)和hexahydrobenzazocinone。单价基团可以是其结构式中具有环酰胺的任何一种，不限于上述具体实例。环酰胺可以是衍生自单环或稠合杂环的环酰胺。稠合杂环优选是通过与苯基稠合形成的杂环。在该情形中，苯基可以被具有1-6个碳原子的低级烷基优选甲基或者具有1-6个碳原子的低级烷氧基优选甲氧基取代。For the cholinesterase inhibitors described herein, examples of monovalent groups derived from cyclic amide compounds include quinazolinones, tetrahydroisoquinolones, tetrahydrobenzodiazepines,

Ketones (tetrahydrobenzodiazepinone) and hexahydrobenzodiazepinone. The monovalent group may be any one having a cyclic amide in its structural formula, and is not limited to the above specific examples. The cyclic amide may be a cyclic amide derived from a single ring or a fused heterocycle. The fused heterocycle is preferably a heterocycle formed by fusion with a phenyl group. In this case, the phenyl group may be substituted with a lower alkyl group having 1 to 6 carbon atoms, preferably methyl group, or a lower alkoxy group having 1 to 6 carbon atoms, preferably methoxy group.

For the cholinesterase inhibitors described herein, examples of monovalent groups include the following:

In the above formula, Y is hydrogen or lower alkyl; V and U are each hydrogen or lower alkoxy (preferably dimethoxy); W ^and W are ^each hydrogen, lower alkyl or lower alkoxy; and W ³ is hydrogen or lower alkyl. The right-hand rings in formulas (j) and (l) are 7-membered rings, and the right-hand rings in formula (k) are 8-membered rings.

所示基团的任何一部分具有羰基或酰胺。For the cholinesterase inhibitors described herein, most preferred examples of R ¹ include monovalent groups derived from indanones having unsubstituted or substituted phenyl groups and monovalent groups derived from cyclic amide compounds. For the cholinesterase inhibitors described herein, the most preferred examples of X include -(CH ₂ ) _n -, amide, or a group represented by the above formula, wherein n is 2. Therefore, the optimal formula

Any portion of the indicated groups has a carbonyl or amide.

表示双键或单键。该化学键只有当R¹是衍生自具有未被取代或被取代的苯基的茚满酮的二价基团(B)时才是双键，在其它情形中均是单键。For the cholinesterase inhibitors described herein, the substituents involved in the description of "substituted or unsubstituted phenyl" and "substituted or unsubstituted aralkyl" in the definition of R ^above are the same as The same substituents as phenyl, pyridyl, pyrazinyl, quinolinyl, indanyl, cyclohexyl, quinoxalinyl or furyl in the above definition of ^R1 . The term "aralkyl" means unsubstituted benzyl or phenethyl or the like. Specific examples of pyridylmethyl include 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylmethyl. Preferable examples of R ² include benzyl and phenethyl. symbol

Indicates a double or single bond. This chemical bond is a double bond only if R ¹ is a divalent group (B) derived from an indanone with unsubstituted or substituted phenyl, in all other cases a single bond.

In one embodiment, a preferred cholinesterase inhibitor for use in the methods and compositions described herein is a compound of formula (VI):

wherein r is an integer from 1 to 10; each R is ^{independently} hydrogen or methyl; K is phenylalkyl or phenylalkyl having a substituent on phenyl; each S is independently hydrogen, C _1-6 Lower alkyl or C _1-6 lower alkoxy; t is an integer of 1-4; q is an integer of 1-3; with the proviso that (S) _t may be methylene dihydrogen connected to two adjacent carbon atoms on the phenyl group; Oxygen or ethylenedioxy.

In other embodiments, the compound of formula (VI) is 1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine; 1-benzyl -4-((5,6-dimethoxy-1-indanone)-2-ylindenyl (ylidenyl))methyl-piperidine; 1-benzyl-4-((5-methoxy -1-indanone)-2-yl)methylpiperidine; 1-benzyl-4-((5,6-diethoxy-1-indanone)-2-yl)methylpiperidine ; 1-benzyl-4-((5,6-methylenedioxy)-1-indanone)-2-yl)methylpiperidine; 1-(m-nitrobenzyl)-4 -((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine; 1-cyclohexylmethyl-4-((5,6-dimethoxy-1- Indanone)-2-yl)methylpiperidine; 1-(m-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine Pyridine; 1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)propylpiperidine; 1-benzyl-4-((5-isopropoxy Base-6-methoxy-1-indanone)-2-yl)methylpiperidine; 1-benzyl-4-((5,6-dimethoxy-1-oxoindanone) -2-yl)propenylpiperidine; a pharmaceutically acceptable salt of one or more of the aforementioned compounds; a stereoisomer of one or more of the aforementioned compounds; or a combination of one or more of the stereoisomers of the aforementioned compounds Pharmaceutically acceptable salt.

In other embodiments, the compound of formula (VI) for use in the methods and compositions described herein is preferably 1-benzyl-4-((5,6-dimethoxy-1-indanone)-2 -yl) methyl piperidine; It is shown in formula (B):

The compound of formula (B) is known as donepezil and may be in polymorphic or polymorphic crystalline forms. For example donepezil may be in the form of polymorph (II), (III), (IV) or (V); preferably the form of polymorph (III). Donepezil may be in polymorphic crystalline (A), (B) or (C) form. Polymorphs, polymorphic crystals, and methods of making polymorphs and polymorphic crystals are described in U.S. Patent Nos. 5,985,864, 6,140,321, and 6,245,911, the entire contents of which are incorporated herein by reference.

In still other embodiments, the compound of formula (III) is 1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine hydrochloride , which is also known as donepezil hydrochloride, as shown in formula (B1):

The compounds of the present invention may have asymmetric carbon atoms and thus may have stereoisomers depending on substituents, the latter falling within the scope of the present invention. For example donepezil or a pharmaceutically acceptable salt thereof may be in the form as described in Japanese Patent Application Nos. 4-187674 and 4-21670, the entire contents of which are hereby incorporated by reference.

Japanese Patent Application No. 4-187674 describes compounds of formula (B2):

It may be in the form of a pharmaceutically acceptable salt such as hydrochloride. Japanese Patent Application No. 4-21670 describes compounds of formula (B3):

It may be in the form of a pharmaceutically acceptable salt such as hydrochloride; and a compound of formula (B4):

It may be in the form of a pharmaceutically acceptable salt such as hydrochloride; and a compound of formula (B5):

In the context of the specification, the terms "donepezil" and "1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine" are meant to include a or more (eg, a combination of two or more) of the following: pharmaceutically acceptable salts; stereoisomers; polymorphs; and polymorphic crystals.

The cholinesterase inhibitors of the present invention are commercially available or can be prepared by methods known in the art, such as described in, for example, U.S. Patent Nos. 4,895,841, 5,985,864, 6,140,321 and 6,245,911; WO 98/39000 and Japanese Patent Application No. 4 - the methods of 187674 and 4-21670, the entire contents of which are hereby incorporated by reference.

Anti-migraine agents for use in the methods and compositions described herein can be any known in the art. Anti-migraine agents include, for example, serotonin antagonists, non-steroidal anti-inflammatory drugs (NSAIDs) (eg, COX-1 inhibitors and/or COX-2 inhibitors), calcium channel blockers, beta-adrenergic blockers anticonvulsants, and antidepressants (such as tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors). Other exemplary anti-migraine agents include PNU-142633, vigabatrin, topiramate, montelukast (preferably its sodium salt), gabapentin, piroxicam (preferably piroxicam beta cyclodextrin), valproate ( Preferably its semisodium salt (semisodium salt)), diclofenac (preferably potassium salt), tiagabine, botulinum, nebivolol, lyslopril, nimodipine, tizanidine, adjuvant Mitriptan, sumatriptan (preferably its succinate), rizatriptan (preferably its benzoate), phenthiazine, oxytolone, naratriptan, lomerizine (preferably its hydrochloride), gilpephrine, flunarizine, almotriptan, alpiropride, tolfenamic acid, migpriv, timolol (preferably its maleate), bucrizine ( preferably its hydrochloride), baclofen, methysergide (preferably its maleate), flunarizine (preferably its hydrochloride), cyproheptadine (preferably its hydrochloride), ergotamine (preferably its tartrate), lidocaine (preferably its hydrochloride), indolamine (preferably its hydrochloride), butorphanol, KT 2962, BMS 181885, ADDS-ergotamine, NPS-1776, GW- 468816, Amitriptyline, Drug Development No. 6313, MT-500, Donipratriptan (preferably its mesylate), ALX-0646, civamide, Propranolol, Zurcasecin, CNS5161, Woflupitant , lanepitant, dapitant, ganaxolone, LY-53857, ergoxol (preferably its maleate), sumatriptan, MT-400, fluoxetine, (S)-fluoxetine , dihydroergotamine (preferably its mesylate), tonabersat, IS-159, BIBN-4096, metoclopramide, naproxen, MT-100 (i.e. metoclopramide and naproxen combination), dotazine, frovatriptan, eletriptan, aspirin, ibuprofen, acetaminophen, amitryptiline, doxepin, ergot preparations, caffeine , caffeine (such as a combination of caffeine and ergotamine), codeine, meperidine, promethazine, atropine, phenobarbital, nifedipine, verapamil, chlorpromazine, lithium, prednisolone Pine, propranolol, phenelzine, mefenamic acid, flufenamic acid, LY334370, indomethacin, chloralpyrine, Isometheptene, butalbital, ketorolac, clonazepam, Atenolol, metoprolol, nadolol, imipramine, nortriptyline, diltiazem, valproic acid, divalproex sodium, or cyproheptadine. Anti-migraine agents are commercially available or can be prepared by methods known in the art.

-8-基)-1-丙酮或(2-[2-(1-苄基哌啶-4-基)乙基]-2，3-二氢-9-甲氧基-1H-吡咯并[3，4-b]喹啉-1-酮。在一实施方案中，本发明提供了药物组合物，其中含有治疗有效量的：(i)多奈哌齐；(ii)3-(2-氰基苯基)-5-(2-吡啶基)-1-苯基-1，2-二氢吡啶-2-酮；和(iii)至少一种可药用赋型剂。所述药物组合物可以任选进一步含有至少一种抗偏头痛剂。In other embodiments, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of: (i) at least one 1,2-dihydropyridine compound, (ii) at least one cholinesterase inhibitor, and ( iii) at least one pharmaceutically acceptable excipient. The present invention also provides combinations comprising therapeutically effective amounts of: (i) at least one 1,2-dihydropyridine compound and (ii) at least one cholinesterase inhibitor; wherein said compounds are administered alone (eg simultaneously, sequentially) to a patient to treat the disease or disorder. The invention provides a commercial package (eg, a kit) containing a therapeutically effective amount of: (i) at least one 1,2-dihydropyridine compound, (ii) at least one cholinesterase inhibitor; and ( iii) Instructions for the simultaneous, separate or sequential use of (i) and (ii) in the treatment of the diseases and disorders described herein. The 1,2-dihydropyridine compound may be any one described herein. For example, the 1,2-dihydropyridine compound may be a compound of formula (I), a compound of formula (II), a compound of formula (III), or compound A. The cholinesterase inhibitor can be any one described herein. Such as described cholinesterase inhibitor can be formula (IV) compound, formula (V) compound, formula (VI) compound, formula (B) compound, formula (B1) compound, formula (B2) compound, formula (B3 ) compound, compound of formula (B4) or compound of formula (B5). In other embodiments, the cholinesterase inhibitor may be tacrine, physostigmine, pyridostigmine, neostigmine, rivastigmine, galantamine, citicoline, Viacridine, huperzine (e.g. huperzine A), metrifos, heptastigmine, Tensiron, phenserine, tolserine, phenylnorcymserine, quinostigmine, ganstigmine, epastigmine, upreazine, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepine

-8-yl)-1-propanone or (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[ 3,4-b] quinolin-1-one. In one embodiment, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of: (i) donepezil; (ii) 3-(2-cyanobenzene base)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one; and (iii) at least one pharmaceutically acceptable excipient. The pharmaceutical composition can be optionally further comprising at least one anti-migraine agent.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of: (i) at least one 1,2-dihydropyridine compound, (ii) at least one anti-migraine agent, and (iii) at least one pharmaceutically acceptable Excipients. The 1,2-dihydropyridine compound may be any one described herein. For example, the 1,2-dihydropyridine compound may be a compound of formula (I), a compound of formula (II), a compound of formula (III), or compound A. The anti-migraine agent can be any of those described herein. For example the anti-migraine agent may be aspirin, ibuprofen, acetaminophen, diclofenac, fenoprofen, ketaprofen, ketorolac, flurbiprofen, meclofenamate, naproxen ergotamine, sumatriptan, zolmitriptan, rizatriptan, naratriptin, almotriptin, frovatriptan, eletriptan, amitriptyline, desipramine, doxepin, Imipramine, nortripytyline, fluoxetine, paroxetine, sertraline, venlafazine, trazodone, bupropion, atenolol, metoprolol, nadolol, propranolol, timolol Lore, diltiazem, nicardipine, nifedipine, nimodipine, verapamil, divalproex sodium, gabapentin, valproic acid, or topiramate. In one embodiment, the anti-migraine agent is aspirin, ibuprofen, paracetamol or naproxen. In another embodiment, the anti-migraine agent is ergotamine, dihydroergotamine, sumatriptan, zolmitriptan, rizatriptan, naratriptan or almotriptan. The pharmaceutical composition may optionally further contain at least one cholinesterase inhibitor.

The present invention provides a method of treating and/or preventing headache in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b) ; wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitor and at least one An anti-migraine agent. Methods of treating headaches include (i) methods to reduce the frequency of headaches, (ii) methods to reduce the severity of headaches, (iii) methods to reduce the duration of headaches, (iv) methods to reduce the frequency and severity of headaches, (v) methods to reduce Methods of headache frequency and duration, (vi) methods of reducing headache severity and duration, and (vii) methods of reducing headache frequency, severity and duration. Methods of treating headaches include treating one or more symptoms caused by the headache. Headaches can be primary or secondary. The 1,2-dihydropyridine compound and the cholinesterase inhibitor and/or anti-migraine agent can be administered to the patient alone or in the form of a pharmaceutical composition.

The present invention provides a method of treating and/or preventing primary or secondary headache in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinergic agent Alkaline esterase inhibitors and at least one anti-migraine agent. Methods of treating primary or secondary headaches include (i) methods of reducing the frequency of primary or secondary headaches, (ii) methods of reducing the severity of primary or secondary headaches, (iii) ) a method of reducing the duration of a primary or secondary headache, (iv) a method of reducing the frequency and severity of a primary or secondary headache, (v) reducing the frequency of a primary or secondary headache and duration, (vi) methods of reducing the severity and duration of primary or secondary headaches, and (vii) methods of reducing the frequency, severity, and duration of primary or secondary headaches . Methods of treating primary or secondary headaches include treating one or more symptoms caused by primary or secondary headaches. The 1,2-dihydropyridine compound and the cholinesterase inhibitor and/or anti-migraine agent can be administered to the patient alone or in the form of a pharmaceutical composition.

The present invention provides a method of treating and/or preventing migraine in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b ); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitor and at least An anti-migraine agent. Methods of treating migraines include (i) methods to reduce the frequency of migraines, (ii) methods to reduce the severity of migraines, (iii) methods to reduce the duration of migraines, (iv) methods to reduce the frequency and severity of migraines , (v) methods of reducing the frequency and duration of migraines, (vi) methods of reducing the severity and duration of migraines, and (vii) methods of reducing the frequency, severity and duration of migraines. Methods of treating migraines include treating one or more symptoms caused by migraines. The 1,2-dihydropyridine compound and the cholinesterase inhibitor and/or anti-migraine agent can be administered to the patient alone or in the form of a pharmaceutical composition.

The present invention provides a method of treating and/or preventing typical migraine in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally ( b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitor and At least one anti-migraine agent. Methods of treating typical migraines include (i) methods to reduce the frequency of typical migraines, (ii) methods to reduce the severity of typical migraines, (iii) methods to reduce the duration of typical migraines, (iv) methods to reduce the frequency of typical migraines and severity, (v) methods to reduce the frequency and duration of typical migraines, (vi) methods to reduce the severity and duration of typical migraines, and (vii) methods to reduce the frequency, severity and duration of typical migraines Methods. Methods of treating classic migraine include treating one or more symptoms caused by classic migraine. "Classic migraine" usually begins with neurological symptoms such as visual scintillation, dazzling zigzag lines, photophobia and spreading scotomas, or vertigo and tinnitus. A typical migraine may have aura symptoms such as feelings of elation, excessive energy, thirst, sugar cravings, and/or sleepiness. At other times, a typical migraine may have aura symptoms, such as mental retardation, feeling impending doom, and/or depression. At other times, there may be no aura symptoms.

The present invention provides a method of treating and/or preventing migraine vulgaris in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitor and at least one anti-migraine agent. Methods of treating migraine vulgaris include (i) methods of reducing the frequency of migraine vulgaris, (ii) methods of reducing the severity of migraine vulgaris, (iii) methods of reducing the duration of migraine vulgaris, (iv) reducing Methods of reducing frequency and duration of general migraine, (v) methods of reducing frequency and duration of general migraine, (vi) methods of reducing severity and duration of general migraine, and (vii) reducing frequency and duration of general migraine Methods for headache frequency, severity, and duration. Methods of treating migraine vulgaris include treating one or more symptoms caused by migraine vulgaris. A "common migraine" is usually an uncontrolled attack of headache that may be accompanied by nausea and/or vomiting. Unlike typical migraine, migraine vulgaris usually has no neurological symptoms before the onset of the headache.

The present invention provides a method of treating and/or preventing complicated migraines in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinergic agent Alkaline esterase inhibitors and at least one anti-migraine agent. The method for treating migraineous cerebral infarction includes (i) a method for reducing the frequency of migraineous cerebral infarction, (ii) a method for reducing the severity of migraineous cerebral infarction, (iii) a method for reducing the duration of migraineous cerebral infarction, (iv) methods of reducing the frequency and severity of migrainous infarctions, (v) methods of reducing the frequency and duration of migrainous infarctions, (vi) methods of reducing the severity and duration of migrainous infarctions, and (vii) Methods of reducing the frequency, severity and duration of migraineous infarctions. The method of treating migraineous cerebral infarction includes treating one or more symptoms caused by migraineous cerebral infarction. "Migrainous cerebral infarction" refers to migraine headache preceded by or accompanied by neurological symptoms (such as neurological symptoms described in typical migraine). In a migraine infarction, numbness and tingling may occur on one side of the body in the lips, face, hand, arm, and/or leg, sometimes accompanied by aphasia. The arm and/or leg may become weak or paralyzed on one side, similar to a stroke. This numbness and weakness may slowly spread from one part of the body to another over a period of minutes. "Migrainous cerebral infarction" includes basal migraine. In basilar migraine, visual disturbances and paresthesias are bilateral and may be accompanied by confusion, paralysis, coma, aggressive outburst, vertigo, diplopia, and/or dysarthria. Basal migraine occurs in 30% of children with migraine.

The present invention provides a method of treating and/or preventing menstrual migraine or premenstrual migraine in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinergic agent Alkaline esterase inhibitors and at least one anti-migraine agent. Methods of treating menstrual or premenstrual migraine include (i) methods of reducing the frequency of menstrual or premenstrual migraine, (ii) methods of reducing the severity of menstrual or premenstrual migraine, (iii) ) a method of reducing the duration of menstrual or premenstrual migraine, (iv) a method of reducing the frequency and severity of menstrual or premenstrual migraine, (v) reducing the frequency of menstrual or premenstrual migraine and duration, (vi) methods of reducing the severity and duration of menstrual or premenstrual migraine, and (vii) methods of reducing the frequency, severity, and duration of menstrual or premenstrual migraine . The method of treating menstrual migraine or premenstrual migraine includes treating one or more symptoms caused by menstrual migraine or premenstrual migraine. "Menstrual migraine"means a migraine that usually occurs about two days before a woman's menstrual cycle and ends about three days after a woman's menstrual cycle. In another embodiment, menstrual migraine refers to migraine that typically occurs about two days before a woman's menstrual cycle until the end of the last day of the woman's menstrual cycle. Menstrual migraines may occur or recur at any time during the menstrual cycle. "Premenstrual migraine"means a migraine that usually occurs about seven days before a woman's menstrual cycle and ends about three days before her menstrual cycle. Premenstrual migraines may occur or recur at any time during the menstrual cycle.

The present invention provides a method of treating and/or preventing ocular migraine or ophthalmoplegic migraine in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-bis A hydropyridine compound and optionally (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one antimigraine agent; or (iii) at least one a cholinesterase inhibitor and at least one anti-migraine agent. Methods of treating ocular or ophthalmoplegic migraine include (i) methods of reducing the frequency of ocular or ophthalmoplegic migraine, (ii) reducing the severity of ocular or ophthalmoplegic migraine extent, (iii) methods of reducing the duration of ocular or ophthalmoplegic migraine, (iv) methods of reducing the frequency and severity of ocular or ophthalmoplegic migraine, (v) methods of reducing Methods of Ocular Migraine or Ophthalmoplegic Migraine Frequency and Duration, (vi) Methods of Reducing Ocular Migraine or Ophthalmoplegic Migraine Severity and Duration, and (vii) Reducing Ocular Migraine or ophthalmoplegic migraine frequency, severity, and duration. Methods of treating ocular migraine or ophthalmoplegic migraine include treating one or more symptoms caused by ocular migraine or ophthalmoplegic migraine. "Ocular migraine" refers to migraine that is usually accompanied by significant visual disturbance. "Ophthalmoplegic migraine" means a migraine associated with paralysis of the eye muscles.

The present invention provides a method of treating and/or preventing fulfilling migraines in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and Optional (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase Enzyme inhibitors and at least one anti-migraine agent. Methods of treating lightning migraines include (i) methods of reducing the frequency of lightning migraines, (ii) methods of reducing the severity of lightning migraines, (iii) methods of reducing the duration of lightning migraines, (iv) reducing Methods of Lightning Migraine Frequency and Severity, (v) Methods of Reducing Lightning Migraine Frequency and Duration, (vi) Methods of Reducing Lightning Migraine Severity and Duration, and (vii) Reducing Lightning Migraine Methods for headache frequency, severity, and duration. Treatments for lightning migraines include treating one or more of the symptoms caused by lightning migraines. "Lightning migraine" refers to a migraine characterized by sudden onset and severity.

The present invention provides a method for treating and/or preventing Harris migraine in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally ( b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitor and At least one anti-migraine agent. Methods of treating Harris migraines include (i) methods of reducing the frequency of Harris migraines, (ii) methods of reducing the severity of Harris migraines, (iii) methods of reducing the duration of Harris migraines, (iv) methods of reducing the frequency of Harris migraines and severity, (v) methods to reduce the frequency and duration of Harris migraines, (vi) methods to reduce the severity and duration of Harris migraines, and (vii) methods to reduce the frequency, severity and duration of Harris migraines Methods. Methods of treating Harris migraine include treating one or more symptoms caused by Harris migraine. "Harris migraine" is also known as periodic migraine neuralgia.

The present invention provides a method of treating and/or preventing hemiplegic migraine in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and optionally (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitor and at least one anti-migraine agent. Methods of treating hemiplegic migraines include (i) methods of reducing the frequency of hemiplegic migraines, (ii) methods of reducing the severity of hemiplegic migraines, (iii) methods of reducing the duration of hemiplegic migraines, (iv) methods of reducing Methods for the frequency and severity of hemiplegic migraines, (v) methods for reducing the frequency and duration of hemiplegic migraines, (vi) methods for reducing the severity and duration of hemiplegic migraines, and (vii) methods for reducing the frequency and duration of hemiplegic migraines Methods for headache frequency, severity, and duration. Methods of treating hemiplegic migraine include treating one or more symptoms caused by hemiplegic migraine. "Hemiplegic migraine" refers to a form of migraine associated with transient hemiplegia.

The present invention provides a method of treating and/or preventing abdominal migraines in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and any Optional (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitors and at least one anti-migraine agent. Methods of treating abdominal migraine include (i) methods of reducing the frequency of abdominal migraine, (ii) methods of reducing the severity of abdominal migraine, (iii) methods of reducing the duration of abdominal migraine, (iv) methods of reducing Methods for reducing the frequency and duration of abdominal migraine, (v) methods for reducing the frequency and duration of abdominal migraine, (vi) methods for reducing the severity and duration of abdominal migraine, and (vii) methods for reducing the frequency and duration of abdominal migraine Methods for headache frequency, severity, and duration. Methods of treating abdominal migraine include treating one or more symptoms caused by abdominal migraine. "Abdominal migraine" is characterized by episodic abdominal pain with no apparent cause.

The present invention provides a method of treating and/or preventing cluster headaches in a patient in need thereof, said method comprising administering a therapeutically effective amount of: (a) at least one 1,2-dihydropyridine compound and any Optional (b); wherein (b) is a therapeutically effective amount of (i) at least one cholinesterase inhibitor; (ii) at least one anti-migraine agent; or (iii) at least one cholinesterase inhibitors and at least one anti-migraine agent. Methods of treating cluster headaches include (i) methods of reducing the frequency of cluster headaches, (ii) methods of reducing the severity of cluster headaches, (iii) methods of reducing the duration of cluster headaches, (iv) methods of reducing the frequency of cluster headaches and severity, (v) methods to reduce the frequency and duration of cluster headaches, (vi) methods to reduce the severity and duration of cluster headaches, and (vii) methods to reduce the frequency, severity and duration of cluster headaches Methods. Methods of treating cluster headaches include treating one or more symptoms caused by cluster headaches. "Cluster headache" is also known as episodic nocturnal headache, migraine neuralgia, histamine headache, and Horton's syndrome. Cluster headaches are characterized by persistent unilateral orbital pain that usually begins within 2 or 3 hours of falling asleep. The pain may be sharp and steady, accompanied by tearing, nasal blockage, followed by rhinorrhea, and sometimes miosis, ptosis, flushing, and edema of the cheeks.

类、氮螺杂癸二酮类(azaspirodecanediones)或哌嗪衍生物。示例性苯并二氮杂

类包括地西泮、阿普唑仑、氯氮

、氯硝西泮、氯

酸盐(clorazepate)、哈拉西泮、lorpam、奥沙西泮及其衍生物和其可药用盐。示例性氮螺杂癸二酮包括丁螺环酮及其衍生物和其可药用盐。示例性哌嗪衍生物包括双羟萘酸羟嗪和盐酸羟嗪及其衍生物和其可药用盐。所述1，2-二氢吡啶化合物和抗焦虑剂可以是单独给药，也可以以组合物形式给药。In other embodiments, the present invention provides methods of treating and/or preventing panic attacks and/or panic disorders comprising administering a therapeutically effective amount of at least one 1,2-dihydropyridine compound and optionally at least one anxiolytic. The anxiolytic agent can be any one in the art. Exemplary anxiolytics include benzodiazepines

Classes, azaspirodecanediones or piperazine derivatives. Exemplary benzodiazepines

Classes include diazepam, alprazolam, chlordiazepoxide

, clonazepam, chlorine

Clorazepate, halazepam, lorpam, oxazepam and their derivatives and their pharmaceutically acceptable salts. Exemplary azaspirodecanediones include buspirone and its derivatives and pharmaceutically acceptable salts thereof. Exemplary piperazine derivatives include hydroxyzine pamoate and hydroxyzine hydrochloride and derivatives thereof and pharmaceutically acceptable salts thereof. The 1,2-dihydropyridine compound and the anti-anxiety agent can be administered alone or in combination.

、氮螺杂癸二酮(azaspirodecanedione)或哌嗪衍生物。示例性苯并二氮杂

包括地西泮、阿普唑仑、氯氮

、氯硝西泮、氯

酸盐、哈拉西泮、lorpam、奥沙西泮及其衍生物和其可药用盐。示例性氮螺杂癸二酮包括丁螺环酮及其衍生物和其可药用盐。示例性哌嗪衍生物包括双羟萘酸羟嗪和羟嗪盐酸盐及其衍生物和其可药用盐。所述1，2-二氢吡啶化合物和抗焦虑剂可以是单独给药，也可以以组合物形式给药。The present invention provides a method of treating and/or preventing acute stress disorder and/or general anxiety disorder, said method comprising administering a therapeutically effective amount of at least one 1,2-dihydropyridine compound and any at least one anxiolytic of choice. The anxiolytic agent can be any one in the art. Exemplary anxiolytics include benzodiazepines

, azaspirodecanedione or piperazine derivatives. Exemplary benzodiazepines

Including diazepam, alprazolam, chlordiazepoxide

, clonazepam, chlorine

salt, halazepam, lorpam, oxazepam and their derivatives and their pharmaceutically acceptable salts. Exemplary azaspirodecanediones include buspirone and its derivatives and pharmaceutically acceptable salts thereof. Exemplary piperazine derivatives include hydroxyzine pamoate and hydroxyzine hydrochloride and derivatives and pharmaceutically acceptable salts thereof. The 1,2-dihydropyridine compound and the anti-anxiety agent can be administered alone or in combination.

The present invention provides methods of sedating a patient comprising administering a therapeutically effective amount of at least one 1,2-dihydropyridine compound. In one embodiment, the present invention provides a method of sedating a patient prior to surgery comprising administering a therapeutically effective amount of at least one 1,2-dihydropyridine compound. In another embodiment, the present invention provides a method of surgical anesthesia for acute sedation in a patient in need thereof, the method comprising administering a therapeutically effective amount of at least one 1,2-dihydropyridine compound.

The 1,2-dihydropyridine compounds and other compounds of the present invention (such as cholinesterase inhibitors, anti-migraine agents, anxiolytics) may contain conventional non-toxic pharmaceutically acceptable carriers, adjuvants and carriers ( Dosage unit formulations as required) for oral, topical, parenteral, inhalation (nasal or buccal) or rectal administration. The term parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, intrasternal injection or infusion techniques.

1,2-dihydropyridine compounds (such as 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one) of the present invention The daily dosage is usually about 30 μg-10 g, preferably 100 μg-5 g, or more preferably 100 μg-100 mg in the case of oral administration. For injection administration, the daily dose is usually about 30 μg-1 g, preferably 100 μg-500 mg, or more preferably 100 μg-30 mg. The compound is administered once daily, or in divided doses per day. When used in the context of dosage, stated weight numbers refer to the weight of 1,2-dihydropyridine, excluding any salts, counterions, hydrates, etc. thereof. Therefore, to obtain the equivalent of 500 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, it may be necessary to use more than 500 mg of the pharmaceutically acceptable salt and/or hydrate of the compound because the pharmaceutically acceptable salt and/or hydrate has an additional weight.

The daily dosage of the cholinesterase inhibitor (such as donepezil) of the present invention is generally about 0.1 mg-100 mg, preferably 1 mg-50 mg, more preferably 5 mg-25 mg. In other embodiments, the daily dosage is between 10 mg and 20 mg; or between 5 mg and 10 mg. The compound is administered once daily, or in divided doses per day. When used in the context of dosage, said weight numbers refer to the weight of the cholinesterase inhibitor of the invention, excluding any salts, counterions, etc. thereof. Thus, to obtain the equivalent of 10 mg of donepezil, it may be necessary to use more than 10 mg of donepezil hydrochloride due to the additional weight of the hydrochloride.

Other compounds described herein (eg, anti-migraine agents, anxiolytics) can be administered at dosages well known in the art, see, eg, The Physician's Desk Reference, patents describing compound dosages, and journals describing compound dosages.

In one embodiment, the administration is by injection, eg, subcutaneously, intramuscularly, intravenously or intraarterially. Injectable preparations such as sterile injectable aqueous or oily suspensions can use suitable dispersing or wetting agents, suspending agents (such as methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, etc.) according to the prior art. , powdered tragacanth gum, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate, etc.), pH regulators, buffers, solubilizers (such as polyoxyethylene hydrogenated castor oil, polysorbate 80. Niacinamide, polyoxyethylene sorbitan monolaurate, polyethylene glycol (Macrogol), ethyl ester of castor oil fatty acid, etc.) and preservatives. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending vehicle. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, in addition fatty acids such as oleic acid may be used in the preparation of injectables. These formulations can be lyophilized by methods known in the art.

Solid dosage forms for oral administration may include chewing gum, capsules, tablets, sublingual tablets, powders, granules and gels. In such solid dosage forms, the active compound may be admixed with one or more inert diluents, such as lactose or starch. In normal practice, such dosage forms may also contain other substances including lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, these dosage forms may also contain buffering agents. Tablets may be prepared with enteric or film coatings, film coatings being preferred.

To prepare tablets, the compound can be mixed with pharmaceutically acceptable carriers known in the art, such as excipients (vehicles) (such as lactose, white sugar, mannitol, sucrose, starch, calcium carbonate, crystalline cellulose, silicic acid, etc.), Binders (such as water, ethanol, myranol, glucose solution, starch solution, gelatin solution, polyvinylpyrrolidone, etc.), disintegrants (such as dry starch, sodium alginate, sodium bicarbonate, calcium carbonate, polyoxyethylene dehydrated Sorbitan fatty acid esters, sodium lauryl sulfate, stearyl monoglyceride, starch, lactose, etc.), absorption enhancers (such as quaternary ammonium bases, sodium lauryl sulfate, etc.), wetting agents (such as glycerin, starch, etc.), lubricants (such as stearates, polyethylene glycol, etc.), and flavoring agents (such as sweeteners). Tablets may be in the form of conventional tablets, molded tablets, flakes and the like.

Sublingual administration refers to administration in the mouth (eg, under the tongue, between the cheek and gum, between the tongue and the roof of the mouth). The abundant vascular mucosal lining of the mouth facilitates the administration of compounds into the body.

In other embodiments, the solid dosage forms can be packaged as granules or powders in pharmaceutically acceptable carriers, and when these granules or powders are out of the packaging, they can be sprayed on food or mixed with liquids such as water or liquid (juice), or Insert these granules into a capsule. In this embodiment, the compounds described herein may be admixed with flavoring or sweetening agents. The packaging material may be a plastic wrap or any other material that prevents water or humidity from reaching the granules and/or powder.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, sublingual solutions, suspensions and syrups containing inert diluents commonly used in the art, such as water. Such compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. To prepare a sublingual solution, the compound can be mixed with various carriers, excipients, pH adjusters, etc. (for example, water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, ethanol, bentonite, tragacanth, gelatin, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavor and color).

For administration by inhalation, the compounds may be delivered from an insufflator, nebulizer, or pressure pack, or other conventional modes of delivery for aerosol sprays. The pressure pack may contain a suitable propellant. Alternatively, for administration by inhalation, the compounds may be administered as dry powder compositions or liquid sprays.

Suppositories for rectal administration can be prepared by mixing the active compound with suitable non-irritating excipients, such as cocoa butter and polyethylene glycols, which are solid at room temperature and liquid at body temperature. Alternatively, enemas may be prepared for rectal administration of a compound described herein.

For topical administration to the epidermis, the compounds may be formulated as ointments, creams or lotions, or as a transdermal patch of the active ingredient. Compounds can also be administered by iontophoresis or osmotic pumps. Ointments, creams and lotions may be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Alternatively, ointments, creams and lotions may be formulated with an aqueous or oily base and may contain one or more emulsifying, stabilizing, dispersing, suspending, thickening and/or coloring agents. For creams or lotions, the compound can be mixed with one or more preservatives (such as benzyl alcohol 1% or 2% (wt/wt)), emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water, sorbic acid The sugar alcohol solution mixes to form a smooth, uniform cream or lotion. Such topical compositions may contain polyethylene glycol 400. To form an ointment, the compound may be combined with one or more preservatives (e.g. benzyl alcohol 2% (wt/wt)), petrolatum, emulsifying wax and Tenox(II) (e.g. butylated hydroxyanisole, propyl gallate Esters, Citric Acid, Propylene Glycol). Knitted pads or rolls of dressing material such as gauze may be impregnated with the transdermal compositions described above for topical application.

The compounds may also be applied topically using a transdermal system, such as an acrylic matrix polymer impregnated with the compounds described herein, bonded with a resinous crosslinker, which is then laminated into an impermeable pad. For example, the compounds may be administered in the form of a transdermal patch, such as a sustained release transdermal patch. Transdermal patches may comprise any conventional form, such as adhesive matrices, polymer matrices, depot patches, matrices or monolithic type laminated structures, which typically consist of backing layers, adhesives, osmotic Accelerators and/or rate control one or more components of the membrane. Transdermal patches typically have a release liner which, when removed prior to use, exposes the adhesive/active ingredient. Transdermal patches are described, for example, in U.S. Patent Nos. 5,262,165, 5,948,433, 6,010,715, and 6,071,531, the entire contents of which are incorporated herein by reference.

The present invention provides nasal administration of compounds to a patient for the treatment of the diseases and disorders described herein. "Nasal administration" or "nasal administration" refers to combining at least one compound with a delivery system suitable for absorption across the nasal mucosa of a patient. In general, lower dosages of the compound may be required for nasal administration when compared to, for example, oral administration.

The compounds can be administered in the form of, for example, nasal sprays, nasal drops, nasal suspensions, nasal gels, nasal ointments, nasal creams, or nasal powders. The compounds can also be administered using nasal tampons or nasal sponges. The compounds can be introduced into the adhesive base by conventional systems, such as natural gums, methylcellulose and derivatives, acrylic polymers (carboxyvinyl) and vinyl polymers (polyvinylpyrrolidone). In this composition, various other excipients known in the art may be added, such as water, preservatives, surfactants, solvents, binders, antioxidants, buffers, bioadhesives, viscosity enhancers and excipients to adjust pH and osmolarity.

Nasal delivery systems can take various forms, including aqueous solutions, non-aqueous solutions, and combinations thereof. Aqueous solutions include, for example, aqueous gels, aqueous suspensions, aqueous lipid dispersions, aqueous emulsions, aqueous microemulsions, and combinations thereof. Non-aqueous solutions include, for example, non-aqueous gels, non-aqueous suspensions, non-aqueous lipid dispersions, non-aqueous emulsions, non-aqueous microemulsions, and combinations thereof.

In other embodiments, the nasal delivery system may be a powder formulation. Powder formulations include, for example, powder mixtures, powder microspheres, coated powder microspheres, lipid dispersions, and combinations thereof. Preferred powder formulations are powder microspheres. The powder microspheres are preferably made of starch, methylcellulose, gum tragacanth, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol alginate, gum arabic, chitosan and various polysaccharides and cellulose in mixtures of two or more thereof are formed.

In certain embodiments, droplets or powders of aqueous and/or non-aqueous solutions delivered to the nasal mucosa can have a particle size, for example, of about 0.1 microns to about 100 microns, about 1 micron to about 70 microns; about 5 microns to about 70 microns; about 50 microns; about 10 microns to about 20 microns. The above particle sizes can be obtained using suitable containers or metering devices known in the art. Exemplary devices include mechanical pumps, where delivery is achieved by piston movement; compressed other devices, where delivery is achieved by manually pumping air into a container; compressed gas (such as nitrogen) where delivery is achieved by controlled release of the compressed gas in a closed container technology; liquefaction propulsion technology in which vaporization of a low-boiling liquid hydrocarbon (such as butane) generates an air pressure and forces the composition through a metering valve, etc. The powder can be administered, for example, in the form of a capsule which is then placed in an inhalation or insufflation device. Needles are pierced through the capsule to make small holes in the top and bottom of the capsule, and air is then delivered to blow the powder particles outward. Powder formulations can also be administered as a jet-spray of an inert gas or suspended in a liquid organic fluid.

In one embodiment, the present invention provides a pharmaceutical composition for nasal administration comprising at least one compound dispersed in a nasal delivery system that enhances the solubility of the compound. Nasal delivery systems that enhance solubility may include one or a combination of: (i) glycol derivatives (e.g., propylene glycol, polyethylene glycol, or mixtures thereof); (ii) sugar alcohols (e.g., mannitol, xylose alcohol or mixtures thereof); (iii) glycerol; (iv) glycol derivatives (such as propylene glycol, polyethylene glycol or mixtures thereof) and glycerin; (v) ascorbic acid and water; (vi) sodium ascorbate and water; or ( vii) Sodium metasulfite and water.

In another embodiment, the present invention provides a pharmaceutical composition for nasal administration comprising at least one compound described herein and a nasal delivery system, wherein the nasal delivery system comprises at least one agent that maintains the pH of the compound described herein. buffer, at least one pharmaceutically acceptable thickener and at least one humectant. The nasal delivery system may optionally further contain surfactants, preservatives, antioxidants, bioadhesives, pH regulators, isotonic agents, solubilizers and/or other pharmaceutically acceptable excipients. Compounds described herein can optionally be dispersed in nasal delivery systems to enhance their solubility.

In another embodiment, the present invention provides a pharmaceutical composition for nasal administration comprising at least one compound described herein and a nasal delivery system, wherein the nasal delivery system comprises at least one solubilizer, at least one A medicinal thickener and at least one humectant. Nasal delivery systems may optionally further contain buffers, pH adjusters, isotonic agents, surfactants, preservatives, antioxidants, bioadhesives and/or other pharmaceutically acceptable excipients. Compounds described herein can optionally be dispersed in nasal delivery systems to enhance their solubility.

In another embodiment, the present invention provides a pharmaceutical composition for nasal administration comprising at least one compound described herein and a nasal delivery system, wherein the nasal delivery system comprises at least one buffer to maintain the pH of the compound, at least one pharmaceutically acceptable thickener, at least one humectant and at least one surfactant. The nasal delivery system may optionally further contain pH adjusters, isotonic agents, solubilizers, preservatives, antioxidants, bioadhesives and/or other pharmaceutically acceptable excipients. Compounds described herein can optionally be dispersed in nasal delivery systems to enhance their solubility.

In yet another embodiment, the present invention provides a pharmaceutical composition for nasal administration comprising at least one compound described herein and a nasal delivery system, wherein the nasal delivery system comprises at least one pharmaceutically acceptable thickener, at least one humectant, at least one surfactant and at least one solubilizer. Nasal delivery systems may optionally further contain buffers, pH adjusters, isotonic agents, preservatives, antioxidants, bioadhesives and/or other pharmaceutically acceptable excipients. The compound can optionally be dispersed in a nasal delivery system to enhance its solubility.

In yet another embodiment, the present invention provides a pharmaceutical composition for nasal administration comprising at least one compound described herein and a nasal delivery system, wherein the nasal delivery system comprises at least one buffer to maintain the pH of the compound, at least one pharmaceutically acceptable thickener, at least one humectant, at least one surfactant, and at least one solubilizer. Nasal delivery systems may optionally further contain buffers, pH adjusters, isotonic agents, preservatives, antioxidants, bioadhesives and/or other pharmaceutically acceptable excipients. Compounds described herein can optionally be dispersed in nasal delivery systems to enhance their solubility.

The buffer is selected to have a pH that maximizes the absorption of the 1,2-dihydropyridine compound through the nasal mucosa. The particular pH of the buffer may vary with the particular nasal delivery formulation and the particular compound chosen. Buffers suitable for use in the present invention include acetates (e.g. sodium acetate), citrates (e.g. sodium citrate dihydrate), phthalates, borates, prolamins, triethanolamine, carbon salts, phosphates (such as potassium dihydrogen phosphate, disodium phosphate) and mixtures of two or more thereof.

The pH of the composition can be maintained from about 3.0 to about 10.0. Compositions having a pH of less than about 3.0 or greater than about 10.0 may increase the likelihood of irritation of the patient's nasal mucosa. Additionally, it is preferred that the pH of the composition be maintained from about 3.0 to about 9.0. For non-aqueous nasal formulations, the appropriate form of buffering agent can be chosen such that when the formulation is delivered into the nasal cavity of a mammal, a selected pH range is obtained upon contact with, for example, the nasal mucosa.

The solubilizing agent used in the composition of the present invention may be any known in the art, such as carboxylic acids and their salts. Exemplary carboxylates include acetate, gluconate, ascorbate, citrate, fumarate, lactate, tartrate, maleate, succinate, or combinations of two or more thereof mixture.

The viscosity of the compositions of the present invention can be maintained at a desired level using pharmaceutically acceptable thickeners. For example, the viscosity can be at least 1000 cps; about 1000 to about 10,000 cps; about 2000 cps to about 6500 cps; or about 2500 cps to about 5000 cps. Thickeners that can be used in the present invention include, for example, methyl cellulose, tragacanth, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginate, acacia, chitosan Sugar and mixtures of two or more thereof. The concentration of thickener depends on the drug chosen and the desired viscosity. Such thickeners can also be used in powder formulations.

Compositions for nasal administration may also contain humectants to reduce or prevent drying of the mucous membranes, thereby preventing irritation to the mucous membranes. Suitable humectants that may be used include, for example, sorbitol, mineral oil, vegetable oil, and glycerin; soothing agents; membrane regulators; sweeteners and mixtures of two or more thereof. The concentration of humectant depends on the drug chosen. In one embodiment, the humectant may be present in the nasal delivery system at a concentration ranging from about 0.01% to about 20% by weight of the composition.

In other embodiments, nasal delivery systems may further contain surfactants to facilitate absorption of the compound. Suitable surfactants include nonionic, cationic and anionic surfactants. Exemplary surfactants include oleic acid, polyoxyethylene derivatives of fatty acids, partial esters of sorbitan, such as Tweens (e.g. Tween 80, Tween 40, Tween 20), Spans (e.g. Span 40, Span 80, Span 20 ), macrogol 40 stearate, polyoxyethylene 50 stearate, fusieates, bile salts, octoxynol, and mixtures of two or more thereof. Exemplary cationic surfactants include salts of long chain hydrocarbons (eg, C6-30 or C10-20) having one or more of the following functional groups: carboxylate, sulfonate, and sulfate. Preference is given to salts of long-chain hydrocarbons having a sulfate functional group, such as sodium cetostearyl sulfate, sodium lauryl sulfate and sodium tetradecyl sulfate. A particularly preferred anionic surfactant is sodium lauryl sulfate (ie sodium lauryl sulfate). The surfactant may be present in an amount from about 0.001% to about 50% by weight, for example from about 0.001% to about 20% by weight.

The pharmaceutical composition of the present invention may further contain isotonic agents such as sodium chloride, dextrose, boric acid, sodium tartrate or other inorganic or organic solutes.

The nasal pharmaceutical compositions of the present invention may optionally be used in combination with pH adjusting agents. Exemplary pH adjusters include sulfuric acid, sodium hydroxide, hydrochloric acid, and the like.

To prolong shelf life, preservatives can be added to compositions for nasal administration. Suitable preservatives that may be used include benzyl alcohol, parabens, thimerosal, chlorobutanol, benzalkonium chloride or mixtures of two or more thereof. Preference is given to using benzalkonium chloride. Typically preservatives are present in concentrations of up to about 2% by weight. However, the precise concentration of preservative depends on the intended use and can be readily ascertained by one skilled in the art.

Other ingredients, such as antioxidants, may be added to extend shelf life. Some examples of antioxidants include sodium metabisulfite, potassium metabisulfite, ascorbyl palmitate, and the like. Antioxidants are generally present in the composition at a concentration of from about 0.001% to about 5% by weight of the total composition.

Nasal delivery systems can be prepared as described in, for example, U.S. Patent Nos. 6,451,848, 6,436,950, and 5,874,450 and WO 00/00199, the entire contents of which are incorporated herein by reference.

Example

The following examples are only for the purpose of illustrating the present invention, and are not meant to limit the spirit or scope of the present invention.

Example 1

Anti-migraine agents are commonly evaluated using the carrageenan-induced thermal hyperalgesia model (Bingham et al., Experimental Neurology, 167:65-73 (2001); Daher et al., Life Sciences, 76:2349-2359 (2005)) . Antimigraine properties of compound A (i.e., 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one) in response to thermal hyperalgesia Evaluated in the following rat carrageenan-induced inflammatory pain model.

Male Wistar rats (5/group) were used in the experiments. Using TAIL FLICK 7360 (Ugo Basile, Italy) to measure the withdrawal latency of the two hind paws of rats to avoid thermal noxious stimuli. 1% carrageenan was injected into the sole of the right hind paw of the rat. 2 hours after carrageenan injection, rats were orally administered 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2 - ketone or vehicle. The withdrawal latencies of the two hind paws of the heat-stimulated rats were measured at 1, 3 and 5 hours after administration.

As shown in Figure 1, withdrawal latencies were shortened in the right hind paw of rats injected with carrageenan. As shown in Figure 2, there was no change in the withdrawal latency of the left hind paw of the rats. The results showed that carrageenan elicited an inflammatory hyperalgesic response in the injected hind paw but not in the contralateral hind paw of the rats. The effect of carrageenan was observed throughout the experimental period.

Figure 1 also shows that 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one at 3 and 6 mg/kg Induced hyperalgesia was suppressed after 1 hour, with a decline in effect after 3 and 5 hours of administration. Figure 2 also shows that 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one did not alter the contralateral hindpaw Latency, thus indicating that 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one did not affect motor function. The above animal model results predict that 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one can treat migraine and headache in humans .

Example 2

To evaluate the efficacy and For safety, a randomized double-blind placebo-controlled, multicenter parallel group study was conducted.

The primary efficacy endpoint was to evaluate the effect of 23-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate in reducing migraine , based on the compound's change in frequency of migraine sessions per 28 days during treatment relative to baseline. A migraine period was defined as the onset, end, or recurrence of migraine within 24 hours. If the migraine lasted longer than 24 hours, it was considered a new migraine period.

The second objective of this study was to evaluate the role of 23-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate in migraine Safety and tolerability in patients; characterizing 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate in Pharmacokinetics in a patient population; determination of plasma concentrations of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one hydrate - Response relationship; and evaluation of changes in migraine severity. Secondary efficacy was determined based on a reduction in one or more of the following indicators relative to Phase 1: (a) the proportion of patients with at least a 50% reduction in the frequency of migraine sessions at 28 days; (b) at 3 Change in frequency of migraine sessions per 28-day period; (c) change in frequency of migraine attacks; (d) change in days required for symptom-reversal treatment per 28-day period; (e) total number of days with migraine episodes per 28-day period; (f) changes in the severity of migraine attacks; (g) changes in the duration of migraine attacks; (h) changes in the patient's Global Impression of Change; and (i) migraine disability assessment (Migraine Disability Assessment (MIDAS) questionnaire score changes.

For the plasma concentration study, C _MinSS , C _MAXSS , and AUC _{0 -TauSS} were calculated by building a population pharmacokinetic model. Posterior estimates of appropriate individual pharmacokinetic parameters were also determined. Interpatient and visit Changes in these parameters between patients.The study of the exposure-response (reduction in migraine frequency within each 28-day period) relationship was performed using a mixed-effects model.

Safety was assessed by the incidence of adverse events and the results of physical and neurological examination, vital signs, clinical laboratory tests, body weight and electrocardiogram.

This study was a 14-week prospective randomized double-blind, placebo-controlled multicenter parallel-group study with a 4-week baseline period and a 4-week single-blind placebo safety period at the end of the study. This study has the following phases. Period 1 is a 4-week baseline period during which the prospective determination of migraine frequency is determined with the aid of the patient's migraine diary. Phase 2 is a dose-escalation period of up to 1-10 weeks, beginning with a dose of 0.5-2.0 mg/day administered once daily in the evening. After 1-5 weeks, the dose was increased to 1.0-2.0 mg/day, and after 1-5 weeks, the dose was increased to 1.5-4.0 mg/day. Patients with intolerable adverse events received a dose that was reduced by one dose step. During this period, blood samples were obtained to determine plasma concentrations. During Phase 2, clinical visits will be performed every 2 weeks. Phase 3 is a maintenance period of 4-12 weeks, during which the dose will not change from the last dose taken during phase 2. Plasma concentration samples were obtained at each visit. During Phase 3, clinical visits will be performed every 4 weeks. Phase 4 lasted 4 weeks, during which all patients took placebo in a single-blind manner. Continue to record the frequency and characteristics of the patient's migraines. The last visit was performed approximately 4 weeks after the end of Phase 3, at which time plasma concentration samples were obtained.

Patient eligibility was determined during the screening process based on Informed Consent signals. Screening evaluations included medical history, comprehensive physical and neurological testing, vital signs, 12-lead ECG, clinical laboratory tests, urine drug screen, rival screen, and administration of MIDAS. During interview screening, eligible patients were instructed to use an electronic diary and were expected to record the onset of migraine and other study-related information on a daily basis. At this point, the patient enters Phase 1.

Patients were allowed to start the study after successfully entering Phase 1 and being confirmed to meet all criteria for inclusion and no exclusion criteria. Patients who experienced fewer than 4 or more than 12 migraines, were unable to adequately complete the electronic diary, or were unable to comply with the protocol during phase 1 were not randomized.

Patients were randomized as males or females aged 18-65 years of any race with a history of migraine (with or without aura according to the Headache Classification Committee of the International Headache Society (HIS, 2004 guidelines)) for at least 12 months and in Onset before age 50, with 4-12 migraine attacks per month during the 3-month period prior to Screening and Phase 1. Patients should have a body mass index (BMI) of 19-40 kg/ ^m2 (inclusive) at screening.

After 180 patients were recruited into the study, they were randomized 1:1 to 90 patients in the placebo group and 90 patients in the 3-(2-cyanophenyl)-5-(2-pyridyl) -1-Phenyl-1,2-dihydropyridin-2-one hydrate. It is expected that 164 patients will complete the study. This study was conducted at approximately 25 survey sites in the United States.

The entire contents of each patent, patent application, and publication cited herein are hereby incorporated by reference.

Those skilled in the art will appreciate that various modifications can be made to the present invention without departing from the spirit or scope of the appended claims.

Claims (38)

1. treat the migrainous method of treatment among the migrainous patient at needs, described method comprises 3-(2-cyano-phenyl)-5-(2-the pyridine radicals)-1-phenyl-1 of drug treatment effective dose, the hydrate of 2-dihydropyridine-2-ketone or its officinal salt, its hydrate or its officinal salt.

2. the process of claim 1 wherein 3-(2-cyano-phenyl)-5-(2-pyridine radicals)-1-phenyl-1, the described treatment effective dose of 2-dihydropyridine-2-ketone is 30 μ g-10g.

3. the process of claim 1 wherein 3-(2-cyano-phenyl)-5-(2-pyridine radicals)-1-phenyl-1, the described treatment effective dose of 2-dihydropyridine-2-ketone is 100 μ g-100mg.

4. the process of claim 1 wherein that described antimigraine is with or without tendency.

5. the process of claim 1 wherein that the migrainous method of described treatment comprises one or more methods that are selected from dizzy, nauseating, vomiting, fatigue, tendency, photophobia and fear the cephalagra in loud of treatment.

6. the process of claim 1 wherein that described antimigraine is antimigraine before classical migraine, common migraine, cephalagra type cerebral infarction, menstrual migraine, the menstruation, ocular migraine, ophthalmoplegic migraine, fulgurating migraine, Harris antimigraine or hemiplegic migraine.

7. the process of claim 1 wherein that described method is used for chronic treatment or acute treatment.

8. the method for claim 7, wherein said antimigraine is paroxysmal or chronic.

9. treat the method for headache in the patient who needs the treatment headache is arranged, described method comprises formula (I) compound of drug treatment effective dose or the hydrate of its officinal salt, its hydrate or its officinal salt:

Wherein:

Q is NH, O or S;

R ¹, R ², R ³, R ⁴And R ⁵Be hydrogen, halogen, C independently of one another _1-6Alkyl or-X-A;

X is singly-bound, optional substituted C _1-6Alkylidene, optional substituted C _2-6Alkenylene, optional substituted C _2-6Alkynylene ,-O-,-S-,-CO-,-SO-,-SO ₂-,-N (R ⁶)-,-N (R ⁷)-CO-,-CO-N (R ⁸)-,-N (R ⁹)-CH ₂-,-CH ₂-N (R ¹⁰)-,-CH ₂-CO-,-CO-CH ₂-,-N (R ¹¹)-S (O) _m-,-S (O) _n-N (R ¹²)-,-CH ₂-S (O) _p-,-S (O) _q-CH ₂-,-CH ₂-O-,-O-CH ₂-,-N (R ¹³)-CO-N (R ¹⁴)-or-N (R ¹⁵)-CS-N (R ¹⁶)-;

R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Be hydrogen, C independently of one another _1-6Alkyl or C _1-6Alkoxyl;

M, n, p and q are integer 0,1 or 2 independently of one another;

A is optional substituted C _3-8Cycloalkyl, optional substituted C _3-8Cycloalkenyl group, the first nonaromatic heterocycles of optional substituted 5-to 14-, optional substituted C _6-14Aromatic hydrocarbon ring or optional substituted 5-to 14-membered aromatic heterocycle; Condition is R ¹, R ², R ³, R ⁴And R ⁵In 3 groups be-X-A; And R ¹, R ², R ³, R ⁴And R ⁵In all the other 2 groups be hydrogen, halogen or C independently _1-6Alkyl.

10. the method for claim 9, wherein said headache are primary headaches or Secondary cases headache.

11. the method for claim 10, wherein said primary headaches be antimigraine, tension headache, cluster headache, sudden antimigraine, because of conjunctival congestion with tear the one-sided neuralgia sample headache of the short time continuation of showing effect, the spontaneous headache of trigeminal neuralgia, shouting pain headache, cough headache, firmly due to headache, headache, hypnosis headache, thunderclap headache, continuity antimigraine or the new life's relevant continuation every day with sexual activity have a headache.

12. the method for claim 10, wherein said Secondary cases headache are the headaches owing to head and/or neck wound; Headache owing to cranium and/or neck vascular disorder; Headache owing to non-vascular encephalic obstacle; Headache owing to one or more medicines; Headache owing to one or more medicine drug withdrawals; Owing to the headache of infecting; Owing to the unbalance headache of homeostasis; Owing to the headache of face structure and/or cranium structural obstructions or; Perhaps owing to the headache of phrenoblabia.

13. the method for claim 9, wherein said headache is an antimigraine.

14. the method for claim 13, wherein said antimigraine is with or without tendency.

15. the method for claim 13, the migrainous method of wherein said treatment comprise one or more methods that are selected from dizzy, nauseating, vomiting, fatigue, tendency, photophobia and fear the cephalagra in loud of treatment.

16. the method for claim 13, wherein said antimigraine are antimigraine before classical migraine, common migraine, cephalagra type cerebral infarction, menstrual migraine, the menstruation, ocular migraine, ophthalmoplegic migraine, fulgurating migraine, Harris antimigraine or hemiplegic migraine.

17. the method for claim 13, wherein said method is used for chronic treatment or acute treatment.

18. the method for claim 13, wherein said antimigraine is paroxysmal or chronic migraine.

19. the method for claim 9, wherein said treatment effective dose are 30 μ g-10g.

20. the method for claim 9, described method also comprise the drug treatment effective dose: (i) anticholinesterase; (ii) anti-migraine agent; Or (iii) anticholinesterase and anti-migraine agent.

21. the method for treatment headache in the patient who needs the treatment headache is arranged, described method comprise the drug treatment effective dose: (i) hydrate of formula (III) compound or its officinal salt, its hydrate or its officinal salt; (ii) formula (VI) compound or its officinal salt; Its Chinese style (III) compound is:

Wherein

X ¹, X ²And X ³Be singly-bound, optional substituted C independently of one another _1-6Alkylidene, optional substituted C _2-6Alkenylene, optional substituted C _2-6Alkynylene ,-O-,-S-,-CO-,-SO-,-SO ₂-,-N (R ⁶)-,-N (R ⁷)-CO-,-CO-N (R ⁸)-,-N (R ⁹)-CH ₂-,-CH ₂-N (R ¹⁰)-,-CH ₂-CO-,-CO-CH ₂-,-N (R ¹¹)-S (O) _m-,-S (O) _n-N (R ¹²)-,-CH ₂-S (O) _p-,-S (O) _q-CH ₂-,-CH ₂-O-,-O-CH ₂-,-N (R ¹³)-CO-N (R ¹⁴)-or-N (R ¹⁵)-CS-N (R ¹⁶);

R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Be hydrogen, C independently of one another _1-6Alkyl or C _1-6Alkyl oxy;

M, n, p and q are integer 0,1 or 2 independently of one another;

A ¹, A ²And A ³Be optional substituted C independently of one another _3-8Cycloalkyl, optional substituted C _3-8Cycloalkenyl group, the first nonaromatic heterocycles of optional substituted 5-to 14-, optional substituted C _6-14Aromatic hydrocarbon ring or optional substituted 5-14-membered aromatic heterocycle; And

R ¹⁷And R ¹⁸Be hydrogen, halogen or C independently of one another _1-6Alkyl; And

Its Chinese style (VI) compound is:

Wherein

R is integer 1-10;

Each R ²²Be hydrogen or methyl independently;

K is the benzene alkyl or has substituent benzene alkyl on phenyl;

Each S is hydrogen, C independently _1-6Low alkyl group or C _1-6Lower alkoxy;

T is integer 1-4;

Q is integer 1-3;

Condition is (S) _tCan be with phenyl on two methylene-dioxy or ethylenedioxies that adjacent carbon atom links to each other.

22. the method for claim 21, its Chinese style (III) compound are 3-(2-cyano-phenyl)-5-(2-pyridine radicals)-1-phenyl-1, the hydrate of 2-dihydropyridine-2-ketone or its officinal salt, its hydrate or its officinal salt.

23. the method for claim 21, its Chinese style (III) compound is with the consumption administration of 30 μ g-10g.

24. the method for claim 21, its Chinese style (VI) compound is donepezil or its officinal salt.

25. the method for claim 21, its Chinese style (VI) compound is with the consumption administration of 1mg-50mg.

26. the method for claim 21, wherein said headache is an antimigraine.

27. the method for claim 26, wherein said antimigraine is with or without tendency.

28. the method for claim 26, the migrainous method of wherein said treatment comprise one or more methods that are selected from dizzy, nauseating, vomiting, fatigue, tendency, photophobia and fear the cephalagra in loud of treatment.

29. the method for claim 26, wherein said antimigraine are antimigraine before classical migraine, common migraine, cephalagra type cerebral infarction, menstrual migraine, the menstruation, ocular migraine, ophthalmoplegic migraine, fulgurating migraine, Harris antimigraine or hemiplegic migraine.

30. the method for claim 26, wherein said method is used for chronic treatment or acute treatment.

31. the method for claim 26, wherein said antimigraine is paroxysmal or chronic migraine.

32. the method for claim 21 is wherein with the hydrate of formula (III) compound, its officinal salt, its hydrate or its officinal salt; And formula (VI) compound or its officinal salt are separately to patient's administration.

33. the method for claim 21 is wherein with the hydrate of formula (III) compound, its officinal salt, its hydrate or its officinal salt; And formula (VI) compound or its officinal salt with pharmaceutical compositions to patient's administration.

34. pharmaceutical composition wherein contains the treatment effective dose: (i) hydrate of formula (III) compound, its officinal salt, its hydrate or its officinal salt; And (ii) formula (VI) compound or its officinal salt; Its Chinese style (III) compound is

Wherein

X ¹, X ²And X ³Be singly-bound, optional substituted C independently of one another _1-6Alkylidene, optional substituted C _2-6Alkenylene, optional substituted C _2-6Alkynylene ,-O-,-S-,-CO-,-SO-,-SO ₂-,-N (R ⁶)-,-N (R ⁷)-CO-,-CO-N (R ⁸)-,-N (R ⁹)-CH ₂-,-CH ₂-N (R ¹⁰)-,-CH ₂-CO-,-CO-CH ₂-,-N (R ¹¹)-S (O) _m-,-S (O) _n-N (R ¹²)-,-CH ₂-S (O) _p-,-S (O) _q-CH ₂-,-CH ₂-O-,-O-CH ₂-,-N (R ¹³)-CO-N (R ¹⁴)-or-N (R ¹⁵)-CS-N (R ¹⁶);

R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Be hydrogen, C independently of one another _1-6Alkyl or C _1-6Alkyl oxy;

M, n, p and q are integer 0,1 or 2 independently of one another;

A ¹, A ²And A ³Be optional substituted C independently of one another _3-8Cycloalkyl, optional substituted C _3-8Cycloalkenyl group, the first nonaromatic heterocycles of optional substituted 5-to 14-, optional substituted C _6-14Aromatic hydrocarbon ring or optional substituted 5-14-membered aromatic heterocycle; And

R ¹⁷And R ¹⁸Be hydrogen, halogen or C independently of one another _1-6Alkyl; And

Its Chinese style (VI) compound is:

Wherein

R is integer 1-10;

Each R ²³Be hydrogen or methyl independently;

K is the benzene alkyl or has substituent benzene alkyl on phenyl;

Each S is hydrogen, C independently _1-6Low alkyl group or C _1-6Lower alkoxy;

T is integer 1-4;

Q is integer 1-3;

Condition is (S) _tCan be with phenyl on two methylene-dioxy or ethylenedioxies that adjacent carbon atom links to each other.

35. the composition of claim 34, its Chinese style (III) compound are 3-(2-cyano-phenyl)-5-(2-pyridine radicals)-1-phenyl-1, the hydrate of 2-dihydropyridine-2-ketone, its officinal salt, its hydrate or its officinal salt.

36. the composition of claim 34, its Chinese style (III) compound exists with the consumption of 30 μ g-10g.

37. the composition of claim 34, its Chinese style (VI) compound is donepezil or its officinal salt.

38. the composition of claim 34, its Chinese style (VI) compound exists with the consumption of 1mg-50mg.

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