JP2002508353A - New heterocyclic compounds - Google Patents

Abstract

  (57) [Summary] The present invention relates to a compound of the formula (I) wherein X, Y, R¹, R^1a, R^Two, R^2a, R¹², R ¹³, A, r, and s are described in detail herein), or salts thereof, methods for their preparation, compositions comprising them, and C-fibers. Play a pathophysiological role by causing neuropathic pain or inflammation, their use for the clinical treatment of painful, hyperalgesic and / or inflammatory conditions, and caused by the secretion and circulation of insulin antagonist peptides Or related indications, such as non-insulin dependent diabetes mellitus (NIDDM) and their use for the treatment of aging-related obesity.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to a novel N-substituted azaheterocyclic compound in which a substituted alkyl chain forms part of an N-substituent, a salt thereof, a process for producing them, a composition containing them, and a C-fiber. Use of said compounds for the manufacture of a composition for the clinical treatment of a painful, hyperalgesic and / or inflammatory condition which plays a pathophysiological role, and said painful, hyperalgesic and / or A method for treating an inflammatory condition. The present invention also provides
The present invention relates to the use of the present compounds for reducing blood glucose and / or inhibiting the secretion, circulation and effects of insulin antagonist peptides such as CGRP or amylin, which are known to interfere with neuropeptides including C fibers. Thus, the compounds can be used to treat non-insulin dependent diabetes mellitus (NIDDM) and obesity associated with aging to improve glucose tolerance.

BACKGROUND OF THE INVENTION The nervous system plays a profound role in the inflammatory response. Retrograde stimulation of sensory nerves causes localized vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1
967, 31, 138-51), and similar responses are seen with subsequent injections of peptides known to be present in sensory nerves. From this and other data, it is hypothesized that peptides released from sensory nerve endings mediate many inflammatory responses in tissues such as skin, joints, urinary tract, eyes, meninges, gastrointestinal tract and airways. You. Thus, inhibition of the release and / or activity of sensory neuropeptides may be associated with, for example, arthritis, dermatitis, rhinitis, asthma,
Useful in the treatment of cystitis, gingivitis, thrombophlebitis, glaucoma, gastrointestinal disorders or migraine.

Furthermore, the fact that C fibers are distributed in the liver, intestine, and pancreas suggests that they regulate various functions. Its peptidic neural distribution has been shown to regulate glucose tolerance in rodents (Karlsson et al. Am. J. Physiol. 26
7, R1071-R1077, 1944, Guillot et al. Life Sci. 969-977, 1996). In addition, the potential effect of CGRP on skeletal muscle glycogen synthesis activity and muscle glucose metabolism, coupled with the notion that this peptide is released from neuromuscular junctions by nerve excitation, causes CGRP to become a glycogen store for phosphorylated glucose. by the release and transfer to glycolytic and oxidative pathways from, suggesting that may play a physiological role in skeletal muscle glucose metabolism (Rossetti et al. Am. J. Physiol. 26 4, E1-E10, 1993) . This peptide represents an important physiological regulator of intracellular glucose transport in physiological conditions, such as exercise, and in senescence, where the circulation of plasma levels of NIDDM or CGRP is significantly increased, such as NIDDM or CGRP. It may also contribute to reduced insulin action and skeletal muscle glycogen synthesis in associated obesity (Melnyk et al. Obesity Res. 3 , 337-344, 1995). Therefore, inhibition of the release and / or activity of the neuropeptide CGRP and other sensory neuropeptides is 2
It may be useful in the treatment of insulin resistance associated with type diabetes or aging.

In US Pat. Nos. 4,383,999 and 4,514,414 and EP 236342 and 231996, N- (4,4-2substituted-3-
Some derivatives of butenyl) azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. EP 342635 and 37480
No. 1 claims an N-substituted azaheterocyclic carboxylic acid, in which the oxime ether and vinyl ether groups each form part of an N substituent, as GABA uptake inhibitors. In British Patents 1,228,736, 1,294,550 and 1,330,966, derivatives of N-substituted piperidines were claimed as being useful as psychotropic agents. Further, International Patent Publication Nos. 9107389 and 922
In 0658, N-substituted azaheterocyclic carboxylic acids were claimed as inhibitors of GABA uptake. EP 221572 claimed that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake. WO 9631498 discloses N-substituted azaheterocyclic carboxylic acids and esters thereof. SUMMARY OF THE INVENTION The present invention provides a compound of the general formula wherein X, Y, R ¹ , R ^1a , R ² , R ^2a , R ¹² , R ¹³ , A, r and s are defined in the detailed part of this specification. I.

The compounds are useful for all painful, hyperalgesic and / or inflammatory conditions in which C fibers play a pathophysiological role, such as nervous pain, neuroinflammation, migraine, neuropathy,
Indications caused by or related to the secretion and circulation of pruritus and rheumatoid arthritis and insulin antagonist peptides and other peptides from the sensory nervous system, such as for obesity associated with non-insulin dependent diabetes mellitus (NIDDM) and aging Is useful for the treatment, prevention, elimination, reduction or improvement of

In another aspect, the present invention relates to a medicament comprising as active ingredient at least one compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. Compositions are included within the scope of the present invention. In another aspect of the invention, a painful, hyperalgesic and / or inflammatory condition in which C fibers play a pathophysiological role, such as neural pain, neuroinflammation, migraine,
There is provided a method of treating obesity caused by or related to neuropathy, pruritus and rheumatoid arthritis, and the secretion and circulation of insulin antagonist peptides, such as non-insulin dependent diabetes mellitus (NIDDM) and aging. .

[0007] The method of treatment comprises administering to the subject a neurologically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, wherein one of the above symptoms is indicated. It may be described as treatment, prevention, elimination, reduction or improvement. A further aspect of the present invention is that all painful, hyperalgesic and / or inflammatory conditions in which C fibers play a pathophysiological role, such as nervous pain, neurogenic inflammation, migraine, neuropathy, pruritus And for the treatment of indications caused or related to the secretion and circulation of insulin antagonist peptides and other peptides derived from rheumatoid arthritis and sensory nerves, such as non-insulin dependent diabetes mellitus (NIDDM) and aging related obesity. It relates to the use of a compound according to the invention for the manufacture of a pharmaceutical composition.

[0008] Further objects will become apparent from the description below. Due to the detailed description of the invention, the invention relates to the general formula I

[0009]

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[Where R¹, R^1a, R^TwoAnd R^2aIs independently hydrogen, halogen, cyano, tri
Fluoromethyl, methylthio, hydroxy, C_1-6Alkyl or C_1-6Alkoki
X is ortho-phenylene, -O-, -S-, -C (R^ThreeR^Four)-, -CH_TwoC
H_Two-, -CH = CH-CH_Two-, -CH_Two-CH = CH-, -CH_Two− (C =
O)-,-(C = O) -CH_Two-, -CH_TwoCH_TwoCH_Two-, -CH = CH-,
−N (R^Five)-(C = O)-,-(C = O) -N (R^Five)-, -O-CH_Two−,
-CH_Two-O-, -O-CH_Two-O-, -CH_Two-O-CH_Two-, -S-CH_Two -, -CH_Two-S-,-(CH_Two) N (R^Five)-, -N (R^Five) (CH_Two) −,
-N (CH_Three) SO_Two−, −SO_TwoN (CH_Three)-, -CH (R⁶) CH_Two−,
-CH_TwoCH (R⁶)-,-(C = O)-, -N (R⁷)-Or-(S = O)-
Where R^Three, R^Four, R^FiveAnd R⁷Is independently hydrogen or C_1-6With alkyl
Yes, and R⁶Is C_1-6Y is alkyl or phenyl;N−,>CH-,>N-(C = O)-or>C= C (R⁸)-
Where only the underlined atoms participate in the ring system and R⁸Is hydrogen or C_1-6With alkyl
A is -CH = CR⁹−, − CR⁹= CH-,-C≡C-,-(C = O)-,-
(C = CH_Two)-,-(CR⁹R^Ten)-, -CH (OR¹¹)-, -CH (NHR ¹¹ )-, Phenylene, C_3-7A cycloalkylene or a single bond, wherein R⁹Passing
And R^TenIs independently hydrogen, C_1-6Unbranched alkyl, C_3-6Branched alkyl or C_3-8 Cycloalkyl and R¹¹Is hydrogen or C_1-6R and s are independently 0, 1, 2, 3 or 4; R¹²Is hydrogen,-(CH_Two)_nOH or-(CH_Two)_pCOR¹⁷And where
n is 1,2,3,4,5 or 6 and p is 0 or 1 and R¹⁷ Is -OH, -NHR²⁰Or C_1-6Alkoxy, where R²⁰Is hydrogen or C_{1- 6} Alkyl; and R¹³Is cyano, -NR^FiveR⁷, -NR^Five-Z or-(CHR^{twenty one})_q-Z
, Where R^FiveAnd R⁷Is as defined above, and q is 0,1,2
, 3,4,5 or 6 and R^{twenty one}Is hydrogen, halogen, cyano, trifluoro
Lomethyl, hydroxy, C_1-6Alkyl, C_1-6Alkoxy, -NR^FiveR⁷Or
-COOH and Z is C_3-8Cycloalkyl, aryl or heteroaryl
Wherein the ring is one or more of halogen, cyano, trifluoromethyl,
Droxy, methylthio, C_1-6Alkyl or C_1-6Optionally substituted with alkoxy
A novel N-substituted azaheterocyclic compound or a medicament thereof.
Permissible salts.

A compound of formula I wherein X is —S— and Y is>N−,>CH- or>C= C
Or where X is -CH_TwoCH_TwoAnd Y is>N-And R¹² Is -CONH_TwoAnd R¹³Is -N (CH_Three)_TwoOr piperidino;
Or where X is -O-, -C (CH_Three)_Two, -CH_TwoCH_Two-, -CH = CH-
, -O-CH_Two-, -CH_Two-O-, -S-CH_Two-Or -CH_Two-S-
Yes; Y is>C= CH-, R¹²Is hydrogen, hydroxy, -CONH_TwoOr -COC _Two H_FiveAnd R¹³Is -N (CH_Three)_Two, Piperidino, morpholino
Where phenyl is optionally substituted with chlorin, methyl or trifluoromethyl
Is known from the prior art.

The compounds of formula I can exist as geometric and optical isomers and all isomers, as separated, pure or partially purified stereoisomers or racemized mixtures thereof, Is included in the scope of the present invention. Isomers can be separated by standard methods, for example, by chromatography techniques or fractional crystallization of appropriate salts.

Preferably, the compounds of formula I 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 hydrochlorides, hydrobromides,
Sulfate, acetate, fumarate, maleate, citrate, lactate, tartrate,
Includes oxalates or similar pharmaceutically acceptable inorganic and organic acid addition salts. Further examples of pharmaceutically acceptable inorganic and organic acid addition salts include the pharmaceutically acceptable salts described in the Journal of Pharmaceutical Science , 66, 2 (1977) known to those skilled in the art.

Also included are the hydrates of the above-mentioned acid addition salts which the present compounds may form. Acid addition salts can be obtained as a direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent, including the appropriate acid and a salt, isolated by evaporation of the solvent or by precipitation or crystallization. The compounds of formula I may be administered in the form of pharmaceutically acceptable acid addition salts or, where possible, as metal or lower alkyl ammonium salts. Such salt forms exhibit about the same activity value as the free base form.

In the structural formulas above and throughout the specification, the following terms have the indicated meanings: alone or in combination, as used herein, the term “C _1-6 alkyl” The term refers to a straight or branched, carbohydrate chain having from 1 to 6 carbon atoms. Examples of such groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, se
c-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,
Including 2-methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4-methylpentyl, neopentyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl, etc. It is not limited to these.

The term “halogen” means fluorine, chlorine, bromine or iodine. As used herein, alone or in combination, “C _1-6 alkoxy”
Is a C _1-6 alkyl of the indicated length, in either a linear or branched or cyclic configuration, attached through the oxygen of said ether having its free valence bond from the oxygen of the ether. It is intended to include groups. 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 cyclopropoxy, cyclobutyroxy, cyclopentyloxy and cyclohexyloxy.

As used herein, the term “C _3-8 cycloalkyl” refers to a carbocyclic group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,
Represents cyclohexyl, cycloheptyl, cyclooctyl and the like. The term "C _3-7 cycloalkylene" as used herein, 2-substituted carbocyclic group having 3 to 7 carbon atoms, for example cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene And so on.

As used herein, the term “aryl” refers to a carbocyclic aromatic ring system such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl) , Phenanthrenyl, fluorenyl, indenyl and the like. The term "heteroaryl" as used herein refers to a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furyl, thienyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiadinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinolinyl, quinolinolyl It is intended to include naphthyridinyl, pteridinyl, carbazolyl, acridinyl and the like. Heteroaryl is also intended to include partially or fully hydrogenated derivatives of the heterocyclic systems listed above. Examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl,
Indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl, and tetrahydrfuranyl.

In a preferred embodiment of the present invention, R¹, R^1a, R^TwoAnd R^2aIs hydrogen, halogen
, Trifluoromethyl or C_1-6Selected from alkyl. Preferably R¹, R ^1a , R^TwoAnd R^2aIs hydrogen. In another preferred embodiment of the present invention, X is -S-, -CH_TwoCH_Two-, -CH
= CH-, -O-CH_Two-, -CH_Two-O-, -OCH_TwoO-, -S-CH_Two−
Or -CH_Two-S-. Preferably X is -CH_TwoCH_Two-.

In another preferred embodiment of the invention, Y is selected from> N— or> C = C (R ⁸ ) —, wherein R ⁸ is hydrogen. Preferably Y is> C = CH-. In another preferred embodiment of the present invention, A is a single bond or-(CR ⁹ R ¹⁰ )-, wherein R ⁹ and R ¹⁰ are hydrogen. In another preferred embodiment of the present invention, r is 0, 1 or 2.

In another preferred embodiment of the invention, s is 0, 1 or 2. In another preferred embodiment of the invention, R¹²Is hydrogen or-(CH_Two)_pCOR¹⁷ Where p is 0 and R¹⁷Is -OH or -NH_TwoIt is. In another preferred embodiment of the invention, R¹³Is cyano, -N (CH_Three)_Two, -N
HZ or-(CHR^{twenty one})_q-Z, wherein q is 0 or 1, and R ^{twenty one} Is hydrogen, cyano or -COOH, and Z is cyclohexyl, phenyl
, Naphthyl or pyrrolidinyl; this ring is optionally substituted with halogen or methyl
Can be done.

A preferred compound of the present invention is: 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-phenyl-4-piperidinecarboxylic acid Acid; 4- (4-chlorophenyl) -1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid; (4-methylphenyl) -1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid; 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-anilino-4-piperidinecarboxamide; 2- ( -(3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinyl) -2-phenylacetonitrile; 2- (1- (3- ( 10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinyl) -2-phenylacetic acid; 1- (3- (10,11-dihydro-5H- Dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-cyano-4-piperidinecarboxylic acid; 1- (3- (10,11-dihydro-5H-dibenzo [b, f] azepine- 5
-Yl) -1-propyl) -4-phenylpiperidine; 4-benzyl-1- (3- (10,11-dihydro-5H-dibenzo [a, d
Cycloheptene-5-ylidene) -1-propyl) -piperidine; 4-cyclohexyl-1- (3- (10,11-dihydro-dibenzo [a, d
] Cycloheptene-5-ylidene) -propyl) -4-piperidinecarboxylic acid; 1- (3- (10,11-dihydro-dibenzo [a, d] cycloheptene-5)
-Ylidene) -1-propyl) -4-((naphthalen-2-yl) methyl) -4
-Piperidinecarboxylic acid; 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-pyrrolidino-4-piperidinecarboxylic acid amide; And their salts acceptable as

The novel compounds of formula I have been shown to inhibit neuroinflammation, which involves the release of neuropeptides from peripheral and central terminals of sensory C fibers. This has been demonstrated in animal models of histamine-induced paw edema by Amann et al. (Europ. J. Pharmacol. 279, 227-
231, 1995), where the novel compounds of formula I are
Shows potential inhibitory effects. The compounds of formula I can be used to treat all painful, hyperalgesic and / or inflammatory conditions, where nervous pain or inflammation, ie: migraine, postoperative pain, burns, bruises Severe painful conditions, exemplified by postherpetic pain (shingles) and pain usually associated with severe inflammation; various types of neuropathy (diabetic, posttraumatic, toxic), neuralgia, rheumatoid arthritis, Spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, cough, asthma, pruritus, chronic pancreatitis,
C fibers play a pathophysiological role by causing pain in osteoporosis, an inflammatory skin disease including psoriasis and autoimmune skin diseases.

Furthermore, the compounds of the general formula I reduce glucose levels and improve glucose tolerance in diabetic rodents (ob / ob mice and diabetic obese Zucker rats), and this has been shown to It has been demonstrated that the release of CGRP from the brain and other peptides from the sensory nervous system may be due to reduced release. Therefore,
The compounds of general formula I can be used for the treatment of obesity associated with NIDDM and aging.
This is demonstrated by the ob //
Experimentally demonstrated by subcutaneous administration of glucose to ob mice.

Compounds of formula I are prepared according to the following method A:

[0026]

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[0027] Formula II wherein R ¹ , R ² , R ^1a , R ^2a , X, Y, A, r and s are as defined above, and W is a suitable leaving group such as halogen, The compound of p-toluenesulfonic acid or mesylate can react with an azaheterocyclic compound of formula III wherein R ¹² and R ¹³ are as defined above, and A compound of Formula I is provided. This alkylation reaction is carried out in a solvent such as acetone, N, N-dimethylformamide, acetonitrile, dibutyl ether, 2-butanone, ethyl acetate, tetrahydrofuran (THF) or toluene, with a base,
For example, the reaction can be carried out in the presence of sodium hydride, potassium carbonate and a catalyst such as an alkali metal iodide at a temperature until the reflux temperature of the solvent used is reached, for example, for 1 to 120 hours. If R ¹⁷ has produced an ester of an alkoxy, then R ¹⁷ is OH of formula I
Is preferably at room temperature, an aqueous alkali metal hydroxide solution and an alcohol,
For example, it can be prepared by hydrolysis of the ester group in a mixture of methanol or ethanol, for example for about 0.5 to 6 hours.

The compounds of formulas II and III can be easily prepared by methods well known to those skilled in the art. Alternatively, compounds of formula I can be prepared according to the following method B:

[0029]

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[0030] Formula II wherein R ¹ , R ² , R ^1a , R ^2a , X, Y, A, r and s are as defined above, and W is a suitable leaving group such as halogen, p- compound toluenesulfonic acid or mesylate) may be reacted with the aza compound of formula IV, and formula ^{V (R 1, R 2,} R 1a, R 2a, X, Y, a, r and s Is as defined above). This alkylation reaction is carried out in a solvent such as acetone, N, N-dimethylformamide, acetonitrile, dibutyl ether, 2-butanone, ethyl acetate, tetrahydrofuran (THF) or toluene and a base such as sodium hydride, potassium carbonate and a catalyst, For example, in the presence of an alkali metal iodide, at a temperature up to the reflux temperature of the solvent used, for example, 1 to 1
It can be performed for 20 hours. Compounds of formula V are represented by formula VI wherein R ¹ , R ² , R ^1a , R ^2a ,
X, Y, A, r and s are as defined above, and G can be converted to a compound of a suitable leaving group such as halogen, p-toluenesulfonic acid or mesylate. The compound of formula VI can react with an α-activated compound of formula VII (where R ¹² and R ¹³ are as defined above) and give a compound of formula I. The alkylation reaction is carried out in a solvent such as N, N-dimethylformamide,
In tetrahydrofuran, ethanol, toluene, N-methylpyrrolidone or hexamethylphosphoramide in the presence of a base such as potassium t-butoxide, sodium ethanoate, sodium hydride, potassium carbonate or triethylamine at the reflux temperature of the solvent used. This is performed at a temperature until the temperature reaches, for example, 1 to 120 hours.
If R ¹⁷ has produced an ester of an alkoxy, the compound of formula I wherein R ¹⁷ is OH is
Preferably at room temperature, it can be prepared in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example by hydrolysis of the ester group for about 0.5 to 6 hours.

The compounds of formulas II, IV and VII can be easily prepared by methods well known to those skilled in the art. In the right environment, the intermediates used in the above methods, for example the compound of formula III, will need to be protected using a suitable protecting group. The carboxylic acid groups can be esterified, for example. The introduction and removal of such groups is referred to as “Protective Groups in
Organic Chemistry "JFW McOrnie ed. (New York, 1973). Pharmacological Methods I. The histamine paw edema test in histamine-induced paw edema rats was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231, 1995).
３００300 g male Sparague-Dawley rats 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 20 minutes later the swollen paw was determined by water flow (Ugo Basile). Test compounds were administered intraperitoneally 15 minutes before anesthesia. II. Ob / ob female mice, whose age at which CGRP release decreased was 16 weeks, were injected subcutaneously with glucose (2 g / kg). After this, blood glucose was measured occasionally in the tail vein by the glucose oxidase method. At the end of the study, the animals were decapitated and the collected blood was stored. Immunoreactive CGRP was measured in plasma by immunoradiometric assay. Two groups of animals were used. One population was treated with vehicle, while the other population received the compound of Formula I via drinking water (100 mg / L) for 5 days prior to testing.

Inhibition values of the histamine-induced edema response of some representative compounds are recorded in Table 1.

[0033]

[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 I or a pharmaceutically acceptable salt thereof, and usually such a composition also comprises , A pharmaceutically acceptable carrier or diluent. Compound comprising at pharmaceutical compositions of the present invention, for example, Remington:. The Science and Practise of Pharmacy, 19 th Ed, may be prepared by such conventional techniques described in 1995. The composition will be apparent in conventional form, for example, as a capsule, tablet, aerosol, solution, suspension or topical application.

A carrier or diluent, or diluted by a carrier, or a capsule,
A typical composition comprises a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable excipient, which may be enclosed in a carrier which may be in the form of a sachet, wrapper or other container. In preparing the present compositions, conventional techniques for preparing pharmaceutical compositions may be used. For example, the active compound will usually be mixed with or diluted with a carrier, or enclosed in a carrier which may be in the form of an ampoule, capsule, sachet, wrapper, or other container. When the carrier is provided as a diluent, it can be a solid, semi-solid, or liquid material that acts as an excipient, excipient, or medium for the active compound. The active compound can be absorbed in a granular solid container, for example, a sachet. Some examples of suitable carriers include 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 esters of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides. Similarly, the carrier or diluent includes any sustained release agent known in the art, such as glyceryl monoesterate or glyceryl distearate, alone or in admixture with a wax. The preparation also comprises a wetting agent,
It may contain emulsifying and suspending agents, preservatives, sweeteners or flavorings. The preparations of the present invention provide a rapid, active ingredient release after administration to a patient by applying methods known in the art.
It may be prepared to provide a sustained or delayed release.

The pharmaceutical composition may, if desired, be formulated with sterilizing agents, such as adjuvants, emulsifiers, salts for affecting osmotic pressure, buffers and / or coloring substances, which do not deleteriously react with the active compound on the mind and body. And can be mixed. This route of administration may be any route that effectively delivers the active compound to the appropriate or desired site of action, for example oral, nasal, transdermal or parenteral, for example rectal, depot, subcutaneous,
It can be by intravenous, intraurethral, intramuscular, topical, intranasal, ophthalmic or ointment, preferably oral route.

If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in powder or pill form, or it may be 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 or a 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 include solubilizing agents, for example, polyethylene glycol, surfactants, absorption enhancers, for example, lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, for example, additives such as parabens.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. 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. Syrups or elixirs may be used where sweetened excipients may be applied.

Typical tablets that can be manufactured by conventional tableting techniques are: Core: Active compound (no compound or salt thereof) 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, Microcrist (Avicel) 70 mg Improved cellulose Gas (Ac-Di-Sol) 7.5 mg Magnesium stearate Coating: HPMC about 9 mg ^* Miwasset 9-40 T may contain about 0.9 mg.

^* Acylated monoglycerides used as plasticizers for film coating The compounds of the present invention may be used in any painful, hyperalgesic and / or inflammatory condition where C-fibers play a therapeutic role, such as neurological Pain, neuroinflammation, migraine, neuropathy, pruritus and rheumatoid arthritis and symptoms caused by or related to the secretion and circulation of insulin antagonist peptides, such as non-insulin dependent diabetes (
NIDDM) and obesity associated with aging, such treatment, prevention,
It can be administered to mammals, especially humans, in need of elimination, reduction or improvement. Such mammals also include both livestock, eg, domestic pets, and non-domestic animals, eg, wildlife.

The compounds of the present invention may be present simultaneously, simultaneously or together with a pharmaceutically acceptable carrier or diluent, in the form of its alkali metal or alkaline earth metal salts, particularly and preferably in an effective amount. May be administered in the form of a pharmaceutical composition thereof. The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of humans, a dosage of about 0.5 to about 1000 mg, preferably about 1 to about 500 mg, of a compound of Formula I is conveniently given 1 to 5 times a day. 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 form of administration, the form desired to be administered, the treatment desired, 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. Would.

In general, the compounds of the present invention can be prepared in unit dosage form comprising, in or together with a pharmaceutically acceptable carrier, from about 50 to about 200 mg of the active ingredient per unit dose. . In general, dosage forms suitable for oral, nasal, pulmonary or transdermal administration include from about 0.5 mg to about 1000 mg, preferably about 1 mg, mixed with a pharmaceutically acceptable carrier or diluent.
From about 500 mg of a compound of formula I.

The method of treatment may be described as the treatment of symptoms caused by or related to secretion and circulation of an insulin antagonist peptide such as CGRP or amylin in a subject in need thereof, Administering to the subject a neurologically 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 preparation of the compounds of the formula I and the preparations containing them are further illustrated in the following examples, which should not, however, 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 either elemental analysis or NMR, where peaks pointing to characteristic protons in the title compound are present at appropriate places. ^{The 1} H NMR shift (δ _H ) is expressed in parts per million (
ppm). M. p. Is the melting point, and C is given and is not accurate. Column chromatography was performed using WC Still et al, J. Org. Chem. (1
978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385). The compounds used as starting materials are either known compounds or compounds which can be easily prepared by methods known per se. Example 1 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-phenyl-4-piperidinecarboxylic acid

[0047]

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3- (10,11-dihydro-5H-dibenzo [a,
d] To a solution of cycloheptene-5-ylidene) propanol (3.5 g, 14 mmol) was added triethylamine (4 ml) and methanesulfonyl chloride (2.0 g, 1
7.4 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. Water was added and the layers were separated. The organic layer was dried (MgSO ₄ ) and 2-butanone (
The solvent was evaporated in vacuo to give a residue that dissolved in 50 ml). Ethyl 4-phenyl-4-piperidine-carboxylate hydrogen bromide (4.4 g, 14 mmol) and potassium carbonate (4.4 g, 32 mmol) were added and the mixture was heated at reflux for 24 hours. The mixture was filtered and the solvent was evaporated in vacuo. 5.3 g of 1 as an oil
(3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5
Silica gel (5%) using ethyl acetate as eluent to give -ylidene) -1-propyl) -4-phenyl-4-piperidinecarboxylic acid ethyl ester.
The oily residue was purified by column chromatography on 0 g).

TLC: Rf = 0.25 (SiO ₂ ; chloroform / ethanol / ammonium hydroxide = 60: 2: 0.1) The above ester (4.75 g, 10.5 mmol) was dissolved in ethanol (40 ml). Dissolve and add 5N sodium hydroxide (5 ml). The mixture is left for 20 hours.
Stir at 40 ° C., evaporate the ethanol in vacuo and add water (50 ml) followed by acetic acid (4 ml). The mixture was extracted with dichloromethane (100 ml), the organic layer was dried (MgSO _4), and evaporated the solvent in vacuo. The residue was crystallized from diethyl ether to give 2.2 g (45%) of the title compound as a solvate of water and acetic acid.

El (m / z): 437 (M ⁺ , C ₃₀ H ₃₁ NO ₂ , 0.1%), 436 (0.
1%), 435 (0.1%), 392 (0.1%), 246 (2.6%), 23
2 (1.5%), 218 (100%), 203 (2.9%), 202 (2.8%
), 190 (2.2%), 172 (4.2%), 91 (6%). C ₂₉ H ₃₁ NO ₂ , 0.5 CH ₃ COOH, 0.5H ₂ O requires C, 77.56%; H, 7.38%, N, 3.02%; found: C, 77. 50%; H, 6.88%, N, 2.88%. Example 2 4- (4-chlorophenyl) -1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid hydrochloride

[0051]

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Ethyl 4- (4-chlorophenyl) -4-piperidinecarboxylic acid toluene-4-sulfonate (2.2 g, 0.005 mol, ester in 2-butanone (60 ml) as p-toluenesulfonate) Except for isolation, prepared analogously as described in Polish Patent 105435 or Belgium Patent 74,1433 (1941)), 5- (3-bromo-1-propylidene) -10,11-dihydro- 5H-dibenzo [a, d] cycloheptene (2.0 g, 0.0064 mol),
Anhydrous potassium carbonate (3.00 g, 0.021 mol) and potassium iodide (2.
0 g, 0.012 mol) was stirred for 7.5 hours at 60-70 ° C. The mixture was diluted with ether (90ml) and water (60ml) and the layers were separated. The aqueous layer was extracted with additional ether (60 ml) and the combined organic extracts were extracted with water (
60 ml) and dried (MgSO ₄ ). The solvent was removed in vacuo and the oily residue (3.47 g) was purified by gradient column chromatography on silica gel using a mixture of benzene and ethyl acetate as eluent. 2.65 g of benzene / ethyl acetate (9: 1) fraction was 4- (4-chlorophenyl)
-1- (3- (10,11-Dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid ethyl ester was provided.

TLC: Rf = 0.65 (SiO ₂ ; chloroform / ethanol (10: 1) saturated with ammonia) The above ester (2.20 g, 0.0044 mol) and 20% sodium hydroxide in ethanol (18 ml) (2 ml) was stirred at room temperature for 24 hours and left for a further 24 hours. The ethanol was evaporated in vacuo and the residue was dissolved in dichloromethane (300ml). The resulting solution was acidified with acetic acid, washed with water (3 × 15 ml), and the organic layer was dried (MgSO ₄ ). The solvent was evaporated in vacuo, the residue was dissolved in a mixture of ether and acetone (1: 1, 20 ml) and the solution was acidified with a solution of hydrogen chloride in ether. The solvent was evaporated in vacuo, the amorphous residue was dissolved twice in acetone (20 ml) and re-evaporated in vacuo. The solid was suspended in dry ether (100 ml) and stirred for 3 hours at room temperature. The precipitate was filtered and dried in vacuo to give 1.85 g (82%) of the title compound.

M. p. 234-239 ° C. C₃₀H₃₀CINO_Two, HCl, 0.25H_TwoTheory for O: C, 70.24%; H, 6.19%, Cl, 13.82%; N, 2.73%;
Found: C, 70.28%; H, 6.22%, Cl, 13.88%; N, 2.60%. Example 3 4- (4-methylphenyl) -1- (3- (10,11-dihydro-5H-di
Benzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-pipe
Lysine carboxylate

[0055]

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Ethyl 4- (4-methylphenyl) -4-piperidinecarboxylate (3.0 g, 0.012 mol, Polish Patent 105 in 100 ml of 2-butanone)
435 or Belgian Patent 74,1433 (1941)), 5- (3-bromo-1-propylidene) -10,
11-dihydro-5H-dibenzo [a, d] cycloheptene (4.50 g, 0.
0145 mol), anhydrous potassium carbonate (5.00 g, 0.036 mol) and potassium iodide (4.0 g, 0.024 mol) were stirred at 80 ° C for 7.5 hours. The mixture was diluted with ether (150ml) and water (150ml) and the layers were separated. The aqueous layer was extracted with additional ether (80 ml) and the combined organic layers were extracted with water (100 ml)
And dried (MgSO ₄ ). The solvent was removed in vacuo and the oily residue (6.60 g) was purified by gradient column chromatography on silica gel using a mixture of benzene and ethyl acetate as eluent. The benzene / ethyl acetate (9: 1) fraction was 2.90 g (50%) of 4- (4-methylphenyl) -1- (3- (10,11-dihydro-5H-dibenzo [a, d Cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid ethyl ester.

TLC: Rf = (SiO_TwoThe above ester (2.50 g, 0.0052 mol) and ethanol in ethanol (25 ml).
And a mixture of 20% sodium hydroxide (3.4 ml) was stirred at room temperature for 36 hours.
At room temperature for 3 days. The ethanol is evaporated in vacuo and the residue is
Dissolved in tan (120 ml). Water (10 ml) was added and the solution was acidified with acetic acid,
Then the aqueous layer was separated. The organic layer was washed with water (10 ml) and dried (MgSO _Four )did. The solvent was evaporated in vacuo and the residue (2.30 g) was taken up in ether and acetone.
Dissolve in the mixture (1: 1, 20 ml) and dilute the solution with hydrogen chloride in ether
And acidified. The solvent is transferred from the separated solid to another container and the precipitate is dried fresh.
Stir for 0.5 h with a portion of the tel (20 ml) and let stand overnight. Filtration and removal
After water, this provided 1.8 g (71%) of the title compound.

M. p. 164-170 ° C. _{C 31 H 33 NO 2, HCl} , 0.5H 2 O of theory: C, 74.91%; H, 7.10%, Cl, 7.13%; N, 2.82%; Found: C , 74.50%; H, 7.21%, Cl, 7.22%; N, 2.65%. Example 4 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-anilino-4-piperidinecarboxamide dihydrochloride

[0059]

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5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [
a, d] cycloheptene (2.65 g, 8.46 mmol), 4-anilino-4-piperidinecarboxamide (1.85 g, 8.44 mmol, Belgian Patent No. 777)
812 (1972)), potassium carbonate (1.3
g, 9.4 mmol) and N, N-dimethylformamide (8 ml) were stirred and heated at 100 ° C. for 5 hours. Add benzene (100 ml) and water (100 ml)
Then the layers were separated. The organic layer was dried (K ₂ CO _3), and evaporated the solvent in vacuo. The residue was purified by gradient column chromatography on silica gel (30 g) using a mixture of benzene and ethyl acetate as eluent. This provided 1.97 g of crude base dissolved in diethyl ether and neutralized with hydrogen chloride in diethyl ether. The precipitate was crystallized from a mixture of ethanol and acetone to give 1.70 g (38%) of the title compound as a hemihydrate.

M. p. 180-182 ° C. C₃₀H₃₃N_ThreeO, 2HCl, 0.5H_TwoTheory for O: C, 67.53%; H, 6.80%, Cl, 13.29%; N, 7.88%;
Found: C, 67.67%; H, 6.84%, Cl, 13.37%; N, 7.75%. Example 5 2- (1- (3- (10,11-dihydro-5H-dibenzo [a, d] cyclo)
Heptene-5-ylidene) -1-propyl) -4-piperidyl) -2-phenyl
Acetonitrile hydrochloride

[0062]

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3- (10,11-Dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propylmethanesulfonate (4.78 g) in dry N, N-dimethylformamide (20 ml) , 0.0145 mol) in a solution of 2- (4-piperidyl) -2-phenylacetonitrile (4.4 g, 0.0219 mol, Tetr
ahedron 22, 1996, 272) and potassium carbonate (5.0 g). The reaction mixture was heated at 80 C for 6 hours. After cooling to room temperature, water (120 ml) was added and the mixture was treated with diethyl ether (2 ml).
× 100 ml). The combined organic layers were washed with water (3 × 50 ml). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (100 g) using chloroform as eluent. This provided 2.5 g of oil. This oil was dissolved in diethyl ether (100 ml) and the solution was acidified with hydrogen chloride in diethyl ether. The precipitate was filtered, washed with diethyl ether and dried in vacuum. This provided 2.2 g (32%) of the title compound.

M. p. 125-131 ° C. _{C 31 H 32 N 2, HCl} , 0.5H 2 O of theory: C, 77.88%; H, 7.17%, N, 5.86%; Cl, 7.42%; Found: C , 77.95%; H, 7.05%, N, 6.05%; Cl, 7.54%. Example 6 2- (1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinyl) -2-acetic acid phenylhydrochloride

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3- (10,11-Dihydro-5H-dibenzo [2-butanone (80 ml)
a, d] cycloheptene-5-ylidene) -1-propylmethanesulfonate (
5.4 g, 0.0165 mol) in a solution of α-phenyl-α- (4-piperidinyl) acetic acid ethyl ester (4.0 g, 0.0165 mol, British Patent No. 58962).
No. 5, C.I. A. 42,226 (1948)) and potassium carbonate (5.7 g, 0.0412 mol) were added and the reaction mixture was added
Heat at 0 ° C. for 4 hours, leave at room temperature overnight, and heat at reflux for 8 hours. The precipitated solid was filtered and the filtrate was evaporated in vacuo. The residue (8) was obtained by column chromatography on silica gel (300 g) using chloroform as eluent.
. 88g) was purified. This means that 4.4 g (56%) of 2- (1- (3
-(10,11-dihydro-5H-dibenzo [a, d] -cycloheptene-5
Ylidene) -1-propyl) -4-piperidinyl) -2-acetic acid phenylethyl ester was provided.

TLC: Rf = 0.20 (SiO ₂ ; chloroform) The above ester (2.0 g, 0.00416 mol) in ethanol (18.5 ml)
)), A solution of sodium hydroxide (0.62 g) in water (2.4 ml) was added. The reaction mixture was stirred at room temperature for 3 days and then heated at reflux for 8 hours. Concentrated hydrochloric acid (2.4 ml) and dichloromethane (120 ml) were added, the organic layer was separated, dried (MgSO ₄ ) and evaporated in vacuo. The residue was stirred with acetone (40 ml) and the solid was filtered and washed with acetone. This is 1.1g
(54%) of the title compound was provided.

M. p. 240-255 ° C (decomposition point) Theoretical value of C ₃₁ H ₃₃ NO ₂ , HCl, 0.5H ₂ O: C, 74.90%; H, 7.10%, N, 2.81%; Cl, 7 .13%; found: C, 74.96%; H, 7.36%, N, 2.81%; Cl, 7.10%. Example 7 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-cyano-4-piperidine-carboxylic acid

[0069]

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Methanesulfonic acid 3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl ester (13.0 g, 39 mmol)
) And diethanolamine (5.2 g, 50 mmol) in acetonitrile (100 ml).
) And heated at 50 ° C. for 20 hours. Cool the reaction mixture to room temperature,
Water (300 ml) was added and the mixture was extracted with ether (3 × 60 ml). The organic layer of the composite was washed with brine (50 ml), dried (MgSO _4), and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel (130 g) using tetrahydrofuran as eluent. This is 10.2 g (75%) of bis (2-hydroxyethyl)-(3- (1
0,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -amine was prepared.

To the above amine (10 g, 29 mmol) dissolved in dichloromethane (200 ml) was added thionyl chloride (10.7 g, 90 mmol) at 0 ° C. and the mixture was left at room temperature for 6 hours. The crude reaction mixture was concentrated in vacuo and tetrahydrofuran (100
ml), redissolved in dichloromethane (50 ml) and precipitated with petroleum ether (100 ml). After 30 minutes, the solvent was transferred to another container and the sticky residue was left under vacuum overnight. This corresponds to 8.9 g (75%) of bis (2-chloroethyl)-(3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -amine hydrochloride. Salt was provided.

The above chloride (0.50 g, 1.2 mmol) and ethyl cyanoacetate (0.45 g, 4
mmol) and (0.55 g, 4 mmol) were suspended in N, N-dimethylformamide (10 ml). Potassium tert-butoxide (0.25 g, 2 mmol) was added and the reaction mixture was left at room temperature overnight. Ice water (50 ml) was added and the reaction mixture was extracted with ether (3 × 50 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo. Mixtures of dichloromethane and methanol (20:
Using 1), by column chromatography on silica gel (20 g),
The resulting oil was purified. The pure fractions were combined, concentrated in vacuo and ethanol (
10 ml). Sodium hydroxide (0.40 g, 10 ml) was added and the mixture was stirred for 30 minutes. Water (20 ml) was added and the mixture was added to ether (2
0 ml). The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid and dichloromethane (
3 × 50 ml). The combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo. The crude product was recrystallized from deuteriochloroform to give 0.
09 g (17%) of the title compound were provided.

TLC: Rf = 0.55 (SiO ₂ ; dichloromethane / methanol / acetic acid = 1)
0: 2: 1) HPLC retention time = 21.32 minutes (5 mm C18 4 x 250 mm column, 0
. Using a 20-80% gradient of 1% trifluoroacetic acid / acetonitrile and 0.1% trifluoroacetic acid / water at room temperature for 30 minutes or longer) Example 8 1- (3- (10,11-dihydro-5H-) Dibenzo [b, f] azepine-5
-Yl) -1-propyl) -4-phenylpiperidine hydrogen oxalate

[0074]

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3- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) -propylmethanesulfonate (2.6 g, 7.85 mmol), 4-phenylpiperidine (1.6 g) , 9.94 mmol), potassium carbonate (3.0 g, 21.7 mmol)
) And methyl ethyl ketone (50 ml) were heated and stirred at 80 ° C. for 24 hours. The mixture was filtered and the solvent was removed by evaporation in vacuo.
The crude residue was purified by column chromatography on silica gel (35 g) using ethyl acetate as eluent. This is 2.4 g as an oily base (
77%) of 1- (3- (10,11-dihydro-5H-dibenzo [b, f] azepin-5-yl) -1-propyl-4-phenylpiperidine. , Prepared by treatment with oxalic acid in a mixture of acetone and diethyl ether.

M. p. 157-159 ° C. Theory for C ₂₈ H ₃₂ N ₂ , C ₂ H ₂ O ₄ : C, 74.05%; H, 7.04%, N, 5.76%; Found: C, 73.87%; H, 7.14%, N, 5.81%. Example 9 4-benzyl-1- (3- (10,11-dihydro-5H-dibenzo [a, d
Cycloheptene-5-ylidene) -1-propyl) -piperidine hydrochloride

[0077]

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5- (3-Bromo-1-propylidene) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene (50 ml) in N, N-dimethylformamide (50 ml)
1.56 g, 0.005 mol), 4-benzylpiperidine (1.75 g, 0.05 mol)
1 mol) and potassium carbonate anhydride (2.8 g) were stirred at 100 ° C. for 2 hours. After cooling, the reaction mixture was diluted with benzene (100 ml) and water (5 × 50 ml)
Washed with), dried (K ₂ CO ₃₎ and evaporated in vacuo. The oily residue (2.8 g) was purified by chromatography on silica gel (80 g) using chloroform as eluent. This gives 1.95 g of 4-benzyl- as oil.
1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -piperidene is provided and solubilized in diethyl ether and Treated with a solution of hydrogen chloride.
The precipitate was filtered, washed with diethyl ether and dried in vacuo to give 1.92 g (
87%) yielded the title compound.

M. p. 134-136 ° C. _{C 30 H 32 N, HCl,} 0.25H 2 O of theory: C, 80.51%; H, 7.54%, Cl, 7.92%; N, 3.13%; Found: C, 80.43%; H, 7.73%, Cl, 8.26%; N, 3.36%. Example 10 4-cyclohexyl-1- (3- (10,11-dihydro-dibenzo [a, d
Cycloheptene-5-ylidene) -propyl) -4-piperidinecarboxylic acid hydrochloride

[0080]

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5- (3-bromopropylidene) -5H-dibenzo [a, d] cycloheptene (4.45 g, 14.2 mmol), ethyl 4-cyclohexyl-4-piperidinecarboxylate (3.4 g, 14.3 g). 2 mmol, GB 1124661 (1967)
)), Potassium carbonate (2.1 g, 15.2 mmol).
) And N, N-dimethylformamide (10 ml) were heated at 120 ° C for 5 hours.
Benzene (50 ml) and water (50 ml) were added and the layers were separated. The organic layer was dried and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using a mixture of benzene and chloroform as eluent, and 2.6 g (39%) of 1- (3- (5H-dibenzo [a,
d] Cycloheptene-5-ylidene) -1-propyl) -4-cyclohexyl-
4-Piperidinecarboxylic acid ethyl ester was provided.

TLC: Rf = 0.65 (SiO ₂ : chloroform / ethanol / ammonia = 30: 1: 0.05) The above ester (1.2 g, 2.5 mmol) was dissolved in tert-butanol (30 ml). And potassium hydroxide (10 g) was added. Mix the mixture at 120 ° C for 10
Heated for hours. Water (50 ml) was added followed by benzene (50 ml) and the layers were separated. The aqueous layer was treated with acetic acid and extracted with dichloromethane. The combined organic layers were dried (MgSO ₄ ) and the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane, treated with hydrogen chloride in diethyl ether and the solvent was evaporated in vacuo. The residue was triturated with diethyl ether. This is 0.68g (55%
) Was provided.

M. p. 241-246 ° C. _{C 30 H 38 NO 2, HCl} , H 2 O of theory: C, 72.34%; H, 8.09%, N, 2.81%; Cl, 7.12%; Found: C, 72 H, 8.06%, N, 2.56%; Cl, 6.92%. Example 11 1- (3- (10,11-dihydro-dibenzo [a, d] cycloheptene-5)
-Ylidene) -1-propyl) -4-((naphthalen-2-yl) methyl) -4
-Piperidine carboxylate

[0084]

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Potassium hexamethyldisilazane in tetrahydrofuran (50 ml) {31.
5 mmol, prepared from hexamethyldisilazane (5.3 g, 32.8 mmol) and potassium hydride (6.3 g, 31.5 mmol, 20% suspension in oil). -Tert-butyloxycarbonyl-4-
Piperidine carboxylate (7.0 g, 26.9 mmol) was added at −70 ° C. while stirring.
Was added dropwise. After 30 minutes, 2-naphthylmethyl bromide (5.6 g, 25.3 mmol) in tetrahydrofuran (30 ml) was added. Stirring was continued at -70 ° C for 2 hours, and the mixture was then left overnight. Water (30 ml) was added and the mixture was extracted with ethyl acetate (200 ml), the organic layer was dried (MgSO ₄ ) and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (100 g) using benzene and chloroform as eluents and ethyl-1-tert-butyloxycarbonyl-4- (2-naphthylmethyl) -4-as an oil.
Piperidine carboxylate (4.8 g) was provided.

TLC: Rf = 0.60 (SiO ₂ : benzene / diethyl ether = 1: 1) The above ester is dissolved in ethyl acetate and the solution is treated with gaseous hydrogen chloride at 0 ° C. for 2 hours did. After standing overnight, the solvent was evaporated in vacuo and the residue was treated with ammonium hydroxide and extracted with diethyl ether. The organic layer was dried (K ₂ CO _3), and the solvent was evaporated, ethyl 4- (2-naphthylmethyl) -
4-Piperidinecarboxylate (3.2 g) was provided.

TLC: Rf = 0.20 (SiO ₂ : benzene / diethyl ether = 1: 1) The above ester (3.2 g, 10.7 mmol) was converted to N, N-dimethylformamide (
10 (m) and 5- (3-bromopropylidene) -5H-dibenzo [a,
d] cycloheptene (3.4 g, 10.8 mmol) and potassium carbonate (1.6 g)
, 11.6 mmol). The mixture was heated at 100 ° C. for 7 hours. Benzene (5
0 ml) and water (50 ml) were added and the layers were separated. The organic layer was dried and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using a mixture of benzene and chloroform as eluent, and 44.0 g (71%) of 1- (3- (5H-dibenzo [a, d] Cycloheptene-5-ylidene) -1-propyl) -4- (2-naphthylmethyl)-
4-Piperidinecarboxylic acid ethyl ester was provided.

TLC: Rf = 0.75 (SiO ₂ : chloroform / ethanol / ammonium hydroxide = 20: 1: 0.05) The above ester (2.28 g, 4.3 mmol) was added to tert-butanol (30 ml).
And potassium hydroxide (10 g) was added. Mix the mixture at 120 ° C for 10
Heated for hours. Water (50 ml) was added followed by benzene (50 ml) and the layers were separated. The organic layer was dried and the solvent was evaporated in vacuo. The residue was dissolved in acetone, treated with hydrogen chloride in diethyl ether, filtered (Norite) and evaporated. The residue was triturated with diethyl ether to form an amorphous solid.
. 35 g (61%) of the title compound were provided.

Theory for C ₃₅ H ₃₅ NO ₂ , HCl, 0.5 H ₂ O: C, 76.83%; H, 6.82%, N, 2.56%; Cl, 6.48%; Values: C, 76.91%; H, 7.17%, N, 2.34%; Cl, 6.30%. Example 12 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-pyrrolidino-4-piperidinecarboxylic acid amide dihydrochloride

[0090]

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To a solution of 1-benzyl-4-pyrrolidino-4-piperidinecarboxamide (4.18 g, 0.0145 mol) in methanol (110 ml) was added Pd (OH) ₂ / C catalyst (1.1 g). And the reaction mixture is brought to 1.6-1.3 MPa at room temperature.
For hydrogenation. The catalyst was filtered off and the filtrate was evaporated down i. This provided 2.8 g (100%) of 4-pyrrolidino-4-piperidinecarboxamide as a solid.

The above piperidine (2.43 g, N, N-dimethylformamide (80 ml)
0.0123 mol), 3- (10,11-dihydro-5H-dibenzo [b, f]
Azepin-5-yl) propyl methanesulfonate (4.05 g, 0.129 mol)
l), potassium carbonate (3.4 g, 0.0246 mol) and sodium iodide (0 g).
. 2g) was stirred at 60 ° C for 5 hours and left at room temperature overnight. The reaction mixture was diluted with benzene (200 ml), the solid was filtered and the filtrate was washed with water (4 × 100 ml)
, Dried (MgSO ₄ ) and evaporated in vacuo. Chloroform and a mixture of chloroform and methanol saturated with ammonia (10
The residue was purified by gradient column chromatography on silica gel (400 g) using 0: 1). This means that 2.30 g (44%) of 1- (3-
(10,11-Dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-pyrrolidene-4-piperidinecarboxamide was provided.

TLC: Rf = 0.18 (SiO ₂ : chloroform saturated with methanol / ammonia = 1: 9) The above carboxamide (2.30 g) was dissolved in ethanol (15 ml) and the solution was hydrogen chloride With saturated ether. The mixture was stirred for 2 hours and the precipitate was filtered, washed with ether (3 × 30 ml) and dried.
This provided 2.6 g of the title compound.

M. p. 219-224 ° C. _{C 27 H 36 N 4 O,} 2HCl, H 2 O of theory: C, 61.94%; H, 7.70%, N, 10.70%; Cl, 13.54%
Found: C, 62.03%; H, 7.48%, N, 10.55%; Cl, 13.74%
. Example 13 1- (3- (10,11-dihydro-dibenzo [a, d] cycloheptene-5
-Ylidene) -1-propyl) -4-dimethylamino-4-piperidinecarboxamide dihydrochloride

[0095]

Embedded image

5- (3-bromopropylidene) -10,11-dihydro-5H-dibenzo [
a, d] cycloheptene (1.87 g, 6.0 mmol), 4-dimethylamino-4
-Piperidinecarboxamide dihydrochloride (1.5 g, 6.2 mmol, J.I.
Med. Chem. 7,619 (1964)), potassium carbonate (4.1 g)
, 30 mmol), potassium iodide (1.0 g, 6.0 mmol) and 2-butanone (3
0 ml) of the mixture was stirred at reflux for 10 hours. The mixture was filtered and the solvent was evaporated, providing 2.8 g of an oil. Using silica gel and a mixture of chloroform and 5,10,20,30 or 40% ethanol as eluent, silica gel (1
This was purified by chromatography on 50 g) to give 1.4 g as a solid.
(58%) of 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-dimethylamino-4-piperidinecarboxamide. . The solid was dissolved in acetone (15ml) and treated with concentrated hydrochloric acid (0.7ml). The resulting mixture was stirred at room temperature for 2 hours and then filtered. The solid was washed with acetone (5ml) and dried to provide 1.3g of the title compound.

M. p. 245-248 ° C. C ₂₆ H ₃₃ N ₃ O, 2HCl, 0.25H ₂ O requires: C, 64.92%; H, 7.44%, N, 8.74%; Cl, 14.74%;
Found: C, 64.95%; H, 7.36%, N, 8.66%; Cl, 14.59%.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 3/10 A61P 3/10 19/02 19/02 25/18 25/18 29/00 29/00 101 101 C07D 211/14 C07D 211/14 211/34 211/34 211/62 211/62 211/66 211/66 401/06 401/06 (81) Designated country 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, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ) , TM), AL, AM, AT, AU, AZ BA, BB, 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, ZW (72) Inventor Hallberg, Rolf Denmark-3490 Kvist Gard, Nibobai 6 (72) Inventors Andersen, Knut Erik, Denmark, Daco-2765 Smelm, Ritterparken 64 (72) Inventors Olsen, Uffeban, Denmark, Daco-2625 Valens Baek, Rusuburedo 111 (72) inventor Shinderaru, Charles Cecco countries, 140 00 Prague 4, Ol Buraefutoba 50 (72) inventor Shiruhankoba, Alexandra Cecco countries, 142 00 Prague 4, base. Stifluff 1311/3 (72) Inventor Konigova, Otirije Cecco, 110 00 Prague 1, Mai Selova 19 (72) Inventor Polifka, Zdenec Cecco, 150 00 Prague 5, Zvolovska 23 F-term (reference) 4C054 AA02 CC02 DD01 EE01 FF04 FF08 FF18 FF19 FF32 FF38 4C063 AA01 AA03 BB03 CC19 DD10 EE01 4C086 AA01 AA02 AA03 AA04 BC21 BC32 GA07 MA01 MA02 MA04 MA05 NA14 ZA01 ZA70 ZA96 ZB11 ZB15 ZC35

Claims (29)

[Claims] 1. A compound of the formula I[Where R¹, R^1a, R^TwoAnd R^2aIs independently hydrogen, halogen, cyano, tri
Fluoromethyl, methylthio, hydroxy, C_1-6Alkyl or C_1-6Alkoki
X is ortho-phenylene, -O-, -S-, -C (R^ThreeR^Four)-, -CH_TwoC
H_Two-, -CH = CH-CH_Two-, -CH_Two-CH = CH-, -CH_Two− (C =
O)-,-(C = O) -CH_Two-, -CH_TwoCH_TwoCH_Two-, -CH = CH-,
−N (R^Five)-(C = O)-,-(C = O) -N (R^Five)-, -O-CH_Two−,
-CH_Two-O-, -O-CH_Two-O-, -CH_Two-O-CH_Two-, -S-CH_Two -, -CH_Two-S-,-(CH_Two) N (R^Five)-, -N (R^Five) (CH_Two) −,
-N (CH_Three) SO_Two−, −SO_TwoN (CH_Three)-, -CH (R⁶) CH_Two−,
-CH_TwoCH (R⁶)-,-(C = O)-, -N (R⁷)-Or-(S = O)-
Where R^Three, R^Four, R^FiveAnd R⁷Is independently hydrogen or C_1-6With alkyl
Yes, and R⁶Is C_1-6Y is alkyl or phenyl;N−,>CH-,>N-(C = O)-or>C= C (R⁸)-
Where only the underlined atoms participate in the ring system and R⁸Is hydrogen or C_1-6With alkyl
A is -CH = CR⁹−, − CR⁹= CH-,-C≡C-,-(C = O)-,-
(C = CH_Two)-,-(CR⁹R^Ten)-, -CH (OR¹¹)-, -CH (NHR ¹¹ )-, Phenylene, C_3-7A cycloalkylene or a single bond, wherein R⁹Passing
And R^TenIs independently hydrogen, C_1-6Unbranched alkyl, C_3-6Branched alkyl or C_3-8 Cycloalkyl and R¹¹Is hydrogen or C_1-6R and s are independently 0, 1, 2, 3 or 4; R¹²Is hydrogen,-(CH_Two)_nOH or-(CH_Two)_pCOR¹⁷And where
n is 1,2,3,4,5 or 6 and p is 0 or 1 and R¹⁷ Is -OH, -NHR²⁰Or C_1-6Alkoxy, where R²⁰Is hydrogen or C_{1- 6} Alkyl; and R¹³Is cyano, -NR^FiveR⁷, -NR^Five-Z or-(CHR^{twenty one})_q-Z
, Where R^FiveAnd R⁷Is as defined above, and q is 0,1,2
, 3,4,5 or 6 and R^{twenty one}Is hydrogen, halogen, cyano, trifluoro
Lomethyl, hydroxy, C_1-6Alkyl, C_1-6Alkoxy, -NR^FiveR⁷Or
-COOH and Z is C_3-8Cycloalkyl, aryl or heteroaryl
Wherein the ring is one or more of halogen, cyano, trifluoromethyl,
Droxy, methylthio, C_1-6Alkyl or C_1-6Optionally substituted with alkoxy
Or a pharmaceutically acceptable salt thereof. 2. The compound of the formula I according to claim 1, wherein X is --S--.
If you see, YN−,>CH- or>C= CH-; and further X is -CH_TwoCH_Two− And Y is>N-And R¹²Is -CONH_Two , Then R¹³Is -N (CH_Three)_TwoOr piperidino; and
X is -O-, -C (CH_Three)_Two, -CH_TwoCH_Two-, -CH = CH-, -O-
CH_Two-, -CH_Two-O-, -S-CH_Two-Or -CH_Two-S-; Y is> C = CH- and R¹²Is hydrogen, hydroxy, -CONH_TwoOr -COO
C_TwoH_Five, Then R¹³Is -N (CH_Three)_Two, Piperidino, morpholino or
Cannot be phenyl, where phenyl is chlorin, methyl or trifluoromethyl
Can be arbitrarily substituted with 3. The compound according to claim ¹ , wherein R ¹ , R ^1a , R ² and R ^2a are independently hydrogen, halogen, trifluoromethyl or C _1-6 alkyl, preferably hydrogen. 4. X is —CH ₂ CH ₂ —, —CH ＝ CH—, —O—CH ₂ —,
_{-CH 2 -O -, - OCH 2} O -, - S-CH 2 - or -CH ₂ -S-, preferably -CH ₂ CH ₂ - which is, according to any one of claims 1 to 3 Compound. 5. The compound according to claim 1, wherein Y is> N- or> C = CH-, preferably> C = CH-. 6. The compound according to any one of claims 1 to 5, wherein A is a single bond or-(CR ⁹ R ¹⁰ )-, wherein R ⁹ and R ¹⁰ are hydrogen. 7. The compound according to claim 1, wherein r is 0, 1 or 2. 8. The compound according to claim 1, wherein s is 0, 1 or 2. 9. The method of claim 1, wherein R ¹² is hydrogen or — (CH ₂ ) _p COR ¹⁷ , wherein p is 0, and R ¹⁷ is —OH or —NH _2. The compound according to item. 10. R ¹³ is _{cyano, -N (CH 3) 2,} -NH-Z or - (C
HR ²¹ ) _q -Z, where q is 0 or 1, and R ²¹ is hydrogen, cyano or —COOH, and Z is cyclohexyl, phenyl, naphthyl or pyrrolidinyl, wherein the ring is halogen or 10. The compound according to any one of claims 1 to 9, which can be optionally substituted with methyl. 11. 1- (3- (10,11-dihydro-5H-dibenzo [a
, D] cycloheptene-5-ylidene) -1-propyl) -4-phenyl-4-
Piperidine carboxylic acid; 4- (4-chlorophenyl) -1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid; 4- (4-methylphenyl) -1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinecarboxylic acid; 1- ( 3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-anilino-4-piperidinecarboxamide; 2- (1- (3- (10, 2- (1) 11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinyl) -2-phenylacetonitrile; 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-piperidinyl) -2-phenylacetic acid; Dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-cyano-4-piperidinecarboxylic acid; 1- (3- (10,11-dihydro-5H-dibenzo [b, f] Azepine-5
-Yl) -1-propyl) -4-phenylpiperidine; 4-benzyl-1- (3- (10,11-dihydro-5H-dibenzo [a, d
Cycloheptene-5-ylidene) -1-propyl) -piperidine; 4-cyclohexyl-1- (3- (10,11-dihydro-dibenzo [a, d
] Cycloheptene-5-ylidene) -propyl) -4-piperidinecarboxylic acid; 1- (3- (10,11-dihydro-dibenzo [a, d] cycloheptene-5)
-Ylidene) -1-propyl) -4-((naphthalen-2-yl) methyl) -4
-Piperidinecarboxylic acid; 1- (3- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-propyl) -4-pyrrolidino-4-piperidinecarboxylic acid amide; 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. 12. 1- (3- (10,11-dihydro-dibenzo [a, d])
Cycloheptene-5-ylidene) -1-propyl) -4-dimethylamino-4-
A compound which is piperidinecarboxamide or a pharmaceutically acceptable salt. 13. A) Formula II embedded image(Where R¹, R^Two, R^1a, R^2a, X, Y, A, r and s are as defined above.
And W is a suitable leaving group) of the formula II
I(Where R¹²And R¹³Is the same as defined above).
Forming a compound of formula I; or B) a compound of formula II(Where R¹, R^Two, R^1a, R^2a, X, Y, A, r and s are as defined above.
And W is a suitable leaving group) and a compound of formula IVWith an aza compound of formula V(Where R¹, R^Two, R^1a, R^2a, X, Y, A, r and s are as defined above.
The same applies) and the compound of formula V is converted to a compound of formula VI(Where R¹, R^Two, R^1a, R^2a, X, Y, A, r and s are as defined above.
And G is a suitable leaving group), and
Compounds of Formula VI and Formula VII(Where R¹²And R¹³Is the same as defined above).
And reacting the compound of formula I (where R¹, R^Two, R^1a, R^2a, X, Y, A, r, s, R ¹² And R¹³Is the same as defined above).
The method for producing the compound according to claim 1. 14. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 12 together with a pharmaceutical carrier or diluent. 15. The composition according to claim 1, together with a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition suitable for treating neurogenic inflammation, comprising an effective amount of a compound according to any one of claims to 12. 16. The method according to claim 1, wherein the pharmaceutically acceptable carrier or diluent is used together with the pharmaceutically acceptable carrier or diluent.
13. A pharmaceutical composition suitable for the treatment of neuropathy, comprising an effective amount of a compound according to any one of claims to 12. 17. The method according to claim 1, together with a pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition suitable for the treatment of rheumatoid arthritis comprising an effective amount of a compound according to any one of claims to 12. 18. The method according to claim 1, wherein the pharmaceutically acceptable carrier or diluent is used together with the pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition suitable for the treatment of non-insulin dependent diabetes mellitus (NIDDM) comprising an effective amount of a compound according to any one of claims to 12. 19. The compound according to any one of claims 1 to 12, comprising between 0.5 mg and 1000 mg per unit dose.
17 is the pharmaceutical composition according to 18; 20. A method of treating neurogenic inflammation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 12. 21. A method for treating neuropathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 12. 22. A method of treating rheumatoid arthritis in a subject in need of treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 12. 23. Non-insulin dependent diabetes mellitus (NIDDM) in a subject in need of treatment comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 12. Treatment method. 24. Non-insulin dependent diabetes mellitus (NIDDM) in a subject in need of treatment comprising administering to the subject a pharmaceutical composition according to claim 23.
) Treatment method. 25. Use of a compound according to any one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of neurogenic inflammation. 26. Use of a compound according to any one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of a neurological disease. 27. Use of a compound according to any one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of rheumatoid arthritis. 28. Use of a compound according to any one of claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of non-insulin dependent diabetes mellitus (NIDDM). 29. Any novel feature of the combination of features described herein.