JP2003518500A - Methods and compositions for the treatment of pain - Google Patents

Abstract

(57) Abstract: Disclosed are methods of treating pain, including the administration of any of the compounds of Structural Formula (I) in an effective amount to ameliorate pain; wherein R ¹ , A, and D are disclosed. Is as defined in the specification. Also disclosed is a pharmaceutical composition comprising an effective amount for improving pain of a compound represented by Structural Formula (I). Embedded image

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION

  The present invention relates to the treatment or prevention of pain or nociception.

[0002]

[Related technology]

Pain is a sensory experience that differs from the sensations of touch, pressure, heat and cold. This pain is often described by the patient in terms such as sharp, dull, tingling, tingling, shattering or burning, and pain refers to both its original sensation and its response to that sensation. It is generally considered to include. This range of sensations, as well as the difference in perception of pain by different individuals, makes it difficult to define the exact pain, but many individuals suffer from severe and persistent pain.

Pain caused by damage to nerve tissue is often manifested as hypersensitivity or hyperalgesia and is called "neuropathic" pain. Pain can also be "caused" by stimulation of nociceptors and transmitted by intact neural pathways, such pain being referred to as "nociceptive" pain.

The level of stimulation at which pain becomes perceived is called the “pain threshold”. Analgesics are pharmaceutical agents that relieve pain by raising this pain threshold without losing consciousness. After administration of the analgesic drug, a stimulus of greater intensity or longer duration is required before the pain is experienced. In individuals suffering from hyperalgesia, analgesic drugs may have antihyperalgesic effects. Compared to analgesics, agents such as local anesthetics block transmission in peripheral nerve fibers and thereby block pain perception. On the other hand, common anesthetics reduce the perception of pain by causing loss of consciousness.

Tachykinin antagonists have been reported to induce antinociception in animals, which is believed to mimic analgesia in humans (Maggi
Et al., J. Auton. Pharmacol. (1993) 13, 23-93). In particular, non-peptide NK-1 receptor antagonists have been shown to cause such analgesia. For example, the NK-1 receptor antagonist RP 67,580 produced analgesia with efficacy comparable to that of morphine (Garret et al., Proc. Na.
tl. Acad. Sci. USA (1993) 88, 10208-10212).

Opioid analgesics belong to the established class of analgesics with morphine-like effects. Synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes: phenanthrene; phenylheptylamine; phenylpiperidine; morphinan; and benzomorphan. Pharmacologically, these compounds have diverse activities, and thus some agonists to opioid receptors (eg morphine); moderate to moderate agonists (eg codeine); and agonist- Some exhibit mixed antagonistic activity (eg, nalbuphine), and some even incomplete agonists (eg, nalorphine)
. Incomplete opioid agonists such as nalorphine (N-alkyl analogues of morphine) antagonize the analgesic effect of morphine, but when given alone,
Nalorphine itself can be a powerful pain reliever.

Of all opioid analgesics, morphine remains the most widely used drug, but in addition to its therapeutic properties, respiratory depression, decreased gastrointestinal motility (causing constipation),
It has a number of drawbacks, including nausea and vomiting. Tolerance and physical dependence also limit the clinical use of opioid compounds.

Aspirin and other salicylate compounds are often used in treatments that prevent the amplification of inflammatory processes in rheumatoid diseases and arthritis, and temporarily relieve pain. Other drug compounds used for these purposes include phenylpropionic acid derivatives such as ibuprofen and naproxen, sulindac, phenylbutazone, corticosteroids, antimalarials (eg, chloroquine and hydroxychloroquine sulfate), and phenemate. (Fenemate) (J. Hosp. Pharm., 36: 622 (May 1979)). However, these compounds have no effect on neuropathic pain.

Available treatments for pain also have drawbacks. Some therapeutic agents require long-term use before the effect is felt by the patient. Other existing drugs have serious side effects in certain patients, and patients must be carefully monitored to ensure that they are not overly risked of any side effects. Most drugs present only provide temporary relief of pain and must be taken consistently on a daily or weekly basis. As the disease progresses, the amount of medication needed to reduce pain often increases, thus increasing the potential for adverse side effects.

The NMDA receptor is defined by the binding of N-methyl-D-aspartate (NMDA) and has several distinct identified binding domains /
Includes an ion channel complex. NMDA itself is a molecule structurally similar to glutamate (Glu), which binds to the glutamate binding site, and is highly selective and has the effect of activating NMDA receptors (Watkins (1987); Ol.
ney (1989)).

Many compounds have NMDA / Glu binding sites (eg, CPP, DCPP-ene, CGP 40116, CGP 37849, CGS 19755, NPC 12).
626, NPC 17742, D-AP5, D-AP7, CGP 39551, C
GP-43487, MDL-100, 452, LY-274614, LY-23
3536, and LY230553). Other compounds, called non-competitive NMDA antagonists, bind to other sites in the NMDA receptor complex (eg phencyclidine, dizocilpin.
e), ketamine, tiletamine, CNS 1102, dextromethorphan, memantine, kynurenic acid, CNQX, DNQX, 6,7
-DCQX, 6,7-DCHQC, R (+)-HA-966, 7-chloro-kynurenic acid, 5,7-DCKA, 5-iodo-7-chloro-kynurenic acid, MDL-28,
469, MDL-100,748, MDL-29,951, L-689,560,
L-687,414, ACPC, ACPCM, ACPCE, alcaine
), Diethylenetriamine, 1,10-diaminodecane, 1,12-diaminododecane, ifenprodil, and SL 82.0715). These compounds have been extensively investigated by Rogawski (1992) and Massieu et al. (1993) and the articles cited herein.

In addition to its physiological function, glutamate (Glu) can be a neurotoxin. Gl
The neurotoxicity of u is called "excitotoxicity". Because Glu's neurotoxic effects, such as its beneficial effects, are mediated by excitatory processes (Olney (199
0); Choi (1992)). Normally, when Glu is released at the synaptic receptor, it only binds to the receptor transiently and then is rapidly cleared from the receptor by the process of transporting it back into the cell. Under certain abnormal conditions (including seizures, epilepsy, and CNS trauma), Glu uptake fails and Glu accumulates at receptors, resulting in sustained excitation of electrochemical activity and neurons with Glu receptors. Lead to the death of. Many neurons in the CNS have Glu receptors, and as a result, excitotoxins have large C
It can cause NS damage.

[0013] Rapid cytotoxic injury is associated with ischemic events, hypoxic events, trauma to the brain or spinal cord, certain types of food poisons involving excitotoxic toxins such as domoic acid, and persistent epileptic seizure activity ( Can occur as a result of neuronal degeneration that mediates seizures that can result from status epilepticus. Most events suggest that Glu mediates significant CNS damage through the NMDA receptor as one receptor subtype, and NM
DA antagonists are well documented to be effective in protecting CNS neurons against cytotoxic degeneration in these rapid CNS injury syndromes (Choi (1988); Olney (1990)).

In addition to neuronal damage caused by sudden seizures, excessive activation of Glu receptors also promotes a more gradual neurodegenerative process, leading to various chronic neurodegenerative diseases (Alzheimer's disease, muscular atrophic side). Can lead to cell death in cord sclerosis, AIDS dementia, Parkinson's disease and Huntington's disease (Olney (199
0)). It is generally believed that NMDA antagonists may prove useful in the drug management of such chronic diseases.

In 1980, PCP (also known as "Angel Dust") was renamed NMDA
It was discovered to act at a "PCP recognition site" within the Glu receptor ion channel. PCP acts as a non-competitive antagonist that blocks the flow of ions through the NMDA ion channel. More recently, it has become clear that drugs acting at the PCP site as non-competitive NMDA antagonists will likely have side effects that cause conditions such as psychotic disorders. Furthermore, it has now been found that certain competitive and non-competitive NMDA antagonists can cause similar pathomorphological effects in the rat brain (Olney et al., (1991); Hargreaves
Et al. (1993)). Such compounds also have psychotic effects in humans
(Kristensen et al., (1992); Herring (1994); Grotta (1994)).

The glycine binding site of the NMDA receptor complex is distinguishable from the Glu and PCP binding sites. Also, the NMDA receptor has recently been discovered to exist as several subtypes characterized by the differential properties of the glycine binding site of this receptor. Many compounds that bind at the NMDA receptor glycine site and are useful in the treatment of stroke and neurodegenerative conditions are described in US Pat. No. 5,604,2.
No. 27; No. 5,733,910; No. 5,599,814; No. 5,593,1
33; ibid 5,744,471; ibid 5,837,705 and i 6,103,
No. 721.

[0017]

SUMMARY OF THE INVENTION It has now been discovered that certain compounds that exhibit the property of binding to the NMDA receptor glycine site are useful for the amelioration of pain, and especially for neuropathic pain.

The present invention provides a method of treating pain, which comprises administering a pain-improving effective amount of any compound of structural formula I;

[Chemical 4] Where R ¹ is halo in such compounds; A is CH (R ² ) (CH ₂ ) _n where _n has a value selected from 0, 1 or 2; R ² is _{1, 2} selected from C ₁ -C ₆ alkyl and D selected from a 5- or 6-membered heteroaryl residue or a benz derivative thereof, selected from nitrogen, oxygen or sulfur 1,2
Or has 3 ring atoms, where D is unsubstituted or substituted with 1, 2 or 3 residues selected from C ₁ -C ₃ alkoxy, halo and cyano.

In a particular embodiment of the invention, the method comprises the step of administering a pain-modifying effective amount of a compound of structural formula I, wherein D is pyridyl, furanyl, benz [ b] furanyl, thienyl, benz [b] thienyl and pyrazinyl.

In another particular embodiment of the invention, the method comprises the step of administering a pain-modifying effective amount of a compound of structural formula I, wherein R ² is methyl, ethyl. , N-propyl, isopropyl, n-butyl and sec-butyl.

Certain embodiments of the invention include treatment with a compound of structural formula II.

[Chemical 5]

An even more particular embodiment of this invention comprises treatment with the exemplary compounds disclosed in detail herein. Another aspect of the invention is a method of making a compound of structural formula I. Yet another aspect of the invention is a pharmaceutical composition comprising a compound of structural formula I; the use of a compound of structural formula I for the preparation of a medicament and a pharmaceutical composition, and human The method comprising binding the compound of the present invention to the NMDA receptor glycine site of a warm-blooded animal such as, and thus, preferably inhibiting the activity of the NMDA receptor.

[0023]

Detailed description of the invention

The compounds of the present invention are compounds within the scope of the general description, and especially those exemplified below. Suitable pharmaceutically acceptable salts of the compounds of the present invention include methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, tris (hydroxymethyl) aminomethane, maleate. And acid addition salts such as the salts formed with phosphoric acid and sulfuric acid. In other embodiments, suitable salts are basic salts, such as alkali metal salts such as sodium, alkaline earth metal (eg calcium or magnesium), organic amine salts (eg triethylamine, morpholine, N-methylpiperidine). , N-ethylpiperidine, procaine, dibenzylamine, choline, N, N-dibenzylethylamine, or amino acids such as lysine).

Another aspect of the invention is a process for preparing the compounds of the invention, which process comprises the steps of: a) preparing a ketone by reacting a nitrile in the presence of a Grignard reagent. , Then forming the above ketone by acidic workup according to the following scheme:

[Chemical 6] Where R is an alkyl group;

B) preparing a Boc protected hydrazine by reacting with the ketone, or aldehyde prepared in step a) according to one of the procedures shown in the scheme below:

[Chemical 7]

C) Coupling the Boc protected hydrazine above according to the process of the following scheme and cyclizing the product to form a compound of structural formula I:

[Chemical 8] Where: CMC is 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide meta (metho) -p-toluenesulfonate; the "R / H / D" group is "-A -D "residue; and in all the processes described above: R ¹ is as defined for Structural Formula I.

In order to use a compound of the invention or a pharmaceutically acceptable salt thereof for therapeutic treatment of pain in a mammal, which may be a human, which may include prophylactic treatment, the compound may be administered pharmaceutically The composition may be formulated according to standard pharmaceutical procedures.

Suitable pharmaceutical compositions containing a compound of the invention may be administered by conventional methods, eg by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes, the compounds of the invention may be applied by means known in the art, for example tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, Formulated in the form of suppositories, granules or aerosols for inhalation, and sterile aqueous or oily solutions or suspensions or emulsions for parenteral (including intravenous, intramuscular or infusion) use. Can be done. The preferred route of administration is oral via tablets or capsules.

In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also include one or more other pharmacologically active agents, or such pharmaceutical compositions may include one or more Can be co-administered with other pharmacologically active agents, either simultaneously or sequentially. The pharmaceutical compositions of this invention are usually administered such that the patient will receive a daily dose effective in ameliorating pain. This daily dose may be given in divided doses if necessary and the precise amount of the compound ingested and the route of administration will depend on the body weight, age and sex of the patient to be treated and the particular disease state to be treated, in the art. It depends on known principles. Administration once a day is desirable.

A further embodiment of the present invention is a compound of structural formula I as defined herein, or a pharmaceutically acceptable salt thereof, which is pharmaceutically acceptable as an excipient or carrier. There is provided a pharmaceutical composition comprising in combination with an additive. Yet a further embodiment of the present invention is the use of a compound of structural formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament useful for binding to the NMDA receptor glycine site in a warm blooded animal such as a human. I will provide a. Yet another embodiment of the present invention provides a method of binding a compound of the invention required for the treatment of pain to a NMDA receptor glycine site of a warm-blooded animal such as human, the method comprising the step of applying an effective amount of a structure Administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.

Definitions The term “alkyl” as used herein includes both straight chain and branched chain alkyl groups, but when each alkyl group is referred to as, for example, “propyl”, it refers to a straight chain. The term "halo" herein means fluorine, chlorine, bromine and iodine. The term “aryl” herein means an unsaturated carbocycle or benz derivative thereof. In particular, aryl means phenyl, naphthyl or biphenyl. More particularly aryl means phenyl.

The term “heteroaryl” or “heteroaryl ring” as used herein, unless otherwise specified, contains up to 5 fully unsaturated or partially unsaturated nitrogen, oxygen and sulfur atoms. A monocyclic, containing a ring-constituting heteroatom of
A 5-14 membered ring cyclic or tricyclic, in which, -CH ₂ - oxidized is that it is replaced by a nitrogen atom constituting the ring is optionally - group -C (O) optionally is Can be formed to form an N-oxide. Examples of such heteroaryls are thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl. , Benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinolinolyl.

The term “heterocyclic group” or “heterocycle” as used herein, unless otherwise specified, is a fully saturated ring-constituting heteroatom of up to five selected from nitrogen, oxygen and sulfur. containing a monocyclic or bicyclic 5-14 membered ring, in which, -CH ₂ - group is -C (O) optionally - may be substituted with. Examples of such heterocyclic groups include morpholinyl, pyrrolidinyl, imidazolidinyl,
Mention may be made of pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.

Here, when any substituent is selected from “one or more” groups, a compound in which all the substituents are selected from one of the specified groups,
And substituents are meant to include compounds in which two or more of the specified groups are selected.

General aspects of the methods, processes and examples described herein are as follows. Concentration was performed by rotary evaporation under reduced pressure. The operation was carried out in a nitrogen atmosphere at ambient temperature, 18-26 ° C.
Column chromatography (flash method) was performed using Merck Kieselgel silica (Art. 9385) unless otherwise stated. The yields are given as examples and are not always the highest obtained.

The structure of the final product of formula I was generally confirmed by NMR and mass spectroscopy. Proton magnetic resonance spectra are, unless otherwise explained,
Measured in DMSO-d ₆ using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz, chemical shifts are measured by internal standard ((scale)
In the ppm downfield from tetramethylsilane, the multiplicity of peaks is therefore: S, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublet; t,
Triplet, dt, triplet double, m, multiplet; bm, shown as broad multiplet, fast-atom bombardment (fa
Data for st-atom bombardment (FAB) mass spectra were obtained by operating a Platform spectrometer (supplied by Micormass) in electrospray. As needed,
Collect either positive or negative ion data, where (M +
H) ⁺ is quoted. IR data was measured by Nicolet Avatar 360 FT-IR. Intermediates were generally not fully characterized and purity was generally confirmed by mass spectroscopy (MS) or NMR analysis.

Meanings of abbreviations and the like are shown below. CDCl ₃ Deuterated chloroform CMC 1-Cyclohexyl-3- (2-morpholinoethyl) carbodiimide meta (metho) -p-toluenesulfonate DCM dichloromethane DCU dicyclohexylurea DHC 1,3-dicyclohexylcarbodiimide DMAP 4- (dimethyl Amino) pyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide m / s mass spectroscopy NMP N-methylpyrrolidinone NMR nuclear magnetic resonance p.o. per os; THF tetrahydrofuran t.i.d. The examples and test examples described above are provided for the purpose of explanation.
It is not intended to limit the invention.

[0038]

【Example】

Example 1: (+/-)-7-chloro-4-hydroxy-2- (3-pyridyleth-1-yl)
-1,2,5,10-Tetrahydropyridazino [4,5-b] quinoline-dione methanesulfonate N- (1-aza-2- (3-pyridyl) prop-1-enyl) (t-butoxy)
Carboxamide To a stirred solution of t-butylcarbazate (2.18 g, 16.5 mmol) in THF (40 mL) was added 3-acetylpyridine (2.00 g, 16.5 mmol) followed by 3 drops of concentrated hydrochloric acid. . After 1 hour, the reaction mixture became cloudy and the solvent was removed under vacuum. The resulting solid was triturated with hexane and filtered to give the title compound as a white solid (3.58g, 93%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.48 (s, 9H); 7.43 (dd, 1H, J = 4.2, 8
.0 Hz); 8.10 (dt, 1H, J = 1.5, 8.0 Hz); 8.55 (d, 1H, J = 4.2 Hz); 8.9
0 (s, 1H); 10.00 (s, 1H).

(+/−)-(t-butoxy) -N-[(3-pyridylethyl) amino] carboxamide N- (1-aza-2- (3-pyridyl) prop-1-enyl) (t- Butoxy) carboxamide (1.0 g, 4.2 mmol) was dissolved in methyl alcohol (80 mL) and placed in a Parr shaking bottle. To this was added 10% Pd / C (250 mg) and the reaction mixture was hydrogenated at 40 psi for 24 hours. The mixture was filtered through diatomaceous earth and washed with methyl alcohol (3 x 100 mL). The combined filtrate and washings were concentrated under vacuum. The resulting oil (about 1.0 g) was used in the next reaction without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.19 (d, 3H, J = 9 Hz); 1.33 (s, 9H);
4.14 (m, 1H); 4.81 (m, 1H); 7.31 (m, 1H); 7.31 (m, 1H); 8.43 (dd, 1H
, J = 1.5, 2.4 Hz); 8.49 (d, 1H, J = 1.5 Hz).

Dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate Methyl 2-amino-4-chlorobenzoate (in t-butanol (22 mL)
2.50 g, 13.5 mmol) and dimethyl acetylenedicarboxylate (2.
A stirred mixture of 05 g, 14.4 mmol) was refluxed under a nitrogen atmosphere for 7 hours. After adding additional dimethyl acetylenedicarboxylate (1.16 g, 8.13 mmol) and refluxing for an additional 2.5 hours, the reaction mixture was allowed to come to room temperature and potassium t-
Butoxide (1.56 g, 13.9 mmol) was added in one portion. A precipitate forms,
The resulting mixture was refluxed for 1.5 hours. The mixture was cooled to room temperature, filtered and the solid separated was washed with t-butanol and diethyl ether. Dissolve the solid in water,
Acidified with N sulfuric acid to form a precipitate. The resulting mixture was extracted with DCM, and the combined extracts were washed with brine and water, dried over MgSO _4, filtered to give a green solid and concentrated. This material was recrystallized from methanol to give the title compound (1.15 g, 47%) as an off-white solid. mp 232-233 ° C; MS (Cl): 296 (M + H). Analysis for C ₁₃ H ₁₀ ClNO ₅ : Calculated.
: C, 52.81; H, 3.41; N, 4.74; Measured value: C, 52.75; H, 3.47; N, 4.69.

3-Carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid Dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (1.0 g, 3 An aqueous solution of sodium hydroxide (0.27 g, 6.75 mmol) was added to a stirred suspension of 0.38 mmol. The suspension dissolved after the addition. The reaction mixture was warmed to 60 ° C. for 1 hour. After this time, the reaction mixture was cooled to room temperature and acidified with concentrated hydrochloric acid. The product was then extracted into dimethyl ether and ethyl acetate. The organic extract was dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a solid (900mg). This material was purified by recrystallisation using ethyl acetate / hexane cosolvent system to give the title compound as a white solid (571 mg, 6
0%). mp 296 ℃ (dec); MS (CI) = 238 (M + H). C ₁₂ H ₈ NO ₅ Cl ・ 0.45 CH ₃ CO ₂ CH ₂ CH ₃・
Analysis for 0.10 H ₂ O: Calculated: C, 51.30; H, 3.68; N 4.34, Found: C, 51.28; H, 3.62; N 3.97 ¹ H NMR 8.22 (d, J = 8.7 Hz, 1H), 7.92 (d, J =
1.8 Hz, 1H), 7.28 (dd, J = 8.7, 1.8 Hz, 1H), 3.90 (s, 3H).

3-Carbomethoxy-2-pyrrolidinocarbamide-7-chloro-4-hydroxyquinoline 3-carbomethoxy-7-chloro-4-hydroxyquinoline-2-carboxylic acid (2.25 g) in THF (20 mL). , 8.0 mmol) and DHC (1.65 g, 8.0 mmol) and pyrrolidine (0.596 g, at room temperature under N ₂ atmosphere).
8.4 mmol) was added. The reaction mixture was stirred for 15 hours at room temperature, after which the by-product urea was removed by filtration. The desired product was purified by flash column chromatography using 5% methanol in chloroform to give the title compound as a brown solid (2.52 g, 94.3%). mp = 215 ° C; MS (CI): 335 (M + H). 300 MHz ¹ H NMR (DMSO-d ₆ ): δ 8.12
(d, J = 8.7 Hz, 1H), 7.60 (d, 1H, J = 1.8 Hz), 7.47 (dd, 1H, J = 8.8, 2.
0 Hz), 3.69 (s, 3H), 3.40-3.49 (m, 2H), 3.27-3.33 (m, 2H), 1.80- 1.96 (m
, 4H).

7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3
-Carboxylic acid 3-carbomethoxy-2-pyrrolidinocarbamide in deionized water (40 mL)-
An aqueous solution of potassium hydroxide (882 mg, 15.75 mmol) (20 mL) was added dropwise to a suspension of 7-chloro-4-hydroxyquinoline (2.52 g, 7.5 mmol). After the addition was complete, the reaction mixture was warmed to 60 ° C. After 3 hours, the reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was then acidified to pH = 1, producing a white precipitate. The solid is isolated by vacuum filtration, washed with water and kept under vacuum at 30 ° C. for 16 hours.
Dried in. The title compound (1.5 g, 64%) was obtained as a white solid. mp = 225-8 ° C; MS (CI): 321 (M + H). 300 MHz ¹ H NMR (DMSO-d ₆ ): δ 8.2
8 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.64 (d, 1H, J = 8.7), 3.52-3.57 (m
, 2H), 3.17-3.19 (m, 2H), 1.83-1.98 (m, 4H).

(+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N- (3-pyridylethyl) ) Carboxamide CMC (2.42 g) in a stirred slurry of 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid (1.2 g, 3.82 mmol) in THF (40 mL). (5.73 mmol) was added and the reaction mixture was stirred for 5 minutes, to which mixture (+/-)-(t-butoxy) -N in THF (20 mL) was added.
A solution of-[(3-pyridylethyl) amino] carboxamide (1.0 g, 4.21 mmol) and DMAP (0.080 g, 0.65 mmol) was added dropwise. The mixture was stirred at room temperature overnight and then refluxed for 3 hours. The reaction mixture was filtered and the collected solid washed with DCM (2 x 150 mL). The combined filtrate and washings were concentrated under vacuum and dried. The resulting yellow foam was chromatographed (silica gel, 95/5 chloroform / methyl alcohol) to give the title compound as a yellow foam (0
.860 g, 41%).

(+/-)-7-Chloro-4-hydroxy-2- (3-pyridyleth-1-yl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline- 1,10
-Dione methanesulfonate (+/-)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl]-in THF (30 mL). N- (3-pyridylethyl) carboxamide (0.860 g, 1.50)
Methanesulfonic acid (4 mL) was added to a stirred solution of (mmol) and the reaction mixture was stirred overnight. Volatiles were removed under vacuum and the resulting oil was poured onto crushed ice.
To this mixture was carefully added 10N sodium hydroxide until a solid precipitate formed. The solution was filtered to give an orange solid. This material was washed with diethyl ether and then sonicated for 15 minutes in 20 mL of 1/1 diethyl ether / methyl alcohol. The insoluble material was collected and washed with the same solvent system to give the title compound as an off-white powder (0.402 g, 54%). (mp> 280 ℃). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.75 (d, 3H, J = 6.9 Hz); 2.34 (s, 3H,
CH ₃ SO ₃ H); 6.33 (q, 1H, J = 6.9 Hz); 7.45 (dd, 1H, J = 1, 5, 8.7 Hz);
7.96 (m, 1H); 8.03 (s, 1H); 8.15 (d, 1H, J = 8.7 Hz); 8.42 (d, 1H, J
= 7.8 Hz); 8.82 (d, 1H, J = 4.8 Hz); 8.91 (s, 1H), 12.04 (s, 1H); 12
.72 (s, 1H) .Calculated for C ₁₈ H ₁₃ ClN ₄ O ₃・ CH ₃ SO ₃ H ・ 1.5 H ₂ O: C, 46.39; H,
4.09; N, 11.38. Actual value: C, 46.35; H, 3.94; N, 11.21.

Example 2: (+/−)-7-Chloro-4-hydroxy-2- (4-pyridyleth-1-yl) -1,2,5,10-tetrahydropyridazino [4,5- b] quinoline-1,10
-Dione methanesulfonate N- (1-aza-2- (4-pyridyl) prop-1-enyl) (t-butoxy)
Carboxamide To a stirred solution of t-butylcarbazate (2.18 g, 16.5 mmol) in THF (40 mL) was added 4-acetylpyridine (2.00 g, 16.5 mmol) followed by 3 drops of concentrated hydrochloric acid. . After 1 hour, the reaction mixture became cloudy and the solvent was removed under vacuum. The resulting solid was triturated with hexane and filtered to give the title compound as a white solid (3.88g, 100%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.47 (s, 9H); 7.55 (dd, 2H, J = 1.5, 4
.5 Hz); 7.97 (s, 1H); 7.99 (d, 2H, J = 4.5 Hz); 11.22 (s, 1H).

(+/−)-(t-butoxy) -N-[(4-pyridylethyl) amino] carboxamide N- (1-aza-2- (4-pyridyl) prop-1-enyl) (t- Butoxy) carboxamide (2.0 g, 8.51 mmol) in ethyl alcohol (90 mL)
And dissolved in Parr shaker bottle. To this was added 10% Pd / C (500 mg) and the reaction mixture was hydrogenated at 40 psi for 24 hours. The mixture was filtered through diatomaceous earth and washed with methyl alcohol (3 x 100 mL). The combined filtrate and washings were concentrated under vacuum. The resulting material was triturated with 90/10 hexane / DCM to give the title compound as a white solid (1.34g, 66%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.19 (d, 3H, J = 6.6 Hz); 1.34 (s, 9H)
; 4.09 (m, 1H); 4.86 (m, 1H); 7.35 (d, 2H, J = 5.7 Hz); 8.21 (s, 1H)
; 8.47 (d, 2H, J = 5.7 Hz).

(+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N- (4-pyridylethyl) ) Carboxamide CMC in a stirred slurry of 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid of Example 1 (1.66 g, 5.17 mmol) in THF (40 mL). (2.82 g, 6.72 mmol) was added and the reaction mixture was stirred for 5 min.To this mixture (+/-)-(t-butoxy) -N-[(4-pyridyl) in THF (20 mL). A solution of ethyl) amino] carboxamide (1.3 g, 5.69 mmol) and DMAP (0.08 g, 0.65 mmol) was added dropwise, the reaction mixture was stirred for 2 h at room temperature before additional CMC (0 . 500 g) was added and the mixture was refluxed overnight The solution was cooled to 50 ° C. and another portion of diimide (0.
500 g) was added and the mixture was refluxed for 3 hours. The cooled reaction mixture was filtered and the collected insoluble material was washed with DCM (2 x 150 mL). The combined filtrate and washings were concentrated under vacuum and dried. The resulting yellow foam was chromatographed (silica gel, 92/8 chloroform / methyl alcohol) to give the title compound as a yellow foam (2.04g, 73%).

(+/−)-7 Chloro-4-hydroxy-2- (4-pyridyleth-1-yl)
-1,2,5,10-Tetrahydropyridazino [4,5-b] quinoline-1,10-
Dione methanesulfonate (+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N in THF (100 mL). To a stirred solution of-(4-pyridylethyl) carboxamide (2.04 g, 3.8 mmol) was added methanesulfonic acid (13.5 mL) and the reaction mixture was stirred overnight.Volatile material was removed under vacuum. The resulting oil was poured into crushed ice, a fine precipitate formed and filtered to give an orange solid, which was washed with diethyl ether and then for 15 minutes 1/1 diethyl ether / methyl alcohol. 40 mL
Sonicated in. This material was washed with diethyl ether to give the title compound as an off-white powder (0.715g, 40%), mp 245-248 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.74 (d, 3H, J = 6.9 Hz); 2.31 (s, 3H,
CH ₃ SO ₃ H); 6.24 (q, 1H, J = 6.9 Hz); 7.45 (dd, 1H, J = 1.8, 8.7 Hz);
7.86 (m, 2H); 8.05 (d, 1H, J = 1.8 Hz); 8.14 (d, 1H, J = 8.7 Hz); 8.8
2 (m, 2H); 12.03 (s, 1H); 12.71 (s, 1H). Calculated value for C ₁₈ H ₁₃ ClN ₄ O ₃・ CH ₃ SO ₃ H ・ 0.8 H ₂ O: C, 47.61; H, 3.91; N, 11.68.Actual value: C, 47.84; H, 3
.79; N, 11.54.

Example 3: (+/−)-7-Chloro-4-hydroxy-2- (4-pyridylprop-1-yl) -1,2,5,10-tetrahydropyridazino [4,5] -B] quinoline-1,1
0-Dione sodium methanesulfonate N-1-aza-2- (4-pyridyl) vinyl) (t-butoxy) carboxamide of t-butylcarbazate (1.94 g, 14.7 mmol) in THF (50 mL). 4-Pyridinecarboxaldehyde (1.57 g, 14.7 mmol) was added to the stirring solution. The reaction mixture was stirred for 18 hours and the solvent was removed. The solid obtained was triturated with hexane, filtered and the title compound obtained as a white solid (3.25 g, 100%) was used without further purification.

(+/−)-(t-Butoxy) -N-[(4-pyridylpropyl) amino] carboxamide N-1-aza-2- (4-pyridyl) vinyl) (t-butoxy) in THF To a stirred solution of carboxamide (2.0 g, 9.40 mmol) was added ethylmagnesium bromide (18.0 mL, 18.8 mmol, 2M solution in THF) slowly at 0 ° C. The solution was stirred for 4 hours, during which time it warmed to room temperature. The volatiles were removed and the reaction mixture was carefully quenched with saturated ammonium chloride solution (30 mL). The aqueous layer was extracted with ethyl acetate (300 mL), then the organic layer was washed with brine.
The organic layer dried over MgSO _4, the solution was concentrated under vacuum. The material was chromatographed (SiO ₂ , ethyl acetate as eluent) to give the title compound as a yellow oil (0.400 g, 18%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.73 (t, 3H, J = 7.5 Hz); 1.44 (m, 2H)
3.92 (br s, 1H); 4.78 (m, 1H); 7.31 (m, 2H); 8.48 (m, 2H).

(+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N- (4-pyridylpropyl) ) Carboxamide CMC in a stirred slurry of 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid of Example 1 (1.22 g, 3.82 mmol) in THF (80 mL). (1.77 g, 4.20 mmol) was added and the reaction mixture was stirred for 5 min.To this mixture (+/-)-(t-butoxy) -N-[(4-pyridyl) in THF (20 mL). Propyl) amino] carboxamide (0.96
g, 3.82 mmol) and DMAP (0.080 g, 0.65 mmol) were added dropwise and the mixture was stirred for 1 h at room temperature. Additional CMC (0.300 g) was added and the mixture was refluxed overnight. The solution was filtered and the insoluble material was washed with DCM (2 x 150 mL). The mother liquor was collected, concentrated and dried. The resulting yellow foam was chromatographed (SiO ₂ , 95/5 chloroform / methyl alcohol) to give the title compound as a yellow foam (1.72 g, 81%).

(+/−)-7-Chloro-4-hydroxy-2- (4-pyridylprop-1-yl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline -1,1
0-dione sodium methanesulfonate (+/-)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl) in THF (60 mL). ] -N- (4-Pyridylpropyl) carboxamide (1.72 g, 1.5 mmol) was added methanesulfonic acid (9 mL) and the reaction mixture was stirred overnight.Volatile material was removed under vacuum. The resulting oil was poured into crushed ice and 10N sodium hydroxide was carefully added to the mixture until a solid precipitate formed.
The solution was filtered to give an orange solid. The material was washed with diethyl ether and then sonicated in 40 mL of 3/1 diethyl ether / methyl alcohol for 15 minutes. The material was washed with diethyl ether to give the title compound (0.57 as an off-white powder.
7 g, 28%) was obtained. (mp> 265 C). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.88 (t, 3H, J = 7.2 Hz); 2.16 (m, 2H)
; 2.31 (s, 3H, CH ₃ SO ₃ H); 5.98 (dd, 1H, J = 5.7, 9.46 Hz); 7.44 (m, 3H
); 8.05 (d, 1H, J = 1.5 Hz); 8.15 (d, 1H, J = 8.7 Hz); 8.58 (m, 2H);
12.04 (s, 1H); 12.69 (s, 1H). C ₁₈ H ₁₃ ClN ₄ O ₃・ 2 CH ₃ SO ₃ Na ・ H ₂ O Calculated: C, 39.59; H, 3.63; N, 8.79. Values: C, 39.73; H, 3.33; N, 8.9
Four.

Example 4: (+/−)-7-chloro-4-hydroxy-2- (propyl-1- (2-pyridyl))-1,2,5,10-tetrahydropyridazino [4, 5-b] quinoline-1,
10-dione methanesulfonate 1-2- (pyridyl) propan-1-one To a stirred solution of 2-cyanopyridine (1.13 g, 10.8 mmol) in diethyl ether (10 mL) at 0 ° C was added ethylmagnesium bromide (16 mL). , 16.0 mmol, 1M solution in THF) was added slowly. The mixture was stirred for 2 hours and then placed in the refrigerator overnight. The reaction mixture was then carefully quenched with saturated ammonium chloride (2 mL) and then acidified with 15% aqueous hydrochloric acid (3 mL). The mixture was stirred for 20 minutes and then made basic by adding 10N sodium hydroxide until the pH was about 9. Ethyl acetate (300 mL) was added to this solution, and the aqueous layer was extracted. The organic layer was washed with brine, dried over MgSO _4, evaporated to dryness,
The title compound was obtained as a yellow oil (1.24 g, 85%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.09 (t, 3H, J = 7.2 Hz); 3.18 (q, 2H,
J = 7.2 Hz); 7.67 (m, 1H); 7.99 (m, 2H); 8.72 (m, 1H).

N- (1-Aza-2- (2-pyridyl) but-1-enyl) (t-butoxy) carboxamide t-Butylcarbazate (1.21 g, 9.15 mmol) in THF (50 mL). ) To a stirred solution of 1-2- (pyridyl) propan-1-one (1.24 g, 9.15).
Mmol) followed by 3 drops of concentrated hydrochloric acid. After 2 hours another 2 drops of concentrated hydrochloric acid was added. The reaction mixture was stirred overnight and the solvent was removed under vacuum. The resulting solid was triturated with hexane and filtered to give the title compound as a white solid (2.25g, 98%).
). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.09 (t, 3H, J = 7.2 Hz); 3.18 (q, 2H,
J = 7.2 Hz); 7.60 (m, 1H); 7.85 (s, 1H); 8.00 (m, 2H); 8.72 (d, 1H,
J = 4.5 Hz).

(+/−)-(t-Butoxy) -N-[(2-pyridylpropyl) amino] carboxamide N- (1-aza-2- (2-pyridyl) but-1-enyl) (t- Butoxy)
Carboxamide (2.25 g, 9.03 mmol) in methyl alcohol (90 mL)
And dissolved in Parr shaker bottle. To this was added 10% Pd / C (500 mg) and the reaction mixture was hydrogenated for 18 hours at 40 psi. The catalyst was filtered over diatomaceous earth, washed with methyl alcohol (2 x 300 mL) and the solvent removed under vacuum to give a white solid (1.34 g, 70%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.74 (t, 3H, J = 7.2 Hz); 1.34 (s, 9H)
; 1.68 (m, 2H); 3.92 (m, 1H); 4.72 (m, 1H); 7.22 (dd, 1H, J = 1.5, 4
.4 Hz); 7.46 (d, 1H, J = 7.8 Hz); 7.75 (app dt, 1H, J = 1.5, 7.8 Hz);
8.15 (s, 1H); 8.46 (m, 1H).

(+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N- (2-pyridylpropyl) ) Carboxamide To a stirred slurry of 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid of Example 1 in THF (60 mL) was added CMC (1.
77 g, 4.20 mmol) was added and the reaction mixture was stirred for 5 minutes. To this mixture was added (+/-)-(t-butoxy) -N-[(2-pyridylpropyl) amino] carboxamide (2.00 g, 6.23 mmol) in THF (20 mL) and DMA.
A solution of P (0.080 g, 0.65 mmol) was added dropwise and the mixture was stirred for 1 hour at room temperature. The mixture was then refluxed overnight. The solution was filtered and the insoluble material was washed with DCM (2 x 15
It was washed with 0 mL). The mother liquor was collected, concentrated and dried. The resulting yellow foam was chromatographed (SiO ₂ , 90/10 chloroform / methyl alcohol) to give the title compound as a yellow foam (3.00 g, 87%).

(+/−)-7-Chloro-4-hydroxy-2- (propyl-1- (2-pyridyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline -1,1
0-dione methanesulfonate (+/-)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] in THF (100 mL). -N- (2-pyridylpropyl) carboxamide (3.00 g, 5.4)
To a stirred solution of (2 mmol) methanesulfonic acid (15 mL) was added and the reaction mixture was stirred overnight. Volatiles were removed under vacuum and the resulting oil was poured onto crushed ice. 10N sodium hydroxide (22 mL) until a solid precipitate formed in this mixture
Was carefully added. The solution was filtered to give an orange solid. This material was washed with diethyl ether, sonicated in 20 mL of water for 15 minutes, filtered and then sonicated in 20 mL of 3/1 diethyl ether / methyl alcohol for 15 minutes. The material was filtered and washed with diethyl ether to give the title compound (0.5 as an off-white powder.
60 g, 21%) was obtained (mp 185-188 ° C). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.90 (t, 3H, J = 7.2 Hz); 2.26 (m, 2H)
; 2.32 (3H, CH ₃ SO ₃ H); 6.05 (dd, 1H, J = 5.1, 10.5 Hz); 7.47 (m, 3H);
8.02 (m, 2H); 8.13 (d, 1H, J = 8.7 Hz); 8.65 (d, 1H, J = 4.5 Hz); 12
.00 (br s, 1H); 12.65 (br s, 1H). Calculated value for C ₁₉ H ₁₅ ClN ₄ O ₃・ CH ₃ SO ₃ H ・ 0.3H ₂ O: C, 49.60; H, 4.07; N, 11.56; Measured value: C, 49.52; H, 4.22; N
, 11.89.

Example 5: (+/−)-7-chloro-4-hydroxy-2- (propyl-1- (3-pyridyl))-1,2,5,10-tetrahydropyridazino [4, 5-b] quinoline-1,
10-dione methanesulfonate N- (1-aza-2- (3-pyridyl) prop-1-enyl) (t-butoxy)
Carboxamide To a stirred solution of t-butylcarbazate (1.94 g, 14.7 mmol) in THF (50 mL) 1- (3-pyridyl) propan-1-one (2.00 g, 14.7).
Mmol) followed by 3 drops of concentrated hydrochloric acid. After 2 hours the reaction mixture became cloudy and the solvent was removed under vacuum. The resulting solid was triturated with hexane and filtered to give the title compound as a white solid (3.66g, quantitative recovery). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.98 (t, 3H, J = 7.5 Hz); 1.49 (s, 9H)
2.75 (q, 2H, J = 7.5 Hz); 7.44 4 (dd, 1H, J = 4.8, 8.0 Hz); 8.10 (a
pp dt, 1H, J = 1.8, 8.0 Hz); 8.56 (d, 1H, J = 4.0 Hz); 8.89 (s, 1H);
10.16 (s, 1H).

(+/−)-(t-Butoxy) -N-[(3-pyridylpropyl) amino] carboxamide N- (1-aza-2- (3-pyridyl) but-1-enyl) (t- Butoxy)
Carboxamide (2.00 g, 8.02 mmol) in methyl alcohol (60 mL)
And dissolved in Parr shaking bottle. To this was added 10% Pd / C (500 mg) and the reaction mixture was hydrogenated for 18 hours at 40 psi. The catalyst was filtered over diatomaceous earth, washed with methyl alcohol (2 x 300 mL) and the solvent removed under vacuum to give a white solid (1.34 g, 73%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.71 (t, 3H, J = 7.5 Hz); 1.34 (s, 9H)
; 1.43 (m, 1H); 1.68 (m, 1H); 3.92 (m, 1H); 4.75 (m, 1H); 7.32 (m,
2H); 7.70 (app dt, 1H, J = 1.5, 7.8 Hz); 8.15 (s, 1H); 8.43 (d, 1H, J
= 1.5 Hz).

(+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N- (3-pyridylpropyl) ) Carboxamide CMC into a stirred slurry of 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid of Example 1 (1.87 g, 5.80 mmol) in THF (60 mL). (2.69 g, 6.35 mmol) was added and the reaction mixture was stirred for 5 min.To this mixture (+/-)-(t-butoxy) -N-[(3-pyridyl) in THF (20 mL). Propyl) amino] carboxamide (1.47)
g, 5.80 mmol) and DMAP (0.070 g, 0.58 mmol) were added dropwise and the mixture was stirred for 1 h at room temperature. The mixture was then refluxed overnight. Filter the solution,
The insoluble material was washed with DCM (2 x 150 mL). The mother liquor was collected, concentrated and dried. The resulting yellow foam was chromatographed (SiO ₂ , gradient gradient starting at 99/1 respectively in chloroform / methyl alcohol and ending at 90/10) to give the title compound as a yellow foam (2. 70 g, 85%).

(+/−)-7-Chloro-4-hydroxy-2- (propyl-1- (3-pyridyl))-1,2,5,10-tetrahydropyridazino [4,5-b] Quinoline-1,
10-dione methanesulfonate (+/-)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] in THF (100 mL). -N- (3-pyridylpropyl) carboxamide (2.70 g, 4.9)
To a stirred solution of 3 mmol) was added methanesulfonic acid (15 mL) and the reaction mixture was stirred overnight. Volatiles were removed under vacuum and the resulting oil was poured onto crushed ice. 10N sodium hydroxide (22 mL) until a solid precipitate formed in this mixture
Was carefully added. The solution was filtered and dried to give an orange solid. This material was washed with diethyl ether, sonicated in 20 mL water for 15 minutes, filtered and then sonicated in 20 mL 5/1 diethyl ether / methyl alcohol for 15 minutes. The material was filtered and washed with diethyl ether. The material was suspended in methyl alcohol (5 mL) and to this was added methanesulfonic acid (ca. 0.060 mL). Diethyl ether (about 30 mL) was added to this solution to precipitate the material. The suspension was sonicated in the same solvent for 15 minutes, filtered and washed with diethyl ether to give the title compound (0.350 g, 12%) as an off-white solid. (mp 248-250 ℃). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.89 (t, 3H, J = 7.2 Hz); 2.18 (m, 1H)
2.26 (m, 1H); 2.32 (CH ₃ SO ₃ H); 6.09 (dd, 1H, J = 5.1, 9.7 Hz); 7.44
(dd, 1H, J = 1.5, 8.5 Hz); 7.84 (app t, 1H, J = 5.4 Hz); 8.04 (d, 1H,
J = 1.5 Hz); 8.15 (d, 1H, J = 8.7 Hz); 8.31 (d, 1H, J = 7.8 Hz); 8.74
(br s, 1H); 8.84 (br s, 1H); 12.01 (br s, 1H); 12.69 (br s, 1H). C ₁₉ H ₁₅ ClN ₄ O ₃・ 2 CH ₃ SO ₃ H ・ 0.2 H ₂ Calculated for O: C, 43.08; H, 4.07; N, 9.5
2; Measured value: C, 43.37; H, 3.78; N, 9.69

Example 6: (+/−)-7-chloro-4-hydroxy-2- (butyl-1- (2-pyridyl))-1,2,5,10-tetrahydropyridazino [4, 5-b] quinoline-1,1
The title compound was prepared from 0-dione methanesulfonate 1- (2-pyridyl) butan-1-one in a manner analogous to the procedure described in Example 5 to give an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.95 (t, 3H, J = 7.5 Hz); 1.32 (m, 2H)
, 2.22 (m, 2H); 2.33 (3H, CH ₃ SO ₃ H); 6.17 (t, 1H, J = 7.8 Hz); 7.45 (d
d, 1H, J = 1.8 Hz, 8.7 Hz); 7.53 (m, 2H), 8.03 (m, 2H); 8.14 (d, 1H, J
= 8.7 Hz); 8.64 (d, 1H, J = 4.8 Hz); 12.59 (br s, 1H). C ₁₉ H ₁₅ ClN ₄ O ₃
1.3 Calculated value for 3CH ₃ SO ₃ H ・ 1H ₂ O: C, 47.39; H, 4.51; N, 10.37. Measured value:
C, 47.60; H, 4.36; N, 10.51.

Example 7: (+/−)-7-chloro-4-hydroxy-2- (butyl-1- (4-pyridyl))-1,2,5,10-tetrahydropyridazino [4, 5-b] quinoline-1,1
0-dione 1-4- (pyridyl) butan-1-one 4-pyridinecarboxaldehyde dimethyl acetal (Sheldrake PW, Sy
nth. Commun. 1993 23 (14), 1967) (3.36 g, 21.9 mmol) was dissolved in THF (30 mL) under a nitrogen atmosphere and cooled to -78 ° C in a dry ice / acetone bath. To this solution was slowly added n-butyllithium (9.22 mL, 23.05 mmol, 2.5 M in hexane). After 15 minutes bromopropane (2.78 g,
2.05 mL, 22.5 mmol) was added and the reaction mixture was stirred for 3 h at -78 ° C. The reaction mixture was then warmed to room temperature overnight. To this mixture was added potassium bicarbonate (saturated aqueous solution, 50 mL) and diethyl ether (50 mL). The layers were separated and the organic layer was dried over Na ₂ SO ₄ and concentrated to a brown oil. The residue is converted to formic acid (43
mL) and stirred at 80 ° C. for 1.5 hours. Formic acid was removed under vacuum and sodium bicarbonate (saturated aqueous solution) was added to the remaining material until the pH was about 8. The aqueous layer was then extracted with DCM and dried over Na ₂ SO ₄ . The organic layer was concentrated to give the title compound as an oil (2.8g, 87%). MS (+ CI) m / z 149.94
.

(+/−)-7-Chloro-4-hydroxy-2- (butyl-1- (4-pyridyl))-1,2,5,10-tetrahydropyridazino [4,5-b] Quinoline-1,1
0-Dione The title compound was prepared from 1- (4-pyridyl)) butan-1-one as a starting material in an analogous manner to the procedure described in Example 5. PH conversion to free base
Was titrated with 1N sodium hydroxide until the pH was neutral. The resulting precipitate was collected by vacuum filtration, washed with diethyl ether, dried under vacuum,
The title compound was obtained as an off-white solid (29%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.92 (t, 3H, J = 7.2 Hz); 1.25 (m, 2H)
, 2.01 (m, 1H); 2.17 (m, 1H); 2.22 (m, 2H); 6.17 (t, 1H, J = 7.8 Hz)
; 7.33 (d, 2H, J = 5.1 Hz); 7.45 (d, 1H, J = 8.7 Hz); 7.53 (m, 2H), 8.
03 (m, 2H); 8.14 (d, 1H, J = 8.7 Hz); 8.52 (d, 2H, J = 5.1 Hz); 11.93
(br s, 1H); 12.57 (br s, 1H). Calculations for the value C ₂₀ H ₁₇ ClN ₄ O ₃ · 0.75H ₂ O: C,
58.77; H, 4.54; N, 13.65. Actual value: C, 58.53; H, 4.31; N, 13.37.

Example 8: (+/−)-7-chloro-4-hydroxy-2- (propyl- (2-methyl-1)
-(4-Pyridyl))-1,2,5,10-tetrahydropyridazino [4,5-b]
Quinoline-1,10-dione methanesulfonate Using 2-bromopropane as a starting material, the title compound was prepared in a similar manner to the procedure described in Example 7 to give an off-white powder. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.84 (d, 3H, J = 6.6 Hz); 0.95 (d, 3H,
J = 6.6 Hz); 2.70 (m, 1H); 2.32 (s, 3H, CH ₃ SO ₃ H); 5.75 (d, 1H, J = 1
0.5 Hz); 7.43 (d, 1H, J = 8.7 Hz), 7.94 (d, 2H, J = 6.3 Hz); 8.03 (s,
1H); 8.14 (d, 1H, J = 8.7 Hz); 8.85 (d, 2H, J = 6.3 Hz); 12.02 (br s,
1H); 12.76 (br s, 1H). C ₂₀ H ₁₇ ClN ₄ O ₃・ 1.0 CH ₃ SO ₃ H ・ 1.0 H ₂ O Calculated value: C, 47.86; H, 4.64; N, 10.58; Actual value: C, 47.85; H, 4.15; N, 10.
10.59.

Example 9: (+/−)-7-chloro-4-hydroxy-2- (propyl- (2-methyl-1)
-(2-Pyridyl))-1,2,5,10-tetrahydropyridazino [4,5-b]
Quinoline-1,10-dione methanesulfonate Using 2-pyridinecarboxaldehyde dimethylacetyl and 2-bromopropane as starting materials, the title compound was prepared in an analogous manner to the procedure described in Example 7, off-white. Of powder was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.84 (d, 3H, J = 6.6 Hz); 0.95 (d, 3H,
J = 6.6 Hz); 2.32 (s, 3H, CH ₃ SO ₃ H); 2.80 (m, 1H); 5.85 (d, 1H, J = 1
0.5 Hz); 7.43 (d, 1H, J = 8.7 Hz), 7.69 (t, 1H, J = 6.6 Hz), 7.85 (d, 1
H, J = 8.1 Hz); 8.03 (s, 1H); 8; 14 (d, 1H, J = 8.4 Hz); 8.20 (t, 1H
, J = 7.8 Hz); 8.74 (d, 1H, J = 4.2 Hz); 12.02 (br s, 1H); 12.71 (br
s, 1H). C ₂₀ H ₁₇ ClN ₄ O ₃・ 1 CH ₃ SO ₃ H ・ 1H ₂ O: C, 48.51; H, 4.65
; N, 10.70; Measured value: C, 48.36; H, 4.52; N, 10.51.

Example 10: (+/−)-7-chloro-4-hydroxy-2- (pentyl-1- (4-pyridyl))-1,2,5,10-tetrahydropyridazino [4, 5-b] quinoline-1,
10-dione methanesulfonate N-1-aza-2- (4-pyridyl) hex-1-enyl) (t-butoxy) carboxamide t-butyl carbazate (0.99 g, 7.54) in THF (50 mL). Mmol) in a stirred solution of 1-4- (pyridyl) pentan-1-one (1.23 g, 7.54
Mmol) followed by 3 drops of concentrated hydrochloric acid. The reaction mixture was stirred overnight and the solvent was removed under vacuum. The resulting solid was triturated with hexane to give the title compound as a white solid (2.15 g, quantitative recovery).

(+/−)-7-Chloro-4-hydroxy-2- (pentyl-1- (4-pyridyl))-1,2,5,10-tetrahydropyridazino [4,5-b] Quinoline-1,
10-dione methanesulfonate N-1-aza-2- (4-pyridyl) in an analogous manner to the procedure described in Example 7.
The title compound was prepared from hexa-1-enyl) (t-butoxy) carboxamide to give the title compound as an off-white powder. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.86 (t, 3H, J = 7.2 Hz); 1.24 (m, 2H)
; 1.35 (m, 2H); 2.15 (m, 2H), 2.33 (3H, CH ₃ SO ₃ H); 6.04 (dd, 1H, J = 5
.1, 10.2 Hz); 7.37 (d, 2H, J = 5.7 Hz); 7.43 (d, IH, J = 8.4 Hz), 8.03
(s, 1H); 8.14 (d, 1H, J = 8.4 Hz); 8.53 (d, 1H, J = 5.7 Hz); 11.97 (
br s, 1H); 12.62 (br s, 1H) .Calculated value for C ₂₁ H ₁₉ ClN ₄ O ₃・ 0.5CH ₃ SO ₃ H ・ 1H ₂ O: C, 54.14; H, 4.86; N, 11.74; Measured Values: C, 54.43; H, 4.35; N, 11.
95.

Example 11: (+/−)-7-chloro-4-hydroxy-2- (3-methyl-1- (2-pyridyl) butyl))-1,2,5,10-tetrahydropyrida 2-Cynopyridine (2.00 g, 19.00 g) in dino [4,5-b] quinoline-1,10-dione methanesulfonate 3-methyl-1 (2-pyridyl) butan-1-one diethyl ether (10 mL). 2 mmol) in a stirred solution of iso-butylmagnesium bromide (14.4 mL,
28.8 mmol, 2M solution in dimethyl ether) was added slowly. The mixture was stirred for 3 hours and then carefully quenched with saturated ammonium chloride (3 mL). The reaction mixture was then acidified with 15% aqueous hydrochloric acid solution (3 mL). 2 this mixture
Stir for 0 minutes and then basify by adding 10N sodium hydroxide until the pH is about 9. Ethyl acetate (300 mL) was added to this solution, and the aqueous layer was extracted with water (30 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness. The material obtained was chromatographed (SiO ₂ , hexane / ethyl acetate; 75/25) to give the title compound as a yellow oil (3.0 g, 9).
6%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.92 (s, 3H); 0.94 (s, 3H); 2.21 (m,
1H, J = 6.9 Hz); 3.05 (d, 2H, J = 6.9 Hz); 7.66 (m, 1H); 7.94 (m, 2H)
8.72 (m, 1H).

N- (1-aza-4-methyl-2- (2-pyridyl) pent-1-enyl) (t
-Butoxy) carboxamide To a stirred aqueous solution of t-butylcarbazate (2.43 g, 18.4 mmol) in THF (150 mL) was added 3-methyl-1 (2-pyridyl) butan-1-one (3.0).
g, 18.4 mmol), followed by 3 drops of concentrated hydrochloric acid. The reaction mixture was stirred overnight and the solvent was removed under vacuum. The resulting solid was triturated with hexane to give the title compound as a white solid (3.93 g, 79%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.85 (d, 3H, J = 6 Hz); 1.50 (s, 9H); 2.89 (d, 1H, J = 7.5 Hz); 7.33 (m, 1H ); 7.78 (t, 1H, J = 6.0 Hz); 7.
95 (d, 1H, J = 8.1 Hz); 8.53 (m, 1H); 10.17 (s, 1H).

(T-Butoxy) -N-[(3-methyl-1- (2-pyridyl) butyl) amino] carboxamide N- (1-aza-4-methyl-2- (2-pyridyl) penta-1 -Enyl) (
t-Butoxy) carboxamide (3.0 g, 10.8 mmol) was dissolved in methyl alcohol (90 mL) and placed in a Parr shaking bottle. 10% Pd / C (50
0 mg) was added and the reaction mixture was hydrogenated for 18 hours at 40 psi. The catalyst was filtered over diatomaceous earth, washed with methyl alcohol (2 x 300 mL) and the solvent removed under vacuum to give an oil. NMR spectroscopy showed that 30% of the starting material remained. The oil was then subjected to the same hydrogenation conditions as above. The catalyst was filtered over diatomaceous earth, washed with methyl alcohol (2 x 100 mL) and the solvent filtered under vacuum to give the title compound as an oil (1.89 g, 38%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.85 (d, 3H, J = 6 Hz); 1.27 (m, 1H);
1.33 (s, 9H); 1.45 (m, 2H); 4.08 (m, 1H); 4.65 (m, 1H); 7.20 (dd, 1
H, J = 1.8, 5.1 Hz); 7.42 (d, 1H, J = 7.8 Hz); 7.72 (dd, 1H, J = 1.8,
7.8 Hz); 8.11 (br s, 1H); 8.45 (d, 1H, J = 5.1 Hz).

(+/−)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl] -N-3-methyl-1 -(2-Pyridyl) butylcarboxamide 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid of Example 1 (2.28 g, 7.11 mmol) in THF (80 mL). ) Was added CMC (3.44 g, 8.12 mmol) and the reaction mixture was stirred for 5 min. (T-butoxy) -N in THF (20 mL) was added to the mixture.
-[(3-Methyl-1- (2-pyridyl) butyl) amino] carboxamide (1
A solution of 0.89 g, 6.77 mmol) and DMAP (0.10 g, 0.80 mmol) was added dropwise and the mixture was stirred for 1 h at room temperature. The mixture was then refluxed overnight. The solution was filtered hot and the insoluble material was washed with DCM (2 x 150 mL). The mother liquor was collected, concentrated and dried. The resulting solid was chromatographed (SiO ₂ , 95/5 chloroform / methyl alcohol) to give the title compound as a yellow foam (3.
58 g, 86%). This material was used as such in the next reaction.

(+/−)-7-Chloro-4-hydroxy-2- (3-methyl-1- (2-pyridyl) butyl) -1,2,5,10-tetrahydropyridazino [4,5 -B] quinoline-1,10-dione methanesulfonate (+/-)-N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinyl) in THF (100 mL). Carbonyl) (3-hydroquinolyl] -N-3-methyl-1- (2-pyridyl) butylcarboxamide (3
To a stirred solution of 0.58 g, 6.16 mmol) methanesulfonic acid (15 mL) was added and the reaction mixture was stirred overnight. Volatiles were removed under vacuum and diethyl ether (200 mL) was added to the remaining oil. The mixture was stirred for 10 minutes and then separated into two layers, an ether layer and a brown oil layer. The ether was decanted off and water (10 mL) was added to the brown oil. After a short time, a precipitate formed and was collected by vacuum filtration. The precipitate was washed with diethyl ether and sonicated in 20 mL of 4/1 diethyl ether / methyl alcohol for 15 minutes. The material was filtered, washed with diethyl ether and dried under vacuum to give the title compound as an off-white powder (1.0 g
, 30%). (mp> 204-207 ° C). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.93 (d, 3H, J = 6.9 Hz); 0.95 (d, 3H,
J = 6.9 Hz); 1.5 (m, 1H); 2.06 (m, 1H); 2.25 (m, 1H); 6.25 (dd, 1H,
J = 4.5, 10.5 Hz); 7.45 (m, 3H); 7.95 (t, 1H, J = 7.8 Hz); 8.05 (s,
1H); 8.15 (d, 1H, J = 8.7 Hz); 8.63 (d, 1H, J = 4.5 Hz); 12.00 (br s,
1H); 12.65 (br s, 1H) .MS (+ CI) m / z 411/413.

Example 12: (+/−)-7-chloro-4-hydroxy-2- (3-methyl-1- (4-pyridyl) butyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1,10-dione The title compound was prepared in an analogous manner to the procedure described in Example 11, using 4-cyanopyridine and isobutylmagnesium bromide as starting materials. The material obtained was precipitated from the aqueous solution by adding saturated aqueous sodium chloride solution. The precipitate was collected by vacuum filtration, washed with diethyl ether and dried under vacuum to give the title compound as an off-white solid (30%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 0.95 (t, 6H, J = 6.9 Hz); 1.5 (m, 1H)
; 1.88 (m, 1H); 2.22 (m, 1H); 6.22 (dd, 1H, J = 4.5, 10.5 Hz); 7.45 (
dd, 1H, J = 1.8, 8.7 Hz); 7.84 (d, 2H, J = 5.1 Hz); 8.05 (s, 1H); 8.1
5 (d, 1H, J = 8.7 Hz); 8.78 (d, 1H, J = 5.1 Hz); 12.00 (br s, 1H); 12
.75 (br s, 1H). C ₂₁ H ₁₉ ClN ₄ O ₃・ 1.6 CH ₃ SO ₃ Na ・ 1.2H ₂ O Calculated: C, 4
2.12; H, 4.09; N, 8.69; Measured value: C, 42.14; H, 4.00; N, 8.66.

Example 13: (+/−)-7-chloro-4-hydroxy-2- (1- (3-methoxypyrido-
4-yl)) ethyl-1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1,10-dione methanesulfonate 3-methoxy-4-cyanopyridine (LaMatting JL, et al
J. Org. Chem. 46, 4179-82, 1981) and methylmagnesium bromide,
The title compound was prepared in a manner similar to the procedure described in Example 11 to give the title compound as an off-white powder (31%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.64 (d, 3H, J = 7.2 Hz); 2.33 (CH ₃ SO ₃ H); 4.06 (s, 3H); 6.23 (q, 1H, J = 6.9 Hz); 7.45 (dd, 1H, J = 2.1, 8.
7 Hz); 7.66 (d, 1H, J = 5.7 Hz); 7.93 (d, 2H, J = 5.4 Hz); 8.05 (d, 1
H, J = 2.1 Hz); 8.14 (d, 1H, J = 8.7 Hz); 8.44 (d, 1H, J = 5.4 Hz); 8
.64 (s, 1H); 8.81 (d, 2H, J = 5.4 Hz); 12.03 (br s, 1H); 12.68 (br s,
1H). Calculated for C ₁₉ H ₁₅ ClN ₄ O ₃・ CH ₃ SO ₃ H ・ 2H ₂ O: C, 45.24; H, 4.36; N,
10.55; Measured value: C, 45.06; H, 4.24; N, 10.45.

Example 14: (+/−)-7-chloro-4-hydroxy-2- (1- (2-methoxypyrido-
5-yl)) ethyl-1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1,10-dione methanesulfonate 2-methoxy-5-cyanopyridine and methylmagnesium bromide as starting materials Was used to prepare the title compound in a manner similar to the procedure described in Example 11 to give the title compound as an off-white powder (22%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.64 (d, 3H, J = 7.2 Hz); 2.37 (CH ₃ SO ₃ H
); 3.83 (s, 3H); 6.20 (q, 1H, J = 7.2 Hz); 6.79 (d, 1H, J = 8.7 Hz);
7.45 (dd, 1H, J = 2.1, 8.7 Hz); 7.68 (dd, 1H, J = 2.4, 8.7 Hz); 8.01
(d, 1H, J = 2.1 Hz); 8.14 (d, 1H, J = 8.7 Hz); 8.16 (d, 1H, J = 2.4 Hz
) .Calculated for C ₁₉ H ₁₅ ClN ₄ O ₄・ 1.5CH ₃ SO ₃ H ・ 2H ₂ O: C, 42.53; H, 4.35; N,
9.68; Measured value: C, 42.47; H, 4.19; N, 9.73.

Example 15: (+/−)-7-chloro-4-hydroxy-2- (2-chloro-pyrid-3-yl) ethyl-1,2,5,10-tetrahydropyridazino [4 , 5-b] quinoline-
1,10-dione N- [1-aza-2- (2-chloro- (3-pyridyl)) prop-1-enyl)
(T-Butoxy) carboxamide The hydrazone starting material was used as a white foam in a similar manner to that of Example 11 using 2-chloro-3-cyanopyridine and methylmagnesium bromide (1.4M in toluene / THF). Produced (90%). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.54 (s, 9H); 2.25 (s, 3H); 7.25 (dd,
1H, J = 4.8, 7.2 Hz); 7.76 (br s, 1H); 7.85 (dd, 1H, J = 1.8, 7.5 Hz)
8.38 (dd, 1H, J = 1.8, 4.8 Hz).

(T-Butoxy) -N-[(2-chloro-3-pyridylethyl) amino] carboxamide N- [1-aza-2- (2-chloro- (3-pyridyl)] in methyl alcohol.
) Propa-1-enyl) (t-butoxy) carboxamide (1.81 g, 6.71)
Sodium cyanoborohydride (14.57 g, 231 mmol) was added to the (mmol). Acetic acid was added to this until pH = 3. The solution was refluxed for 3 hours, at which time the reaction mixture was cooled and stirred overnight at room temperature. The reaction mixture is concentrated,
Partitioned between ethyl acetate (100 mL) and sodium bicarbonate (450 mL). The aqueous layer was adjusted to pH 8 with sodium hydroxide (10N aqueous solution) and further extracted with ethyl acetate. The ethyl acetate layers were combined, dried over Na ₂ SO ₄ and concentrated to give a yellow foam. Chromatography of this material (SiO ₂ , DCM / methyl alcohol;
100/0 to 90/10 gradient) and gave the title compound as a yellow foam (1
.60 g, 88%) was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.16 (d, 1H, J = 6.9 Hz); 1.34 (s, 9H)
; 4.46 (m, 1H); 4.96 (br s, 1H); 7.52 (m, 1H); 8.06 (dd, 1H, J = 1.8,
7.8 Hz); 8.21 (s, 1H); 8.28 (m, 1H)

N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (
Pyrrolidinylcarbonyl) (3-hydroquinolyl)]-N- (2-chloro-3-
Pyridylmethyl) carboxamide Prepared in an analogous manner to Example 11 and used in the next reaction without further purification. (+/-)-7-chloro-4-hydroxy-2- (2-chloro (3-pyridyl)
Ethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1
, 10-Dione N-[(t-butoxy) carbonylamino] [7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) (3-hydroquinolyl)] in THF (100 mL).
-N- (2-chloro-3-pyridylmethyl) carboxamide (2.10 g, 3.6
To 6 mmol) was added methanesulfonic acid (14 mL), the mixture was stirred overnight and then gently refluxed for 5 hours. Volatiles were removed under vacuum and diethyl ether (200 mL) was added to the remaining oil. The mixture was stirred for 10 minutes and then separated into two layers, an ether layer and a brown oil layer. The ether was decanted off and water (20 mL) followed by sodium chloride (25 mL saturated aqueous solution) was added to the brown oil. After a short time, a precipitate formed and was collected by vacuum filtration. Sonicate the precipitate in water (10 mL), filter, and for 15 minutes 4/1 diethyl ether / methyl alcohol 20 mL.
Sonicated in. The material was filtered, washed with diethyl ether and dried under vacuum to give the title compound as an off-white powder (0.632g, 41%). (m.p> 220-225 ° C). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.64 (d, 3H, J = 6.9 Hz); 6.21 (q, 1H, J = 6.9 Hz); 7.45 (m, 2H); 7.87 (d, 1H, J = 6.3 Hz); 8.03 (d, 1H, J
= 2.1 Hz); 8.14 (d, 1H, J = 8.7 Hz); 8.33 (m, 1H); 8.64 (s, 1H); 8.8
1 (d, 2H, J = 5.4 Hz); 11.90 (br s, 1H); 12.53 (br s, 1H). Calculated value for C ₁₈ H ₁₂ Cl ₂ N ₄ O ₃・ 0.35 H ₂ O: C, 52.79 ; H, 3.13; N, 13.68; Measured value: C,
52.84; H, 3.07; N, 13.58.

Example 16: (+/−)-7-chloro-4-hydroxy-2- (2-chloro (4-pyridyl))
Ethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline-1
, 10-Dione The title compound was prepared in a similar manner to the preparation of Example 15, using 2-chloro-4-cyanopyridine and methylmagnesium bromide (1.4M toluene / THF) as starting materials. The title compound was isolated as an off-white solid (35% for final crystallization step). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 1.64 (d, 3H, J = 6.9 Hz); 6.15 (q, 1H,
J = 6.9 Hz); 7.31 (d, 1H, J = 5.1 Hz); 7.43 (m, 2H); 8.03 (d, 1H, J
= 2.1 Hz); 8.14 (d, 1H, J = 8.7 Hz); 8.36 (d, 1H, J = 5.4 Hz); 11.97
(br s, 1H); 12.61 (br s, 1H). Calculated value for C ₁₈ H ₁₂ Cl ₂ N ₄ O ₃・ 0.45 H ₂ O: C,
52.56; H, 3.16; N, 13.62; Measured value: C, 52.65; H, 3.05; N, 13.51.

Example 17: (+/−)-7-chloro-4-hydroxy-2- (1- (benzo [b] furan-
2-yl) ethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinolin-1,10-dione N '-(1-benzofuran-2-yl-ethylidene) -hydrazinecarvone Acid t
-Butyl ester Benzofuran-2-yl methyl ketone (5.0 g, 3 in THF (200 mL).
To a solution of 1 mmol) t-butylcarbazate (4.1 g, 31 mmol) was added followed by concentrated HCl (10 drops). The reaction mixture was stirred at room temperature overnight at which point THF was removed in vacuo and the remaining solid was triturated with hexane and filtered to give the title compound as a white solid (8.2g, 30mmol, 96). %). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 10.03 (s, 1H); 7.65 (d, J = 7.8 Hz, 1H
); 7.60 (d, J = 8.1 Hz, 1H); 7.35 (dd, J = 7.2, 7.2 Hz, 1H); 7.26 (s,
1H); 7.26 (m, 1H); 2.17 (s, 3H); 1.50 (s, 9H).

N ′-(1-benzofuran-2-yl-ethyl) -hydrazinecarboxylic acid t-butyl ester N ′-(1-benzofuran-2-yl-ethylidene) in MeOH (55 mL).
A solution of hydrazinecarboxylic acid t-butyl ester (3.0 g, 11 mmol) in sodium cyanoborohydride (3.4 g, 55 mmol), then pH.
Sufficient acetic acid (about 7 mL) was added to adjust to 3. The solution was heated to 65 ° C. and after 1 and 3 hours more sodium cyanoborohydride was added (
About 2g each). After 4 hours reaction time, the reaction mixture was then cooled to room temperature, diluted with water and methanol and removed under reduced pressure. The remaining material was diluted with ethyl acetate, washed with saturated aqueous NaHCO ₃ , water, brine and dried over Na ₂ SO ₄ . The mixture was filtered and concentrated to give the title compound as a white solid (3.1 g, 11 mmol,
100%). This material was used without further purification.

N '-(1-Benzofuran-3-yl-ethyl) -N'-[7-chloro-4-oxo-2- (pyrrolidine-1-carbonyl) -1,4-dihydroquinoline-3-
Carbonyl] -hydrazinecarboxylic acid t-butyl ester 7-chloro-4-oxo-2- (pyrrolidinylcarbonyl) hydroquinoline-3-carboxylic acid of Example 1 in THF (30 mL) (1.77 g, 5. CMC (4.67 g, 11.0 mmol) was added to a stirred slurry of (51 mmol). To this yellow canary mixture was added (1.5 g, 5.51 mol) and N, N- in THF (25 mL).
A solution of dimethyl-aminopyridine (100 mg, 827 mmol) was added. The resulting mixture was refluxed under N ₂ for 3 hours, then cooled and filtered. Concentrate the filtrate,
Filter through a small column of silica gel (10% MeOH / CH ₂ Cl ₂ ) to give the title compound as a pale yellow solid. This material was subjected to the next reaction without further purification. MS m / z 579.2 (M + l).

7-Chloro-4-hydroxy-2- (1- (benzo [b] furan-2-yl) ethyl) -1,2,5,10-tetrahydropyridazino [4,5-b] quinoline -1,
10-dione N '-(1-benzofuran-3-yl-ethyl) -N in MeOH (20 mL).
′-[7-chloro-4-oxo-2- (pyrrolidine-1-carbonyl) -1,4
-Dihydroquinoline-3-carbonyl] -hydrazinecarboxylic acid t-butyl ester (1.0 g, 1.74 mmol) in 0 ° C solution of methanesulfonic acid (3.4 mL, 52.3 mmol) in MeOH (10 mL). At room temperature was added dropwise. The mixture was allowed to come to room temperature and stirred for 24 hours, at which time water (about 100 mL) was added and the precipitate was collected. The solid was sonicated for 20 minutes (50 mL of 10% MeOH / Et ₂ O) and the solid collected. This sonication step was repeated and a brown solid was finally collected. This material was dried for 1.5 hours at 500 mTorr and 30 ° C to give the title compound (26
0 mg, 630 mmol, 36%) was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 12.56 (s, 1H); 11.93 (s, 1H); 8.16 (d
, J = 8.7 Hz, 1H); 8.02 (d, J = 1.8 Hz, 1H); 7.60 (dd, J = 1.5, 5.7 Hz
, 1H); 7.50 (d, J = 7.5 Hz, 1H); 7.44 (d, J = 7.2 Hz, 1H); 7.25 (m, 2
H); 6.88 (s, 1H); 6.41 (q, J = 7.2 Hz, 1H); 1.71 (d, J = 6.9 Hz, 3H).
Calculated value for C ₂₁ H ₁₄ ClN ₃ O ₄・ 0.2 H ₂ O: C, 61.31; H, 3.53; N, 10.21. Actual value: C, 61.14, 61.19; H, 3.54, 3.53; N, 10.25, 10.25.

Example 18: (+/−)-7-chloro-4-hydroxy-2- (furan-2-ylmethyl)-
1,2,5,10-Tetrahydropyridazino [4,5-b] quinoline-1,10-dione The title compound was synthesized by the method of Example 17 using 2-acetylfuran as a starting material. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.56 (s, 1H); 11.91 (s, 1H); 8.15 (d,
J = 8.4 Hz, 1H); 8.02 (d, J = 1.8 Hz, 1H); 7.57 (s, 1H); 7.43 (dd, J
= 8.7, 1.5 Hz); 6.42-6.35 (m, 2H); 6.27 (q, J = 6.9 Hz, 1H); 1.61 (d,
J = 6.9 Hz, 3H).

Example 19: 7-chloro-4-hydroxy-2- (1- (thien-3-yl) ethyl) -1,
2,5,10-Tetrahydropyridazino [4,5-b] quinoline-1,10-dione The title compound was synthesized by the method of Example 17 using 2-acetylthiophene as a starting material. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (br s, 1H); 11.90 (br s, 1H); 8.1
5 (d, J = 8.7 Hz, 1H); 8.02 (d, J = 1.2 Hz, 1H); 7.46-7.49 (m, 1 H);
7.44 (d, J = 8.7 Hz, 1H); 7.34 (s, 1H); 7.02 (d, J = 5.1 Hz, lH); 6.2
6 (q, J = 6.9 Hz, 1 H); 1.65 (s, 3 H).

Example 20: 7-chloro-4-hydroxy-2- (1- (benz [b] thien-3-yl) ethyl) -1,2,5,10-tetrahydropyridazino [4,5] -B] quinoline-1,
10-dione Example 1 using 2-acetyl-3-methylbenzothiophene as starting material
The title compound was synthesized by the method of 7. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H); 11.88 (s, 1H); 8.18 (d,
J = 8.7, 1H); 7.96-8.00 (m, 2H); 7.77-7.82 (m, 2H); 7.43 (dd, J = 1.2
, 8.7, 1H); 7.31-7.37 (m, 2 H); 6.61 (q, J = 6.9 Hz, 1H); 1.75 (s, 3
H).

Example 21: 7-Chloro-4-hydroxy-2- (1- (benz [b] thien-2-yl) ethyl) -1,2,5,10-tetrahydropyridazino [4,5] -B] quinoline-1,
10-dione The title compound was synthesized by the method of Example 2 using 2-acetylbenzothiophene as a starting material. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.63 (br s, 1H); 11.96 (br s, 1H); 8.1
6 (d, J = 8.7 Hz, 1H); 8.03 (d, J = 1.5 Hz, 1H); 7.88 (d, J = 7.5 Hz,
1H); 7.79 (d, J = 7.2 Hz, 1H); 7.44 (d, J = 8.7 Hz, 1H); 7.37-7.28 (m
, 3H), 6.52 (q, J = 6.3 Hz, 1H); 1.79 (d, J = 6.6 Hz, 3H).

Example 22: 7-Chloro-4-hydroxy-2- (1- (5-cyanothien-2-yl) ethyl) -1,2,5,10-tetrahydropyridazino [4,5-b ] Quinoline-1,1
0-dione The title compound was synthesized by the method of Example 2 using 2-acetyl-5-cyanothiophene as a starting material. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.69 (br s, 1H); 11.93 (br s, 1H); 8.1
4 (d, J = 8.7 Hz, 1H); 8.03 (d, J = 1.8 Hz, 1H); 7.84 (d, 7 = 3.9 Hz,
1H); 7.44 (dd, J = 1.8, 8.4 Hz, 1H); 7.23 (d, J = 3.9 Hz, 1H); 6.48 (
q, J = 6.9 Hz, 1H); 1.72 (d, J = 6.9 Hz, 3H).

Example 23: 7-Chloro-4-hydroxy-2- (ethyl-1- (pyrazin-2-yl))-
1,2,5,10-Tetrahydropyridazino [4,5-b] quinoline-1,10-dione The title compound was synthesized by the method of Example 2 using acetylpyrazine as a starting material. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.55 (br s, 1H); 11.94 (br s, 1H); 8.6
1 (s, 2H); 8.54 (s, 1H); 8.15 (d, J = 8.7 Hz, 1H); 8.03 (s, 1H); 7.
44 (d, J = 8.1 Hz, 1H); 6.29 (q, J = 6.9 Hz, 1H); 1.73 (d, J = 6.9 Hz,
3H).

Tests for Biological Function Test A: Inhibition of [ ³ H] -MDL105,519 Binding Compound binding to the NMDA receptor glycine site is associated with tritiated MDL105,519 binding to brain membranes bearing the receptor. It is assessed by measuring the ability of the test compound to inhibit binding. Rat Brain Membrane: The rat brain membrane used in this experiment is the Analytical Biological Serv.
BM Baron et al., J. Pharmacol. Exp. Th, obtained from ices Inc.
er. 250, 162 (1989). Briefly, male SD (Sp
Rague Dawley) Fresh brain tissue including cerebral cortex and hippocampus collected from rat 0.3
Homogenize in 2M sucrose and centrifuge at low speed to separate the cell membrane from other cell constituents. The membrane was then washed 3 times with deionized water and washed with 0.04
% Triton X-100. Finally, the membrane is 50 mM Tris, pH 7.4.
It was washed 6 times in citrate buffer and stored at -80 ° C until use.

[ ³ H] -MDL 105,519 (72 Ci / mmol) was purchased from Amersham. Cold MDL 105,519 was purchased from Sigma / RBI. The binding assay is essentially as shown below in BM Baron et al., J. Pharmacol. Exp. Ther. 279, 62 (19
96). On the day of the experiment, thaw the brain membrane at room temperature and
Suspended in 7.4 50 mM tris acetate buffer ("TAB"). 75 μg / m
l of protein (using BioRad's dye) was used for competitive binding. The experiment was performed using a 96-well plate. The membrane was treated with 20 μL of various concentrations of compound and 1.2 M [ ³ H]-
Incubated with MDL 105,519 for 30 minutes at room temperature in a total volume of 250 μL. Unlabeled MDL 105,519 was used for 100 μM to examine non-specific binding. Unlabeled MDL 105,519 and compound were dissolved in DMSO as a 12.5 mM stock solution. The final concentration of DMSO in each well was kept below 1% and it was found that this concentration did not change the binding results. After incubation, unbound [ ³ H] -MDL 105,519 was labeled with GF / using a Packard harvester.
B Unifilter was removed by filtration onto plates. The filter was washed 4 times with TAB (total volume 1.2 mL buffer) cooled on ice. The plate was dried overnight at room temperature, and 45 μL of MICROSCINTO was added to each well, and the bound radioactivity was measured using Packard Top Count.

Human Brain Membrane: Human brain membrane is manufactured by Analytical Biological Services Inc. Obtained, and the assay was performed as described above for rat brain membranes. Data analysis: Data were analyzed using Microsoft Excel spreadsheet and GraphPad Prizm software and compound titers were expressed as Ki (nM).

Test B: Formalin Test The formalin test is an assay that measures the ability of compounds to suppress formalin-induced nociceptive behavior in rats (D. Dubuisson, et al., Pain 4,
161-174 (1997); H. Wheeler-Aceto et al., Psychopharmacology 104, 35-44 (
1991); TJ Coderre, et al., Pain 54, 43-50 (1993)). In this test, two distinct phases of formalin-induced behavior were observed. Noxious drugs injected into the foot (
The first phase response caused by acute nociception for formalin) occurs between 0 and 5 minutes. A resting period of 5 to 15 minutes follows the injection. After a period of quiescence, a second phase response triggered by central nervous system sensitization in the dorsal horn occurs after 15 minutes and continues for up to 60 minutes. Central nervous system sensitization in the spine augments nociceptive afferent nerve inputs, causing a more intense continuation of pain transmitted to the brain. Therefore, inhibition of the phase 2 response indicates a central function of drug action.

The procedure for the formalin test is as follows: Male rats are placed in a Plexiglas chamber and observed for 30-45 minutes for baseline activity.
The test animals are pre-administered with different doses of vehicle or test compound. A solvent or a test compound is administered to the test animal, and after 3 hours, 0.05 mL of sterile 1% formalin is injected subcutaneously in the back of the hind limb. The number of paw contractions (responses) between the first phase (0 to 5 minutes) and the second phase (20 to 35 minutes) are counted and recorded. Shrink response is compared to the mean value of saline control group and calculated as% inhibition. The ED ₅₀ represents the dose at which 50% inhibition of nociceptive response occurred in the first or second phase response. The first phase response may be suppressed by peripherally acting compounds and by centrally acting compounds. The second phase response is suppressed by centrally acting compounds.

% Inhibition of nociceptive response = 100 × (number of reactions in solvent group−number of reactions in test compound group) / number of reactions in solvent group In order to examine the significant difference in the action of compounds, Student's t test was used for statistical analysis. . Data are reported as the dose giving the percent inhibition of response.

Test C: Neuropathic Pain Model (Chronic Constrictive Nerve Injury) The antihyperalgesic properties of compounds can be tested by the model of chronic constrictive nerve injury (“CCI”). This study is associated with nerve damage caused directly by trauma or pressure or indirectly by a wide range of diseases such as infection, cancer, metabolic status, toxins, malnutrition, immune dysfunction, and musculoskeletal changes. Is a model for neuropathic pain. In this model, unilateral peripheral hyperalgesia is produced in the rat by neural connection (GJ Bennett, et al., Pain 33, 87-107 (1998)).

As a procedure, SD rats (250-350 g) are anesthetized with sodium pentobarbital and the common sciatic nerve is exposed at the level of the mid thigh by blunt dissection through two femurs. The proximal nerve branch of the ischia trifurcation (about 7 mm) is released from the tissue and ligated with chrome intestinal suture at four points. The sutures are tied with a ligature spacing of approximately 1 mm. The incisions are overlaid and closed to allow the animals to recover. Thermal hyperalgesia is measured using the flexor flexor test (K. Hargreaves, et al., Pain 32, 77-78 (1988)).
To perform this test, the animals are acclimated to the glass raised floor. A radiant heat source is applied through the glass floor to the hind limb of the central plantar (nerve area of the sciatic bone) with a 20 second pause to avoid damage to the skin. The latency to flexor reflex in both hind limbs is recorded.

Injured paws with ligated nerves show shorter flexor latency of the foot than undamaged or sham-operated paws. Responses to test compounds are evaluated at various time points after oral administration to determine the onset and duration of compound action. In carrying out this test, a group of CCI rats is orally administered with a solvent or a test compound three times a day for 5 days. Paw flexor latency is 10 minutes before the first daily administration and 2 after the daily administration
Alternatively, the measurement is performed after 3 hours. The effect of the compounds is expressed as the mean percent reduction in hyperalgesia when compared to vehicle-treated test animals, which is calculated as follows: [(Solvent group average-Test compound group average) / Solvent group average] x 100 Data analysis was performed by the multiple average comparison test method (Dunnett's test), and the results are shown. Expressed in mg / Kg / day, this gives a statistically significant percent reduction in hyperalgesia.

Table 1 shows the results of tests A, B and C for some compounds of the invention.
Those with no data in the table were not tested.

[Table 1]

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, B Z, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, J P, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Megan Murphy             Delaware, USA 1985 0-5437.             Wilmington. P O Box             15437. Concord Pike 1800. Astra             Zeneca (72) Inventor Rebecca Ann Urbanek             Delaware, USA 1985 0-5437.             Wilmington. P O Box             15437. Concord Pike 1800. Astra             Zeneca (72) Inventor Wenhua Siau             Delaware, USA 1985 0-5437.             Wilmington. P O Box             15437. Concord Pike 1800. Astra             Zeneca (72) Inventor Fransis Marie McLaren             Delaware, USA 1985 0-5437.             Wilmington. P O Box             15437. Concord Pike 1800. Astra             Zeneca (72) Inventor Cary Lynn Hawkler             Delaware, USA 1985 0-5437.             Wilmington. P O Box             15437. Concord Pike 1800. Astra             Zeneca F term (reference) 4C065 AA04 AA18 BB10 CC09 DD03                       EE02 HH01 JJ05 KK09 LL04                       PP07 PP12 PP14 QQ02                 4C086 AA01 AA02 CB09 MA01 MA02                       MA04 MA05 NA14 ZA08 ZC42

Claims (5)

[Claims] 1. A method for treating a painful patient, comprising administering any compound of structural formula I in an effective pain ameliorating amount. [Chemical 1] In the above formula, R ¹ is halo, A is CH (R ² ) (CH ₂ ) _n in which _n has a value selected from 0, 1 or 2, and R ² is C ₁ -C ₆ alkyl. Selected, and D is selected from 5- or 6-membered heteroaryl residues or benz derivatives thereof and has 1, 2 or 3 ring atoms selected from nitrogen, oxygen or sulfur, wherein D is unsubstituted or substituted with 1, 2 or 3 residues selected from C ₁ -C ₃ alkoxy, halo and cyano. 2. The method of claim 1, wherein in the compound of structural formula I, D is selected from pyridyl, furanyl, benz [b] furanyl, thienyl, benz [b] thienyl and pyrazinyl. 3. The method according to claim ² , wherein in the compound represented by Structural Formula I, R ² is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and sec-butyl. 4. The method of claim 1, which comprises administering any of the compounds of structural formula II in an amount effective to improve pain. [Chemical 2] 5. A pharmaceutical composition comprising a pain-relieving effective amount of a compound of structural formula I together with a pharmaceutically acceptable excipient or diluent. [Chemical 3] In the above formula, R ¹ is halo, A is CH (R ² ) (CH ₂ ) _n in which _n has a value selected from 0, 1 or 2, and R ² is C ₁ -C ₆ alkyl. Selected, and D is selected from 5- or 6-membered heteroaryl residues or benz derivatives thereof and has 1, 2 or 3 ring atoms selected from nitrogen, oxygen or sulfur, wherein D is unsubstituted or substituted with 1, 2 or 3 residues selected from C ₁ -C ₃ alkoxy, halo and cyano.