JP2002506869A - New heterocyclic compounds - Google Patents

Abstract

(57) The present invention provides a compound represented by the general formula (I): (Wherein X, Z, R ¹ , R ² and r are as defined herein), or a salt thereof, to a process for preparing them, And those for the clinical treatment of painful, hyperalgesic, and / or inflammatory conditions in which C fibers play a pathophysiological role by inducing neural pain or inflammation And the use thereof for the treatment of indications caused by or associated with the secretion and circulation of insulin antagonistic peptides, such as non-insulin dependent diabetes mellitus (NIDDM) and obesity associated with aging.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to novel N-substituted azaheterocyclic compounds or salts thereof, to methods for preparing them, to compositions containing them, to C-fibers inducing neural pain or inflammation. The use of compounds to prepare compositions for the clinical treatment of painful, hyperalgesic and / or inflammatory conditions by playing a pathophysiological role, and to the painful, hyperalgesic And / or methods of treating inflammatory conditions. The present invention also relates to the use of the present compounds for the treatment of non-insulin dependent diabetes mellitus (NIDDM), insulin resistance and obesity associated with aging, which compounds interfere with neuropeptides containing C-fibers, It is known to inhibit the secretion and circulation of insulin antagonist peptides such as CGRP or amylin.

BACKGROUND OF THE INVENTION The nervous system exerts a significant effect on inflammatory responses. Retrograde stimulation of sensory nerves localizes vasodilation and increases vascular permeability (Janecso et al., Br. J. Pharmacol. 1
967, 31, 138-151), a similar response is observed after injection of a peptide known to be present in sensory nerves. From this and other data, peptides released from the ends of sensory nerves mediate many inflammatory responses in tissues such as skin, joints, ureter, eye, meninges, gastrointestinal and respiratory tract. Thus, inhibition of sensory neuropeptide release and / or activity may be useful for treating, for example, arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombophlebitis, glaucoma, gastrointestinal disorders, or migraine.

[0003] Furthermore, the fact that C fibers innervate the liver, intestine and pancreas suggests that they control a variety of functions, peptidergic innervation controls glucose tolerance in rodents (Karlson et al., Am. J. Physi
ol. 267, R1071-R1077, 1994, Guillot et al., Life Sci 969-977, 1996). Furthermore, the potential effects of CGRP on skeletal muscle glycogen synthase activity and muscle glucose metabolism, together with the finding that this peptide is released from the neuromuscular junction by neuronal excitation, CGRP is involved in glycogen storage from glycogen storage to glycolysis and oxidative pathways. Suggests that directing phosphorylated glucose may play a physiological role in skeletal muscle glucose metabolism (Rossetti et al., Am. J. Physiol. 264 , E1-E10,
1993). This peptide may be an important physiological modulator of intracellular glucose transport in physiological conditions such as exercise, and pathophysiology where circulating levels of CGRP are significantly increased, such as NIDDM or aging-related obesity. Can also contribute to the reduction of insulin action and skeletal muscle glycogen synthase in inflammatory conditions (
Melnyk et al., Obesity Res. 3 , 337-344, 1995). Therefore, neuropeptide CG
Inhibition of RP release and / or activity may be useful in treating insulin resistance associated with type 2 diabetes or aging.

[0004] US Pat. Nos. 4,383,999 and 4,514,414 and EP23
Some derivatives of N- (4,4-disubstituted-3-butenyl) azaheterocyclic carboxylic acids are claimed in 6342 and EP231996 as inhibitors of GABA uptake. In EP 342635 and EP 374801 N-substituted azaheterocyclic carboxylic acids in which the oxime ether and vinyl ether groups each form part of an N-substituent are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 922658 an N-substituted azacyclic carboxylic acid is claimed as a GABA uptake inhibitor. EP 221572 claims that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

[0005] Several tetracyclic piperazino-azepines are known in the literature, including mianserin, which can be used to treat depression. EP 421823 and 593164
Describe tetracyclic dibenzo-pyrazino-azepines and benzo-pyrido-pyrazino-azepines as having anti-allergic and anti-asthmatic activity. Furthermore, EP 457857 is, inter alia, an antiallergic antiasthmatic (anti).
Disclosed are tetracyclic dibenzo-pyrazino-azepines as agents and agents for bronchial asthma.

SUMMARY OF THE INVENTION The present invention relates to compounds of general formula I, wherein X, Z, R ¹ , R ² and r are as defined in the detailed part of this description. The compounds are useful for all painful, hyperalgesic and / or inflammatory conditions related to inflammatory conditions in which C fibers play a pathophysiological role, such as nervous pain, nervous inflammation,
Indications caused by or associated with migraine, neuropathy, pruritus and rheumatoid arthritis, and insulin antagonistic peptides and other peptides from the sensory nervous system, such as non-insulin dependent diabetes mellitus (NIDDM) ,
It is useful for treating, preventing, eliminating, alleviating or ameliorating obesity associated with insulin resistance and aging.

[0007] In another aspect, the present invention provides a composition comprising, within its scope, at least one compound of the general formula or a pharmaceutically acceptable salt thereof, as an active ingredient, with a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions that are included together. In another aspect of the invention, the painful C-fiber plays a pathophysiological role,
Methods for treating hyperalgesic and / or inflammatory conditions such as neuropathic pain, neurogenic inflammation, migraine, neuropathy, pruritus and rheumatoid arthritis, and secretion and circulation of insulin antagonistic peptides Provided are methods of treating an indication caused or associated therewith, such as non-insulin dependent diabetes mellitus (NIDDM), insulin resistance and aging-related obesity.

[0008] The method of treatment can be described as treating, preventing, eliminating, alleviating or ameliorating one of the above-mentioned indications, which comprises a neurologically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Administering the salt to the subject. Further aspects of the invention include all painful, hyperalgesic and / or inflammatory conditions in which C fibers play a pathophysiological role, such as neuralgia, neurogenic inflammation, migraine, neuropathy, pruritus And indications caused by or related to the treatment of rheumatoid arthritis, and by the secretion and circulation of insulin antagonist peptides,
For example, the use of a compound of the invention for the preparation of a pharmaceutical composition for the treatment of non-insulin dependent diabetes mellitus (NIDDM), insulin resistance and aging related obesity.

[0009] Further objects will become apparent from the description below. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a compound of general formula I:

[0010]

Embedded image

Wherein R ¹ and R ² are independently hydrogen, halogen, trifluoromethyl, hydroxy, C _1-6 -alkyl or C _1-6 -alkoxy; X is -O-,- R is 0,1,2,3,4,5,6,7,8,9 or 10; and Z is S- or -S (= O)-;

[0012]

Embedded image

Wherein R ³ is — (CH ₂ ) _m OH or — (CH ₂ ) _p COR ⁴ , wherein m and p are independently 0, 1, 2, 3, or 4; R ⁴ is OH, NH ₂ , NH
OH or C _1-6 -alkoxy)) or a pharmaceutically acceptable salt thereof.

[0014] The compounds according to the invention can exist as geometric and optical isomers, all isomers as separated, pure or partially pure stereoisomers or racemic mixtures thereof being included in the scope of the present invention . The isomers can be separated by suitable chromatography techniques or standard methods such as fractional crystallization. Preferably, the compounds according to the invention exist as individual geometric or optical isomers.

The compounds according to the invention may optionally be present as pharmaceutically acceptable acid addition salts, metal salts or optionally alkylated ammonium salts. Examples of such salts are inorganic and organic acid addition salts, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, citric acid, lactic acid, tartaric acid, oxalic acid or similar medicaments. There are acceptable inorganic or organic acid addition salts. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts can be found in the Journal of P.K.
and pharmaceutically acceptable salts listed in harmaceutical Science, 66, 2 (1977).

[0016] Pharmaceutically acceptable acid addition salts also include hydrates that the present compounds can form. Acid addition salts may be obtained as the direct product of the compound. Alternatively, the salt can be isolated by dissolving the free base in a suitable solvent containing a suitable acid and evaporating the solvent or separating the salt and solvent.

The compounds according to the invention can be administered in pharmaceutically acceptable acid addition salt form or, if possible, as a metal or lower alkylammonium salt. Such salt forms are about the same as the free base forms Indicates the activity of the order. Throughout the foregoing structural formulas and throughout this specification, the following terms have the indicated meanings. The term “C _1-6 -alkyl” as used herein, alone or in combination,
A straight or branched chain saturated hydrocarbon having up to 6 carbon atoms. Typical C _1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-butyl
-Pentyl, iso-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4-methylpentyl, neopentyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2- And trimethylpropyl.

The term “C _1-6 -alkoxy” as used herein, alone or in combination,
It is intended to include C _1-6 -alkyl groups of the indicated length in either a straight, branched or ring form linked via the ether oxygen with a free valence bond from the ether oxygen. Examples of straight chain alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy,
Cyclopentyloxy and cyclohexyloxy.

The term “halogen” means fluorine, chlorine, bromine or iodine. In a preferred embodiment of the present invention, R ¹ and R ² are hydrogen, halogen, trifluoromethyl or C _1-6 -alkyl. Preferably, R ¹ and R ² are hydrogen. In another preferred embodiment of the invention, X is -O- or -S-.

In another preferred embodiment of the invention, r is 0, 1, 2, 3, or 4. In another preferred embodiment of the present invention, Z is -R ^3. In another preferred embodiment of the present invention, R ³ is — (CH ₂ ) _p COR ⁴ , wherein p is 0, 1, 2, or 3. In yet another preferred embodiment of the present invention, R ⁴ is OH.

Preferred compounds of the present invention include 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl ) -Butanoic acid; 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) -butanoic acid; or There are pharmaceutically acceptable salts thereof.

Further preferred compounds of the present invention include 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepine-2 -Yl) -pentanoic acid; 3- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) -propionic acid 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -pentanoic acid; 3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -propionic acid; or a pharmaceutically acceptable salt thereof. .

The compounds according to the invention have been shown to inhibit neurogenic inflammation associated with the release of neuropeptides from the peripheral and central ends of sensory C fibers. Experimentally,
This can be demonstrated in the animal model of histamine induced paw oedema of Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995), wherein the compound according to the invention is Shows a potential inhibitory effect. The compounds according to the invention can be used to treat all painful, hyperalgesic and / or inflammatory conditions in which C-fibers play a pathophysiological role by inducing neural pain or inflammation. it can. Acute pain states, exemplified by migraine, post-operative pain, burns, bruises, post-herpetic pain (Zoster) and pain commonly associated with acute inflammation, and various types of neuropathy (diabetes, post-traumatic) , Poisons), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, cough, asthma, itch, chronic pancreatitis, inflammatory skin diseases, such as psoriasis And chronic painful and / or inflammatory conditions exemplified by autoimmune skin diseases, osteoporosis.

Furthermore, the compounds of general formula I reduce glucose levels and improve glucose tolerance in diabetic rodents (ob / ob mice and diabetic obese Zucker rats), and this results in CGRP from peripheral nerve endings. And reduced release of other peptides from the sensory nervous system. Thus, compounds of general formula I may be useful in treating obesity associated with NIDDM, insulin resistance and aging. Experimentally, this means that the compound of formula I can be treated ip before
This can be demonstrated by icv administration of histamine chloride to I mice.

The compound of formula I can be prepared by the following method:

[0026]

Embedded image

Compounds of formula II wherein R ¹ , R ² and X are as defined above, wherein r and Z are as defined above and W is a suitable leaving group such as hydrogen, p Reacting with a compound of formula III which is toluenesulfonate and mesylate to form a compound of formula I. The alkylation reaction is carried out in a solvent such as dimethyl sulfoxide,
N, N-dimethylformamide, acetone, dibutyl ether, 2-butanone,
In tetrahydrofuran (THF), dioxane or toluene, in the presence of a base such as sodium or potassium carbonate and a catalyst such as an alkali metal iodide, at a temperature up to the reflux temperature for the solvent used, for example 1 to 120 hours ,It can be carried out. When an ester is prepared wherein R ⁴ is alkoxy, the compound of formula I wherein R ⁴ is OH is preferably prepared at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol, such as methanol or ethanol, e.g. 0.5 ~
It can be prepared by hydrolyzing the ester group for 48 hours.

The compounds of formulas II and III can be prepared immediately by methods known to those skilled in the art. Pharmacological methods I. Histamine-induced paw edema The rat histamine paw oedema test was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995). Briefly, male Sprague-Dowley rats weighing 250-300 g were anesthetized with sodium pentobarbital and placed on a table heated to 32 ° C. Ten minutes later, histamine (50 microliters, 3 mg / ml) was injected into the right hind paw, and after 20 minutes the swelling of the palm was determined by water plethysmography (Ugo
Basile). Test compounds were administered intraperitoneally 15 minutes before anesthesia.

II. Hishimin- induced hyperglycemic conscious non-fasted 25 g male NMRI mice in mice were treated with Nishibori et al.
J. Pharmacol. Exp. Therap. 241, 582-286, 1987) was administered with histamine chloride (90 nmol). Blood glucose 0 and 4 after histamine infusion
Measure at 0 minutes. The test compound was injected ip at 1.0 mg / kg 30 minutes before histamine injection.
Is administered. Inhibition (%) refers to the ability of a compound to inhibit histamine-induced elevation of blood glucose.

III. Reduced Release of CGRP 16 week old ob / ob female mice were injected subcutaneously with glucose (2 g / kg). Thereafter, blood glucose in tail vein blood was measured by the glucose oxidase method. Animals were decapitated at the end of the study and torso blood was collected. Immunoreactive CGRP was measured in plasma by radioimmunoassay. Two groups of animals were used. One group was treated with vehicle and the other group was given 5 days before testing
Drinking water gave the compound of formula I (100 mg / l).

The values for the inhibition of histamine-induced hyperglycemia for representative compounds are shown in Table 1.

[0032]

[Table 1]

Pharmaceutical composition The present invention also relates to a pharmaceutical composition comprising as active ingredient at least one compound of the general formula or a pharmaceutically acceptable salt thereof, usually such a composition Also included are carriers or diluents that are acceptable as a carrier. Pharmaceutical compositions containing the compounds of the invention include, for example, Remington: The Science and Pr.
^{actise of Pharmacy, 19 th Ed.} , as described in 1995, may be prepared by conventional techniques. The composition may be in conventional form, for example, a capsule, tablet, aerosol, solution, suspension or topical application.

A typical composition is a carrier or diluent, or associated with a pharmaceutically acceptable excipient that may be diluted by the carrier, or a capsule, satchet, paper, or other container. Containing a compound of general formula I or a pharmaceutically acceptable acid addition salt thereof, encapsulated in a carrier which can be in the form of In making the compositions, conventional techniques for the preparation of pharmaceutical compositions can be used. For example, the active compound
Generally, it will be mixed with a carrier, or diluted by a carrier, or encapsulated in a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a particulate solid container, for example, in a sachet. Particular examples of suitable carriers are water, saline, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, clay, sucrose, cyclodextrin, amylose, magnesium stearate, talc , Gelatin, agar, pectin, acacia, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulation may also contain wetting, emulsifying and suspending agents, preservatives, sweetening or flavoring agents. The formulations of the present invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The pharmaceutical composition may be sterilized and, if necessary, do not deleteriously react with the active compound.
It can be mixed with auxiliaries, emulsifiers, salts for acting on osmotic pressure, buffers and / or coloring substances and the like. The route of administration may be oral, nasal, pulmonary, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic, at a site appropriate or required for action. Any route may be used to effectively transport the active ingredient, as a liquid or ointment.

When using a solid carrier for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizers such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabens.

For parenteral application, injection solutions or suspensions, preferably aqueous solutions, containing the active compounds in polyhydroxylated castor oil are particularly suitable. Tablets, dragees or capsules with talc and / or carbohydrate carriers or binders and the like are particularly suitable for oral application. Preferred carriers for tablets, dragees, or capsules include lactose, corn starch, and / or potato starch. If a sweetened vehicle can be used, syrup or elixir can be used.

Typical tablets that can be prepared by conventional tableting techniques include: Core: Active compound (free compound or salt thereof) 100 mg Colloidal silicon dioxide (Aerosi) 1.5 mg Cellulose 70 mg microcrystalline (Avicel) modified cellulose gum (Ac-Di-Sol) 7.5 mg magnesium stearate Coating: HPMC approx. 9 mg ^* Mywacett 9-40 Tapprox. 0.9 mg ^* Acylated monoglyceride was used as plasticizer for film coating.

The compounds of the present invention may be used in all painful, hyperalgesic and / or inflammatory conditions related to the pathophysiological role of C fibers, such as nervous pain, inflammation, diabetic neuropathy and Treatment, prevention, elimination of rheumatoid arthritis, and conditions caused or related to the secretion and circulation of insulin antagonist peptides, such as non-insulin dependent diabetes mellitus (NIDDM), insulin resistance or aging related obesity; It can be administered to mammals in need of relief or improvement, especially humans. Such mammals include livestock, such as domestic pets, and non-domestic animals,
For example, it includes both wildlife animals.

The compounds of the invention may be in the form of their alkali metal or alkaline earth metal salts, together with, or simultaneously with, or together with, a pharmaceutically acceptable carrier or diluent, particularly and preferably in the form of their pharmaceutical compositions. An effective amount can be administered. The compounds of the present invention are effective over a wide dosage range. For example, in treating humans, a dose of about 0.5 to about 1000 mg, preferably about 1 to about 500 mg, of a compound of the present invention can be administered, conventionally 1 to 5 times daily. The most preferred dosage is about 50 to about 200 mg per dose, for example, when administered to a human.
Precise dosages will depend on the mode of administration, the treatment required, the mode of administration, the subject to be treated and the weight of the subject to be treated, and the preferences and experience of the attending physician or veterinarian.

Generally, the compositions of the present invention are formulated in unit dosage form containing, per unit dose, from about 50 to about 200 mg of the active ingredient, in or with a pharmaceutically acceptable carrier. Generally, dosage forms suitable for oral, nasal, pulmonary or transdermal administration will comprise from about 0.5 mg to 1000 mg, preferably about 1 mg, mixed with a pharmaceutically acceptable carrier or diluent.
From about 500 mg of the compound of formula I.

A method of treating is a treatment of an indication caused or related to secretion and circulation of an insulin antagonist peptide such as CGRP or amylin in a subject in need thereof, wherein the subject is provided with neurological It can be described as a treatment comprising the step of administering to the subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

Any novel feature or combination of features described herein is considered essential to the invention. EXAMPLES The methods for preparing the compounds of the present invention and preparations containing them are further detailed in the following examples, which should not be construed as limiting.

Hereinafter, TLC is thin layer chromatography, CDCl ₃ is deuteriochloroform, and DMSO-d ₆ is hexadeuteriodimethylsulfoxide. The structure of the compound is confirmed by elemental analysis or NMR. here,
If appropriate, provide the peak assigned to the characteristic proton in the title compound. ¹ H NMR shifts (δ _H ) are expressed in parts per million (ppm). M.
p. Is the melting point, expressed in ° C., uncorrected. Column chromatography is
Merck silica gel 60 (Art 9385) using WC Still et al., J. Org.
em. (1978). The compound used as starting material was
Known compounds or compounds which can be prepared immediately by processes known per se.

Example 1 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -butanoic acid Chloride

[0047]

Embedded image

[0048] 2-Methyl- (1,3,4,14b-tetrahydro- in toluene (12 mL)
2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepine) (
2.0 g, 7.5 mmol, Neth. Appl. 6709520, Chem. Abs. 70, 115192 (1969)
(Prepared as described in) at 60 ° C was added dropwise to a stirred solution of ethyl chloroformate (1.26 g, 1.1 mL, 11.7 mmol) in toluene (8 mL). The mixture was heated at reflux for 2 hours. After cooling, the mixture was washed with a saturated solution of sodium bicarbonate (2 × 10 mL), water (10 mL), dried (MgSO ₄ ) and evaporated. The residue (2.5 g) was purified by column chromatography on silica gel (50 g) using benzene as eluent to give 1.95 g (80%) of 2-ethoxycarbonyl- (1,3,4 , 1
4b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,
4] Oxazepine).

TLC: R _f = 0.25 (SiO ₂ : chloroform / benzene = 1: 4) Carbamate as described above (1.9 g, 5.9 mmol), potassium hydroxide (1.2 g)
And a mixture of ethanol (2 mL) was stirred and heated at reflux for 3.5 hours.
The solidified mixture was dissolved in water (20 mL) and the mixture was extracted with dichloromethane (3 × 15 mL). The combined extracts were washed with water - washed with brine, dried (K ₂ CO _3), and evaporated in vacuo. The residue was crystallized from a mixture of benzene and n-hexane. This is 1.1 g (75%) of 1,3
4,14b-tetrahydro-2H-dibenzo- [b, f] pyrazino [1,2-d
[1,4] oxazepine was provided.

The above-described oxazepine (1.1 g, 4.4 mm) in dimethyl sulfoxide (1 mL)
ol), ethyl 4-chlorobutyrate (1.14 g, 5.45 mmol), potassium carbonate (0.9 g, 6.5 mmol) and sodium iodide (0.32 g) were added. Heated to 60-70 ° C. for hours, then left overnight. The reaction mixture was diluted with benzene (70 mL), the precipitated solid was filtered off, washed with benzene (2 × 10 mL), and the filtrate was washed with water (5 × 15 mL). The benzene solution was dried (MgSO ₄ ) and the solvent was evaporated under vacuum. The residue (2.4 g) was purified on silica gel (60 g) using chloroform as eluent.
Purified by column chromatography in g). This is 1.72 g (93
%) Of 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) butyric acid ethyl ester as an oil. did.

TLC: R _f = 0.52 (SiO ₂ : chloroform) Ethyl ester described above (1.7 g, 40 mmol), 4N sodium hydroxide (9 mL)
) And ethanol (15 mL) were stirred at room temperature for 3 hours and left overnight. The reaction mixture was then poured into dichloromethane (200 mL) and acidified to pH 1 with concentrated hydrochloric acid. The dichloromethane layer was separated, washed with water (10 mL), dried and evaporated under vacuum. The oily residue was re-evaporated twice with acetone and then triturated with hot acetone. The precipitate was removed by filtration, washed with acetone and dried. This provided 0.85 g (57%) of the title compound as a solid. M. p. 223-232 ° C. Calculated _{(C 20 H 22 N 2 O} 3, HCl, 0.25H 2 O): C, 63.32%; H, 6.24%; N, 7.38%; Cl, 9.35%; measured Values: C, 63.46%; H, 6.27%; N, 7.14%; Cl, 9.33%. Example 2 Hydrogen 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) butyrate-oxalate

[0052]

Embedded image

1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1
, 2-d] [1,4] thiazepine (2.8 g, 10.4 mmol, Neth. 6709520, C
hem Abstr. 70, 115192 (1969)), ethyl 4-chlorobutyrate (3.0 g, 20 mmol), potassium carbonate (2.2 g, 16 mmol),
A mixture of sodium iodide (1.5 g, 10 mmol) and acetone (100 mL) was heated with stirring at reflux for 14 hours. The inorganic salts were filtered off and the filtrate was evaporated in vacuo to give a residue, which was purified by chromatography on silica gel (50 g) using ethyl acetate as eluent. This is 2.7g
(68%) of 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b
[, F] pyrazino [1,2-d] [1,4] thiazepin-2-yl) butyric acid ethyl ester was provided as an oil.

TLC: R _f = 0.61 (SiO ₂ : chloroform / ethanol / ammonia = 20: 1: 0.05) The above ester (2.70 g, 7.1 mmol) was dissolved in ethanol (40 mL), % Sodium hydroxide (5 mL) was added. The mixture was left at room temperature for 7 days, the ethanol was evaporated under vacuum and water (20 mL) was added. The mixture was extracted with diethyl ether and the phases were separated. Acetic acid (4 mL) was added to the aqueous phase,
The product was extracted with dichloromethane (50mL). The organic phase is dried (Mg
SO ₄ ) and the solvent was evaporated under vacuum. The residue was dissolved in acetone and treated with a solution of oxalic acid dihydrate in acetone. This provided 2.36 g (73%) of the title compound after filtration and drying. M. p. 214-216 ° C. Calculated _{(C 20 H 22 N 2 O} 2 S, C 2 H 2 O 4, 0.75H 2 O): C, 57.69%; H, 5.61%; N, 6.12%; S, 7.00%; Found: C, 57.59%; H, 5.29%; N, 5.97%; S, 6.96%. Example 3 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) -pentanoic acid

[0055]

Embedded image

1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1
, 2-d] [1,4] thiazepine (1.37 g, 5.1 mmol, Neth 6709520, C.I.
A. 70, 115192 (prepared as described in 1969)), ethyl 5-bromopentanoate (1.77 g, 8.5 mmol), potassium carbonate (1.45 g, 10.5 mm).
ol) and acetone (40 mL) was heated with stirring at reflux for 14 hours. The mixture was filtered and the filtrate was evaporated under vacuum. The residue is
Purification by chromatography on silica gel (50 g) using ethyl acetate as eluent. This means that 1.95 g (96%) of 5- (1,3,4,14b-
Tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) pentanoic acid ethyl ester was provided as an oil.

TLC: R _f = 0.54 (SiO ₂ : chloroform / ethanol / ammonia = 20: 1: 0.05) The above ester (1.95 g, 4.9 mmol) was dissolved in ethanol (30 mL), and % Sodium hydroxide (3 mL) was added. The mixture was left at room temperature for 7 days, the ethanol was evaporated under vacuum and water (20 mL) was added. The mixture was extracted with diethyl ether and the phases were separated. Acetic acid (2 mL) was added to the aqueous phase and the solid was removed by filtration. By recrystallization of the solid from ethanol,
1.52 g (73%) of the title compound were provided as crystals. M. p. 226-230 ° C. Calculated _{(C 21 H 24 N 2 O} 2 S, 1 / 4H 2 O): C, 67.62%; H, 6.62%; N, 7.51%; S, 8.60%; measured value : C, 68.02%; H, 6.56%; N, 7.50%; S, 8.29%. Example 4 3- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) propionic acid

[0058]

Embedded image

1,3,4,14b-Tetrahydro-2H-dibenzo [b, f] pyrazino [1
, 2-d] [1,4] thiazepine (1.5 g, 5.6 mmol), ethyl acetate (0.
A mixture of 61 g, 6.1 mmol) and ethanol (40 mL) was heated at reflux for 5 minutes, then left at room temperature for 24 hours to give crude 3- (1,3,4,14b-tetrahydro-2H-dibenzo). [B, f] pyrazino [1,2-d] [1,4] thiazepine-
2-yl) propionic acid ethyl ester was provided.

To the above crude mixture was added 20% sodium hydroxide (3 mL) and the solution was left for 7 days. The ethanol was evaporated under vacuum and water (20 mL) was added. The mixture was extracted with diethyl ether (20 mL) and the phases were separated. Acetic acid (2 mL) was added to the aqueous phase and the solid was filtered. Crystallization from ethanol provided 1.67 g (88%) of the title compound as crystals. M. p. 218-220 ° C. Calculated _{(C 19 H 20 N 2 O} 2 S, 1 1 / 2H 2 O): C, 62.10%; H, 6.31%; N, 7.62%; S, 8.73%; measured Values: C, 62.32%; H, 6.53%; N, 7.61%; S, 8.79%. Example 5 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -pentanoic acid-hydrochloride

[0061]

Embedded image

Ethyl 5-bromopentanoate (1.66 g, 0.0079 mol) and potassium carbonate (1.75 g, 0.0127 mol) were added to 1,3,4,14b- in 2-butanone (45 mL). Tetrahydro-2H-dibenzo [b, f] pyrazino [1,
2-d] [1,4] -oxazepine solution (1.6 g, 0.0063 mol, Neth
Appl. 6709520, prepared as described in Chem. Abs. 70, 115192 (1969), and the reaction mixture was heated to 70-80 ° C. for 17 hours. The mixture was diluted with benzene (50 mL), the solid was filtered, washed with benzene (2 × 10 mL), and the filtrate was evaporated under vacuum. The residue was purified on silica gel (1: 1) using benzene and a mixture of benzene and chloroform (1: 1) as eluent.
2.35 g (97%) purified by column chromatography on 100 g).
Of crude 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] -pyrazino [1,2-d] [1,4] oxazepin-2-yl) pentanoic acid ethyl ester. .

TLC: R _f = 0.32 (SiO ₂ : chloroform) The crude base was dissolved in diethyl ether (40 mL) and treated with oxalic acid (0.895 g) in ethanol (2 mL). The crystalline hydrogen oxalate was removed by filtration and recrystallized from a mixture of 96% ethanol (40 mL) and diethyl ether (40 mL). This means that 2.33 g (78%) of 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl ) Ethyl pentanoate hydrogen oxalate was provided.

A mixture of the above ethyl ester (2.0 g, 0.005 mol), 15% sodium hydroxide (7 mL) and ethanol (10 mL) was stirred at room temperature for 3 hours,
I left it. Next, the reaction mixture was poured into dichloromethane (150 mL), and concentrated hydrochloric acid was used to adjust the pH.
Acidified to 1. The organic phase was separated, washed with water (10 mL), dried (Mg
SO ₄ ) and evaporated under vacuum. The oily residue was re-evaporated twice with acetone and then triturated with hot acetone (20 mL). The solid was removed by filtration, washed with acetone and dried. This was a crystalline solid (1.67 g, 82%
) Provided the title compound (1.67 g, 82%). M. p. 221-226 ° C. Calculated (C ₂₁ H ₂₄ N ₂ O ₂ , HCl): C, 64.86%; H, 6.48%; N, 7.20%; Cl, 9.12%; H, 6.71%; N, 7.06%; Cl, 8.83%. Example 6 3- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -propionic acid-hydrochloride

[0065]

Embedded image

1,3,4,14b-Tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepine in ethanol (30 mL) (1.3 g, 0.3 g).
00515 mol) and ethyl acrylate (0.64 g, 0.00644 mol)
Was heated to 70 ° C. for 3 hours. The mixture was evaporated under vacuum and the residue was neutralized with a solution of oxalic acid (0.63 g) in ethanol (2 mL). The precipitated hydrogen oxalate was removed by filtration and recrystallized from a mixture of absolute ethanol (55 mL) and ether (50 mL). This corresponds to 1.58 g (69%) of 3- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl ) Propionic acid ethyl ester hydrogen oxalate was provided as a crystalline solid.

The above ester (base liberated from hydrogen oxalate; 1.26 g, 0.0035
7 mol) in ethanol (9 mL) and 15% sodium hydroxide (5 mL) was added. The reaction mixture was stirred for 3 hours at room temperature and left overnight. The reaction mixture was poured into dichloromethane (150 mL) and acidified to pH 1 with concentrated hydrochloric acid. The dichloromethane layer was separated, washed with water (10 mL), dried (MgSO ₄ ) and evaporated under vacuum. The oily residue was re-evaporated twice with acetone and then triturated with hot acetone (20 mL). This provided the title compound as a crystalline solid (0.87g, 68%). M. p. 192-196 ° C. Calculated (C ₁₉ H ₂₀ N ₂ O ₃ , HCl): C, 63.24%; H, 5.87%; N, 7.76%; Cl, 9.83%; H, 6.04%; N, 7.69%; Cl, 9.86%.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/02 A61P 19/02 25/02 25/02 25/06 25/06 29/00 29/00 101 101 C07D 513/04 391 C07D 513/04 391 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL , PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, B , BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU , SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Andersen, Knut Erik, Denmark, Danko-2605 Brenby, Hubedemmarksby 10 (72) Inventor Olsen, Uveban, Denmark-2625 Valensbek, Horsbrett 111 (72) Inventor Polifka, Zdenek Cecco, 150 00 Prague 5, Zvorovsk 23 (72) ) Inventor Shinderaru, Charles Cecco countries, 140 00 Prague 4, Ol Buraetoba 50 F-term (reference) 4C072 AA01 AA06 BB02 BB07 CC02 CC11 CC16 EE09 EE19 FF08 GG01 UU01 4C086 AA01 AA02 AA03 CB22 CB30 MA01 NA14 ZA01 ZA02 ZA08 ZA89 ZB11 ZB15 ZB21 ZC35

Claims (32)

[Claims] (1) Formula 1: Wherein R ¹ and R ² are independently hydrogen, halogen, trifluoromethyl, hydroxy, C _1-6 -alkyl or C _1-6 -alkoxy; X is —O—, —S— or R is 0,1,2,3,4,5,6,7,8,9 or 10; and Z is Wherein R ³ is — (CH ₂ ) _m OH or — (CH ₂ ) _p COR ⁴ , wherein m and p are independently 0, 1, 2, 3, or 4 and R ⁴ is OH , NH ₂ , NHO
H or C _1-6 -alkoxy)) or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ¹ and R ² are selected from hydrogen, halogen, trifluoromethyl or C _1-6 -alkyl, preferably hydrogen. 3. A compound according to any one of the preceding claims, wherein X is -O- or -S-. 4. The compound according to claim 1, wherein r is 0, 1, 2, 3, or 4. Wherein Z is A compound according to any one of the preceding claims, characterized in that a -R ^3. 6. The method according to claim 1, wherein R ³ is — (CH ₂ ) _p COR ⁴ , wherein p is 0, 1, 2, or 3. Compound. 7. The compound according to claim 1, wherein R ⁴ is OH. 8. The following compound: 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl)- Butanoic acid; 4- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) -butanoic acid; A compound selected from pharmaceutically acceptable salts. 9. The following compound: 5- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl)- Pentanoic acid; 3- (1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] thiazepin-2-yl) -propionic acid; 5- ( 1,3,4,14b-tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -pentanoic acid; 14b-Tetrahydro-2H-dibenzo [b, f] pyrazino [1,2-d] [1,4] oxazepin-2-yl) -propionic acid; or a pharmaceutically acceptable salt thereof. 10. A process for preparing a compound of general formula I, comprising a compound of formula II: Wherein R ¹ , R ² and X are as defined above, with a compound of formula III
: Wherein R and Z are as defined above, and W is a suitable leaving group, to form a compound of Formula I. 11. Pharmaceutical composition comprising as active ingredient a compound according to claim 1 together with a pharmaceutical carrier or diluent. 12. A pharmaceutical composition suitable for treating neurogenic inflammation, comprising administering an effective amount of a compound according to any one of claims 1 to 9 to a pharmaceutically acceptable carrier or diluent. And a pharmaceutical composition comprising the same. 13. A pharmaceutical composition suitable for treating neuropathy, comprising combining an effective amount of a compound according to any one of claims 1 to 9 with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition comprising: 14. A pharmaceutical composition suitable for treating rheumatoid arthritis, which comprises combining an effective amount of a compound according to any one of claims 1 to 9 with a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions containing together. 15. A pharmaceutical composition suitable for treating migraine, comprising an effective amount of a compound according to any one of claims 1 to 9 together with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition comprising: 16. A pharmaceutical composition suitable for treating pruritus, comprising an effective amount of a compound according to any one of claims 1 to 9 together with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition comprising: 17. A pharmaceutical composition suitable for treating non-insulin dependent diabetes mellitus (NIDDM), comprising an effective amount of a compound according to any one of claims 1 to 9 in pharmaceutically acceptable form. A pharmaceutical composition comprising a carrier or diluent. 18. A pharmaceutical composition suitable for treating insulin resistance, comprising: administering an effective amount of a compound according to any one of claims 1 to 9 to a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions containing together. 19. The pharmaceutical composition according to any one of claims 11 to 18, comprising 0.5 mg to 1000 mg of the compound according to any one of claims 1 to 9 per unit dose. 20. A method of treating neurogenic inflammation, which comprises an effective amount of claim 1.
A method comprising administering a compound according to any of claims 9 to 9 to a subject in need of said treatment. 21. A method of treating neurogenic inflammation, comprising administering the pharmaceutical composition of claim 11 to a subject in need of said treatment. 22. A method for treating non-insulin dependent diabetes mellitus (NIDDM), comprising administering an effective amount of a compound according to any one of claims 1 to 9 to a subject in need of said treatment. Including methods. 23. A method of treating non-insulin dependent diabetes mellitus (NIDDM), comprising administering the pharmaceutical composition of claim 11 to a subject in need of said treatment. 24. A method of treating insulin resistance comprising administering to a subject in need of said treatment an effective amount of a compound according to any one of claims 1-9. 25. A method of treating insulin resistance, comprising administering the pharmaceutical composition of claim 11 to a subject in need of said treatment. 26. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating neurogenic inflammation. 27. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating neuropathy. 28. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating rheumatoid arthritis. 29. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating migraine. 30. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating pruritus. 31. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating non-insulin dependent diabetes mellitus (NIDDM). 32. Use of a compound according to any one of claims 1 to 9 for preparing a pharmaceutical composition for treating insulin resistance.