MXPA00004399A - Imidazoylalkyl substituted with a five, six or seven membered heterocyclic ring containing one nitrogen atom - Google Patents

Abstract

Disclosed are compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof. Also disclosed are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a Compound of Formula (I). Further disclosed is a method of treating allergy (for example asthma), inflammation, hypotension, raised intraocular pressure (such as glaucoma) i.e., a method of lowering intraocular pressure, sleeping disorders, states of hyper and hypo motility and acidic secretion of the gastrointestinal tract, hypo and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimer's, Schizophrenia, obesity and migraine) comprising administering an effective amount of a compound of Formula (I) to a patient in need of such treatment. Also disclosed are methods for treatment of upper airway allergic responses comprising administering a compound, or salt or solvate thereof, of Formula (I) in combination or admixture with a histamine H1 receptor antagonist.

Description

IMIDAZOILALQUILO SUBSTITUTES WITH A HETEROCICLIC RING OF FIVE, SIX OR SEVEN MEMBERS THAT CONTAINS AN ATOM OF NITROGEN BACKGROUND The H3 receptor sites are known and of common interest to those skilled in the art - for example, see: West, Jr. et al., "Biexponential Kinetics of (R) -a [3H] Methylhistamine Binding to the Rat Brain H3 Histamine Receptor ", Journal of Neurochemistry, Vol. 55, No. 5, pp. 1612-1616, 1990; West. Jr. et al., "Identification of Two H3-Histamine Receptor Subtypes", Molecular Pharmacology, 38: 610-613; and Korte et al., "Characterization and Tissue Distribution of H3 Histamine Receptor in Guinea Pigs by Na-Methylhistamine", Biochemical and Biophysical Research Communications, Vol. 168, No. 3, pp. 979-986. Arrang et al. In U.S. 4,767,778 (issued August 30, 1988) describes a pharmaceutical composition containing a histamine derivative having the formula: wherein R1, R2, and R4 represent a hydrogen atom or a methyl, or R1 and R taken together represent a methylene group, and R3 is a hydrogen atom, a methyl or a carboxy, with the proviso that Ri, R2 R3 and R4 are not simultaneously methyl groups. It is stated that the derivatives behave as complete agonists of the H3 receptors in the brains of rats and that they produce a maximum inhibition of release that is identical to that induced by histamine (approximately 60%). It has also been claimed that histamine derivatives strongly inhibit the release and synthesis of histamine by very selectively stimulating H3 receptors. Therefore, according to Arrang et al., It is possible that the derivatives reduce histaminergic transmission in the digestive tract and in the nervous, cardiovascular and immune systems. Arang et al. Affirms that the derivatives can be used in therapy as a drug that has a sedative effect, as a sleep regulator, as an anticonvulsant, as a regulator of hypothalmic-pituitary, antidepressant secretion, and modulator of cerebral circulation. According to Arrang et al., The inhibition of the release of inflammatory messengers in various allergic conditions (eg, asthma) is assumed to be a result of the stimulation of the H3 receptors of the lungs. It has also been described that the inhibition of gastric histamine release probably exerts antisecretory and antiulcerative effects. According to Arrang et al., Modifying the release of messengers from immune responses probably modulates these latter responses. The Derwent Summary 86-273706 / 42 for European Patent 0 197 840 describes imidazole derivatives having the formula: wherein Ei is H, methyl or ethyl; R is H or R2; and R 2 is C 1-6 alkyl-piperonyl, 3- (benzimidazolone-1-yl) propyl, -CZ-NHR 5 or a group (i): where n is 0-3; X is a bond, O, S, NH, CO, CH = CH or a group (ii): R3 is H, methyl or halo, CN, CF3 or COR4; R is C 1-6 alkyl, C 6-3 cycloalkyl or phenyl (optionally substituted with methyl or F); Z is O, S, NH, N-methyl or N-CN; and R 5 is C 1-8 alkyl, C 3-6 cycloalkyl (optionally substituted with phenyl), C 3-6 cycloalkyl (C 1-3) alkyl, phenyl (optionally substituted with methyl, halo or CF 3), phenyl (C 1-3) alkyl, naphthyl, adamantyl or p-toluenesulfonyl. It has been claimed that these compounds are psychotropic agents. It has also been claimed that these compounds antagonize histamine H3 receptors and increase the rate of brain turnover of histamine. The Derwe summary 90-184730 / 24 for US Pat. No. 4,925,851 discloses compounds 2- or 4- (2- (1 H-imidazol-1-yl) ethyl) piperidine which with useful as antitumor agents to inhibit lymphomas, sarcoma, myelomas and leukemia. The compounds have the formula: wherein R is -CH2 (CH2) m-Me, -CO- (CH2) m-Me or -CO-CMe2; M is 2-18; R2 is H or Me, Ri is - (CH2) n -R3; n is 0-13; R3 is H, i-Pr or t-Bu; and the floating group is in the 2- or 4- position; with the proviso that (1) the sum of the C atoms in R-i does not exceed 13; and (2) the sum of the C atoms in R and R-i does not exceed 25. WO 93/12107 published June 24, 1993, discloses a compound having the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein (A) m is a number selected from the group consisting of: 1 and 2: (B) n and p are integers and each is independently selected from the group consisting of: 0, 1, 2, 3, and 4 so that the sum of n and p is 4 and T is a ring of 6 members; (C) R3 and R4 are each independently linked to the same carbon atom or a carbon atom different from the T ring so that there is only one R3 group and one R4 group on the T ring, and each R1, R2, R3, and R4 is independently selected from the group consisting of: (1) H; (2) alkyl Ci to Ce, and (3) - (CH2) q -R6 where q is an integer of: 1 to 7, and R6 is selected from the group consisting of: phenyl, substituted phenyl, -OR7, -C (O) OR7, -C (O) OR7, -OC (O) OR7, -C (O) NR7r8, CN and -SR7 in which R7 and R8 are as defined below, and wherein the substituents in said substituted phenyl is each independently selected from the group consisting of -OH, -O-alkyl (C? a C, 6), halogen, Ci alkyl to Ce, -CF3, -CN, and NO2, and wherein said substituted phenyl contains from 1 to 3 substituents; (D) R5 is selected from the group consisting of: (1) H; (2) Ci to C2o alkyl; (3) C3 to C6 cycloalkyl; (4) -C (O) OR7; where R7 is the same as R7 defined below except that R7 is not H; (5) -C (O) OR7; (6) -C (O) OR7R6; (7) allyl; (8) propargyl; and (9) - (CH2) q-R6, where q and R6 are as defined above, and when q equals 1, then R6 is not OH or SH; (E) R7 and R6 are each independently selected from the group consisting of: H, Ci to C6 alkyl; (F) the dotted line () represents a double bond that is optionally present when m is 1, and n is not 0, and p is not 0, and when said double bond is present then R2 is absent; and (G) when m is 2, each R1 is an equal or different substituent for each m, and each R2 is a same or different substituent for each m, and at least two of the substituents R1 and / or R2 are H. These two last documents claim the use of the compounds for the treatment of allergy and other disorders. European patent 0 428 434 A2 as well as WO 96/29315 and WO 95/06037 describe a wide range of compounds and claim their use as an H3 (ant) agonist receptor. The previously cited documents also include an illustrative summary of the art that refers to this field of chemistry. U.S. Patent Application No. 08/689951 filed August 16, 1996, and U.S. Patent Application No. 08/909319 filed August 14, 1997 (equivalent to Argentine Patent Application No. P 97) 01 03693), describe compositions for the treatment of allergic rhinitis symptoms using a combination of at least one histamine Hi receptor antagonist and at least one histamine H3 receptor antagonist. In view of the interest of the art in the compounds that affect the H3 receptors, new compounds that have antagonistic activity on the H3 receptors would be very well received, they would be a appreciated contribution in the art. This invention provides just such a contribution by providing new compounds having H3 antagonist activity.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to compound have the formula I or the pharmaceutically acceptable salts or solvates thereof, wherein: X is a straight chain alkyl group having 1 to 7 carbon atoms or an alkene or alkyne group with 2 to 4 carbon atoms; wherein said alkyl or alkene groups are optionally substituted with up to two (i.e., 1 or 2) R7 groups: n is 0, 1 or 2, m and p are 0 to 4; when m is 0 to 4; Y represents -SO2-; -CS-; -CO-; CONR5-; -CO (CH2) wO- (where w is 1 to 4); -COO-; CON (OR5) -; -C (NR5) NR5-; -SO2NR5 or -CSNR5-; when m is 2 to 4; and presents all the preceding groups when m is 0 to 4 and, in addition, Y represents -CHOR5-; -OR-; -NR5CONR5-; -NR5CO-; NR5-; -OCONR5-; -NR5C (NR5) NR5-; -NR5CSNR5; -NR5CS- or -NR5SO2-; -NR5C (0) O-; or -CSNR5-; each R 5 independently represents hydrogen, alkyl or benzyl; R6 represents aryl, heteroaryl, or a 3- to 7-membered heterocyclic group having one to three heteroatoms in the ring, wherein the heteroatoms are selected from N, S, and O, and wherein said R6 group is optionally substituted with one to three substituents as defined below; when Y is -SO2-, then R6, in addition to the preceding groups also represents alkyl having one to seven carbon atoms or a group NR10R11 in which R10 and R1 are independently selected from H, alkyl or trihalomethyl; each R1 is independently hydrogen, alkyl or trihalomethyl; each R7 is independently selected from hydrogen, alkyl, trihalomethyl, phenyl or benzyl, wherein said phenyl and benzyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, trihalomethyl, CN, NO2, OR10 or NR10R11 are as they have been defined previously. This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound (or a salt or solvate thereof) having the formula I. This invention also provides a method for treating allergies (eg, asthma), inflammation , cardiovascular diseases, hypotension, elevated intraocular pressure (such as glaucoma), that is, a method to decrease intraocular pressure, sleep disorders (for example hyperinsomnia, drowsiness, narcolepsy and lack of sleep, such as insomnia), Gl tract, states of hyper- and hypomotility and acid secretion of the gastrointestinal tract, disorders of the central nervous system, hypo- and hyperactivity of the central nervous system (for example, agitation and depression) and other CNS disorders (such as Alzheimer's disease) , schizophrenia, obesity and migraine) which comprises administering an effective amount of a compound, or a salt or solvate thereof, having the formula I, to a patient in need of said treatment. This invention further provides a method for treating allergic responses of the upper respiratory tract comprising administering an effective amount of a compound, or a salt or solvate thereof, having the formula I in combination or mixture with a receptor antagonist. Hi appropriate.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms have the following meanings unless otherwise indicated: alkyl - represents a saturated, straight or branched hydrocarbon chain, having 1 to 6 carbon atoms; lower alkyl (including the lower alkoxy alkyl portions) - represents a straight or branched saturated hydrocarbon chain having from one to six carbon atoms, preferably 1 to 4; cycloalkyl - represents a saturated carbocyclic ring having from 3 to 6 carbon atoms, optionally substituted with 1 to 3 groups independently selected from the group consisting of lower alkyl, trihalomethyl and NR 10 R 11, wherein R 10 and R 11 are as previously defined; halogen (halo) - represents fluoro, chloro, bromo or iodo; aryl - represents a carbocyclic group having from 6 to 14 carbon atoms having at least one benzenoid benzyl, with all available substitutable aromatic carbon atoms of the carbocyclic group, proposed as possible adhesion rates, said carboxylic group being optionally substituted with 1 to 3 groups, each independently selected from halo, alkyl, hydroxy, phenoxy, amino, lower alkylamino, dialkylamino lower, (for example, NR10R11 where R10 and R11 are independently selected from hydrogen, lower alkyl or trihalomethyl), lower alkoxy, lower polyhaloalkoxy (e.g., OR10 where R10 is as previously defined), polyalkyl lower (e.g., trihalomethyl), CN, or N02; including the preferred aryl groups 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl; heterocyclic - represents unsaturated saturated and unsaturated cyclic organic groups having at least one O, S and / or N atom that interrupts a structure of a carbocyclic ring consisting of a ring or two fused rings, where each ring is 3 to 7 members (for example, 5, 6 or 7 members), whose ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms; for example, 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidinyl, 2- or 3-piperazinyl, 2- or 3-thiomorphonyl; said heterocyclic group being optionally substituted with 1 to 3 groups independently selected from alkyl, trihalomethyl and NR 10 R 11, wherein R 10 and R 11 are independently selected from hydrogen, alkyl or trihalomethyl, said substituents being attached to the carbon atoms (substitutable carbon atoms) in the ring so that the total amount of substituents in the ring is from 1 to 3; and wherein said heterocyclic ring contains nitrogen atoms, said nitrogen atoms (i.e., the substitutable nitrogen atoms) being optionally substituted with lower alkyl (eg, methyl), such as, for example, N-methylpyrrolidinyl; heteroaryl - represents a cyclic organic group having at least one O, S and / or N atom which interrupts a carboxylic ring structure and which has a sufficient quantity of delocalized pi electrons to give them aromatic character, having an aromatic heterocyclic group of 2; to 14, preferably 4 or 5 carbon atoms, for example, 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazonyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, etc .; and the preferred heteroaryl groups are 2-, 3- and 4-pyridyl; said heteroaryl groups being optionally substituted with 1 to 3 groups, each optional substituent independently being selected from alkyl, halogen, trihalomethyl, CH, N02, OR10 or NR10R11 wherein R10 and R11 are independently selected from hydrogen, alkyl or trihalomethyl, and said substituents being bonded to the carbon atoms (substituted carbon atoms) in the ring such that the total amount of substituents in the ring is from 1 to 3; DMF - represents N, N-dimethylformamide; SEM - represents 2- (trimethylsilyl) ethoxymethyl; THF - represents tetrahydrofuran; DMAP - represents dimethylaminopyridine; DIPA - represents diisopropylamine; DMSO - represents dimethyl sulfoxide; DBU - represents diazabicycloundecene; DBN - represents diazacyclononane; LAH - represents lithium-aluminum hydride; FAB - represents fast atom bombardment; Cl - represents chemical ionization; The - represents impact of electrons; HOBT - represents 1-hydroxybenzotriazole; EDCI - represents 1- (dimethylaminopropyl) -3-ethylcarbodimide hydrochloride; LC / MS - represents liquid chromatography / mass spectrometry; TFA - represents trifluoroacetic acid; Tr - represents trityl; and LRMS - represents low resolution mass spectrometry. Likewise; Unless otherwise indicated, substituents for the various embodiments described below are as defined for formula I. Preferred compounds are represented by formula II where q is 1 to 7, m is 0 to 4, n is 0 to 1, p is 0 to 4, and is selected from -SO2-, -SO2NH-, -CONH-, -CO-, C (NH ) NH-, or -CO (CH2) wO-, or, when it is 2 to 4; And, in addition to the groups mentioned above, it also represents -NHCONH-, -O- or -NHC (NH) NH-; and w, R1, R6, and R7 as defined above. Preferably R6 is phenyl or substituted phenyl. Most preferred are the compounds of formula II in which (1) q is 1 to 4; (2) n is 0 or 1; (3) m is 0 to 4 (more preferably 0 to 3, and even more preferably 0 to 2); (4) p is 0 to 2; (5) Y is -CONH-, -CO-, - SO2-, -CO (CH2) 2O- or -O- (when m is greater than or equal to 2, that is, Y can also be -O- when m is 2 to 4); (6) R6 is phenyl wherein said phenyl is optionally substituted with one, two or three substituents independently selected from halogen, preferably fluorine or chlorine, CF3, Ci to C4 alkoxy, OCF3, N02, or NR10R11, with R10 and R11 being as have defined previously. For compounds having the formula II, R1 and R7 are preferably hydrogen. For the compounds of formula II, preferably when R6 is monosubstituted phenyl said solvent is in the 3- or 4- position and said substituent is selected from fluorine, chlorine, methoxy or trifluoromethoxy, and when R6 is disubstituted phenyl said substituents are in the positions 3.5- and said substituents are the same and are selected from fluorine, chlorine, methoxy or trifluoromethoxy. The compounds of this invention include, are not limited to The compounds of this invention also include but are not limited to Some compounds of this invention may exist in different isomeric forms (e.g., enantiomers and diastereomers). The invention contemplates all such isomers in both pure form and in mixture including racemic mixtures. The enol forms are also included. The compounds of formula I can exist in unsolvated form as well as in solvated form, including hydrated forms, for example, hemihydrates. In general, solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to unsolvated forms for the purposes of the present invention. Some basic compounds of the invention also form pharmaceutically acceptable salts, for example, acid addition salts. For example, nitrogen atoms can form salts with acids. Examples of acids suitable for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, matanesulfonic and other mineral and carboxylic acids which are well known to the subject matter experts. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms in some physical properties such as, in the solubility in polar solvents, weight the acidic and basic salts are otherwise equivalent to their respective free base forms for the purposes of the invention . All such acid salts and bases are intended to be converted into pharmaceutically acceptable salts within the scope of the invention and all such acid salts and bases are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. Numerous chemical substances are known that have histamine Hi receptor antagonistic activity. Many useful compounds can be classified as enolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. H- * receptor antagonists include without limitation: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cirpoheptadine, carbioxamine, descarboethoxy-thyroidtadine (also known as SCH-34117), diphenhydramine, doxylamine, dimetindene; ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, cetotifen, loratadine, lovocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelenamine, temelastin, trimeprazine and triprolidine. Other compounds can be easily evaluated to determine activity for Hi receptors by known methods, including specific blocking of the contractile response to histamine of the isolated guinea pig ileum. See for example, WO 98/06394 published February 19, 1998. For example, the H3 agonists of this invention can be combined with a Hi antagonist selected from astemizole, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine (known also as SCH-34117), diphenylhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole or terfenadine.

Also, for example, the H3 antagonists of this invention can be combined with a Hi antagonist selected from azathidine, bromopheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxyloratadine (also known as SCH-34117), diphenylhydramine, ebatin, phenophenadine, loratadine or norastemizole. Representative combinations include: the H3 antagonists of this invention with loratadine, H3 antagonists of this invention with descarboethoxyloratadine, H3 antagonists of this invention with fexofenadine and H3 antagonists of this invention with cetirizine. Those skilled in the art know that the term "upper respiratory tract" refers to the upper respiratory system, i.e., the nose, throat, and associated structures. The compounds of this invention can be prepared according to appropriate procedures known in the art for the preparation of similar compounds, for example the methods described in the literature to which we have not previously referred. The following processes can be employed for the purpose of producing compounds of formula I. Unless otherwise indicated, the reaction is carried out at an appropriate temperature which allows the reaction to proceed at a reasonable rate until its completion. .

General Preparation Schemes In general, the compounds of this invention are prepared by first providing starting compounds having the general formula which then in a further step are reacted with a compound having the general formula L- (CH2) mY- (CH2) p-R6 followed by removal of the protective group Z to provide a compound having the formula I. In the The preceding formulas R1, R6, R7, X, Y, m, n and p are as defined for formula I above. L represents a leaving group such as Cl, Br, I, and activated versions of OH such as OSO2CF3 generated independently or in situ. The following reaction schemes illustrate the various stages of the procedures used.

Preparation of pyperidines (n = 1) Reaction scheme 1 - Compounds in which X is ÍC ± la); 1-7 Stage 1 0 ° C-room temperature Compound 1, in which (1) D is halogen, preferably iodide, (2) Z represents a protecting group such as triphenylmethyl, 2- (trimethylsilyl) -ethoxymethyl and the like, and (3) R 1 it can be either hydrogen, alkyl, or trihalomethyl, dissolved in a suitable solvent such as methylene chloride and treated with a Grignard reagent, such as ethylmagnesium bromide. The subsequent addition of an appropriate aldehyde 2 (M = (CH2) or -6) yields compound 3.

Stage 2 In step 2, compound 3 is dissolved in an organic solvent, such as methylene chloride, and treated with a tertiary amine base such as triethylamine, and with an acylation catalyst, such as dimethylaminopyridine. Subsequent treatment with acetic anhydride provides the compound of formula 4.

Stage 3 In step 3, compound 4 is dissolved in an appropriate organic acid, such as acetic acid, and hydrogenated under pressure (1.1248-4.218 kg / cm2) in the presence of an appropriate catalyst such as platinum oxide to provide compound 5. .

Reaction scheme 2 Compounds in which X is - (CH?)? Z Stage 1 In step 1, compound 1, wherein (1) D = halogen, preferably iodide, (2) X represents a protecting group such as triphenylmethyl, 2- (trimethylsilyl) ethoxymethyl and the like, and (3) R2 represents benzyl or substituted benzyl, is dissolved in an appropriate solvent or in a mixture of solvents selected from ethereal or dialkylamine solvents. A mixture of tetrahydrofuran / diisopropylamine is preferred. Addition of compounds of formula 6 followed by addition of an appropriate catalyst, such as bistriphenylphosphine palladium dichloride and copper iodide, and stirring at a temperature of 21-60 ° C provides compound 7.

Stage 2 In step 2, compound 7 is dissolved in an appropriate organic solvent or mixtures thereof (examples of solvents include methylene chloride, methanol and acetic acid) and hydrogenated with a catalyst such as palladium or palladium hydroxide. , at pressures comprised between 16-60 psi to provide compound 8.

Stage 3 In step 3, a compound 8 is dissolved in an appropriate alcohol such as methanol, and treated with a few drops of hydrochloric acid (1 M) and hydrogenated with an appropriate catalyst, such as palladium or palladium hydroxide, at pressures between 1.1248-4.218 kg / cm2 to provide compound 5A.

REACTION SCHEME 3 Preparation of compound 10 (where R is the group - (CH2) m-Y- (CH2) p-Rd).

Those skilled in the art will appreciate that the amount of HCl (r) molecules is based on the amount of basic groups that are present in compound 10. Compound 5 is reacted with L- (CH2) mY- (CH2) p -R6 to produce the compound 9. L is a leaving group, such as Cl, Br, I and activated versions of OH such as OSO2CF3 generated independently or in situ. When Y is -C (O) NH-, -OCO and SO2-, and m is 2, then compound 5 is reacted with reagents such as (CH2 = CH) C (0) 0 (CH2) pR6, (CH2 = CH) C (0) ONR5 (CH2) PR6, and (CH2 = CH) S02 (CH2) pR6. The reactions are carried out in appropriate solvent, such as ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, water, methylene chloride, and toluene, with or without the presence of appropriate bases such as triethylamine, lithium diisopropylamide or chloride of sodium, at temperatures that fall within the range -78 ° to 200 ° C. When Z is triphenylmethyl, the compound 9 is deprotected by treatment with dilute aqueous acid, such as HCl or HBr, at a temperature of about 25 ° to 100 ° C to produce compound 10. Other protecting groups are extracted by methods that are well known in art.

Preparation of compounds having a 7-membered heterocyclic ring REACTION SCHEME 4 Compounds in which X is -CH2- Stage 1 In step 1, compound 11 (prepared analogously to the procedures indicated in European J. Med Chem. 1979, 14, 157-164 and Tetrahedron Letts, 1990, 31, 933-936) is recited with a ZCI compound in an appropriate organic solvent at a temperature of from 0 ° C to about 50 ° C in the presence of an organic base to produce compound 12. Z represents a protecting group, preferably carbobenzyloxy. Suitable solvents include THF, ether, dioxane or the like. Suitable bases include tritylamine and the like.

Stage 2 In step 2, compound 12 is reduced to aldehyde 13 using an appropriate reducing agent using, such as BH3 »SMe2 or the like, in an appropriate organic solvent, such as THF, ether, dioxane or the like, at a temperature of 0 ° C to 100 ° C.

Stage 3 In step 3, compound 13 is reacted with the Grignard reagent formed from iodoimidazole in the same manner as described for step 1 of reaction scheme 1 to obtain alcohol 14.

In step 4, compound 14 is reduced to compound 15 in an appropriate polar organic solvent using H2 in the presence of a metal catalyst and a trace of acid at a temperature of from 25 ° C to 75 ° C. Suitable solvents include MeOH, EtOH and ¡-PrOH, EtOH being preferred, and catalysts may include Pd / C or Pt02 or the like.

Stage 5 In step 5, compound 15 is reacted with LR in an appropriate solvent such as THF, ether, or the like in the presence of an appropriate tertiary amine base such as triethylamine at a temperature of from 0 to 100 ° C, preferably 25 ° C, to produce compound 16. R is - (CH 2) m-Y- (CH 2) p-R 6 and L is a leaving group as defined in reaction scheme 3 above.

Stage 6 In step 6 it is carried out in a manner similar to the deprotection step in reaction scheme 3 which was given above to give compound 17.

REACTION SCHEME 5 X es - (CH ^ Stage 1 In Step 1, the aldehyde 13 is reacted with the Witting reagent in an appropriate ethereal solvent in the presence of a strong base at a temperature of from -25 ° C to 80 ° C to give the compound 19. Suitable solvents they include THF, ether, dioxane, and the like. The strong bases may include lithium or potassium diisopropylamine, and lithium, sodium or potassium bis (trimethylsilyl) -amide or the like. Other suitable bases may also include NaH or KH in an appropriate polar aprotic solvent, such as DMSO.

Stage 2 In step 2, enol ether 19 is hydrolyzed to aldehyde 20 by treatment with a dilute mineral acid such as HCl or HBr, at a temperature of from 0 to about 80 ° C. The aldehyde 20 can then be converted to the desired objectives in a manner similar to that described in reaction scheme 4, step 3 to 6.

REACTION SCHEME 6 The aldehyde 20 can be converted to the aldehyde 21 in a manner similar to that described in the reaction scheme 5. The compound 21 can then be converted to the desired objectives in a manner similar to that described in reaction scheme 4, steps 3. a 6. It can be applied to a sequence similar to compound 22 and higher homologs.

REACTION SCHEME 7 Preparation of pyrrolidines (n = 0) Stage 1 23 24 where s is 0 to 5, and R14 represents a lower alkyl (e.g., methyl or ethyl). In step 1, an appropriate Horner-Emmons reagent such as trimethyl or triethyl phosphonoacetate is treated with a strong base, such as NaH, KH, diisopropylamide or lithium or the like, in an appropriate solvent such as THF, ether, dioxane or the like . The phosphate carbanion is then reacted with the aldehyde 23 for 30 minutes up to 24 hours at a suitable temperature to complete the reaction and provide the ester 24.

Stage 2 In step 2, the ester 24 is reacted with a substituted or unsubstituted nitroalkane such as nitromethane, or nitroethane, in a polar aprotic solvent such as acetonitrile, THF or the like, preferably acetonitrile, in the presence of an amine base, such as DBU, DBN, triethylamine or the like, preferably DBU, at a temperature of from 0 to 80 ° C, preferably 25 ° C, for 24 hours to provide the nitroester 25.

Stage 3 In step 3, the nitro group of nitroester 25 is reduced to the amine using hydrogen and an appropriate metal catalyst, such as Pd / C, Ra-N, or the like, in an appropriate aprotic solvent such as methanol, ethanol or the like, at a temperature of from 25 ° to 80 ° C. The resulting amino ester is cyclized to the lactam by heating in an appropriate aprotic solvent such as methanol or ethanol at a temperature up to 80 ° C in the presence of a small amount of base such as potassium carbonate or the like to give compound 26.

Stage 4 In step 4. Compound 26 is reacted with an appropriate reducing agent, such as LAH, BH3, or the like, preferably LAH, in an appropriate solvent, such as THF, ether, dioxane or the like, at a temperature between 0o at 80 ° C, preferably 60 ° C, for a period of time comprised between 30 minutes and 24 hours, preferably 3 hours to give the compound 27. The compound 27 is then reacted with a compound having the formula L- (CH 2 ) mY- (CH2) p-R6 followed by deprotection in a manner similar to the procedure indicated for reaction 3 above. The starting compounds of formula 23 are either known compounds or can be obtained according to methods that are well known in the art, for example following the preparations of the steps indicated for the above compounds 13, 20 and 22. Those skilled in the art will readily appreciate that different variations of the preceding procedures are possible. For example, substituents R1 and R7 may be present in the starting materials or may be introduced at any convenient stage of the process. The following examples are given for the purpose of illustrating, but not limiting, the present invention.

EXAMPLE 1 Stage A 28 29 To a flask containing oxalyl chloride (13.8 g, 9.5 ml, 109 mmol) in methylene chloride (300 ml) at -78 ° C was added DMSO (19.9 g, 255 mmol) per drop. When gas evolution ceased, the mixture was stirred for 8 minutes and a solution of alcohol 28 (10.0 g, 27.2 mmol) in methylene chloride (50 ml) was added. The reaction was maintained at -78 ° C for 50 minutes, triethylamine (45 ml, 255 mmol) was added, and the reaction was allowed to proceed at room temperature for 45 minutes. The content was diluted with a solution of NH 4 Cl and extracted with methylene chloride. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was chromatographed on silica gel (10 to 30% acetone in methylene chloride) to give the product 29 as a light yellow oil (7.7 g, 77%): LRMS (Cl, M + H ) = 367. To a flask containing NaH (95%, 2.0 g, 79 mmol) was added dry THF (600 ml) under a nitrogen atmosphere. To this mixture was added trimethylphosphonoacetate (14.0 g, 77.5 mmol) by dripping through a syringe. Gas evolution was observed and the result was a viscous white mixture. The mixture was heated at 35 ° C for 30 minutes and then allowed to cool again to room temperature. Aldehyde 29 (14.5 g, 39.6 mmol) in dry THF (200 ml) was added via syringe to the reaction mixture. TLC (40% EtOAc-Hex) indicated that the reaction was complete after stirring for 45 minutes at room temperature. The content was diluted with water, and then the aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to give a recrystallized solid from Et2O-hexane (1: 2 v / v) to obtain 5.9 g of the pure material. The mother liquors were chromatographed on silica gel (40% EtOAc-hexane? -60% EtOAc) to provide an additional 7.7 g of material, with a combined yield of 81%. LRMS (Cl, M + H = 423 analytical CHN for (C28H26N202); C, 79. 25; H, 6.22; N, 6.60; Found C, 79.11; H, 6.39; N, 6.66. p.f. = 129-130.5 ° C Stage B To a solution of CH3CH (300 mL) of 30 (11.0 g, 26.1 mmol) was added CH3NO2 (29.3 g, 26 mL, 480 mmol) followed by DBU (5.1 g, 5.0 mil, 33.4 mmol). The reaction mixture was stirred under a nitrogen atmosphere for 18 hours, at which time no starting material was observed by TLC (40% EtOAc-Hex). The solvents were evaporated under reduced pressure and the residue was chromatographed directly on silica gel (50% EtOAc-Hex? 70% EtOAc) obtaining 13.1 g (> 100% crude yield) of the product as a colorless oil. LRMS (CL, M + H) = 484. Analytical CHN for (C 29 H 29 N 3 O 4); C, 72.03; H, 6.04; N, 8.69: Found C, 72.06; H, 6.34; N, 8.66. p.f. = 97.5-99.5 ° C Stage C Compound 31 (2 x 5 g, 20.7 mmol) was dissolved in a solution of absolute EtOH-THF (60-20, v / v). Ra-NI (-2 x 5 g) was added, and the even vessel was pressurized to 3.515 kg / cm2 with hydrogen. After stirring for 4-6 hours the TLC indicated that the reduction of the amino ester (10% MeOH-EtOAc) had been completed. The catalyst was removed by filtration through celite. Evaporation under reduced pressure afforded the amino ester intermediate which was subsequently cyclized to the lactam by reflux in MeOH with a small amount of K2CO3 for 3 hours. Removal of K2CO3 by filtration and evaporation of the solvent gave an oil which was chromatographed on silica gel (10% MeOH-CH2Cl2 - * > 10% MeOH + 2% NH4OH) to give the product as an amorphous solid. whitish color, 8.1 g (92%). LRMS (Cl, M + H) = 422. Analytical CHN for (C 28 H 27 N 3 O x 1.5 mol H2O): C, 74.91; H, 6.57; N, 9.36: Found C, 74.76; H, 6.17; N, 9.14. P.f. = 171-173.5 ° C.

Stage D To a flask containing a THF solution (12 ml) of LAH (180 mg, 4.80 mmol, 10 equivalents), a THF solution of 32 was added at room temperature. The mixture was heated at 60 ° C for 3 hours and then allowed to cool to room temperature. The reaction was quenched by the addition of solid Na2SO4 x 10H2O. After 20 minutes 5% NaOH (~1 ml) was added which caused the viscous gray mixture to become colorless and homogeneous. After 20 more minutes the mixture was filtered through celite and the filter cake was washed well with THF and with MeOH. The effluent was concentrated under reduced pressure and then chromatographed on silica gel (10% MeOH-CH 2 Cl 2 -> 10% MeOH + 2% NH 4 OH) to give 168 mg (73%) of the product 33 in the form of a hygroscopic foam. LRMS (Cl, M + H) = 408.

Stage E To a solution of CH2Cl2 (6 mL) of (+/-) 33 (315 mg, 0.774 mmol) was added Et3N (2 mL 14.4 mmol) followed by p-chlorosulfonyl chloride (215 mg, 1.09 mmol) at room temperature . The mixture was stirred under a nitrogen atmosphere for 21 hours and then evaporated to volume A and chromatographed on silica gel (1% MeOH-CH2Cl2 ---> 3% MeOH) which gives an amorphous white solid. Trituration with hexane-acetone followed by evaporation gave a fluffy white foam. LRMS (Cl, M + H) = 582.

Stage F Conventional deprotection of HCl of 34 afforded the hydrochloride salt of 35 as a light tan solid. LRMS (Cl, M + H) = 340.

EXAMPLE 1A Chiral synthesis Stage A A solution of 36 (2.0 g) in ethanol (20 ml) and 10% palladium on carbon (0.3 g) was hydrogenated on a Parr shaker at 4,218 kg / cm2 for 24 hours. Then the catalyst was filtered and the filtrate was evaporated under reduced pressure. The residual oil was dissolved in dichloromethane (20 ml). To the solution was added di-tert-butyldicarbonate (2 g) followed by 4-dimethylaminopyridine (0.05 g). The reaction mixture was stirred at 70 ° C for 1 hour and then evaporated under reduced pressure. The product was then chromatographed by evaporative chromatography on silica gel (50 ml). Elution with 8% methanol-dichloromethane affords after evaporation under reduced pressure the title compound 37 in the form of a colorless oil (1.1 g), MS (Cl) m / e = 146 (M-56).

Stage B A solution of 37 (1.1 g) and triethylamine (0.84 ml) in dichloromethane was cooled in an ice bath and stirred while a solution of mesyl chloride (0.47 ml) in dichloromethane (5 ml) was added dropwise. The reaction mixture was stirred for 1 hour and then washed with water, dried over sodium sulfate and filtered through a plug of silica gel. The filtrate was evaporated to provide mesylate 37a which was then dissolved in acetone (30 ml) containing sodium iodide (1.6 g). The reaction mixture was heated under stirring in an oil bath (70 ° C) for 24 hours and then cooled. The insoluble salts were removed by filtration and the filtrate was evaporated under reduced pressure. The residual product was dissolved in dichloromethane and washed with water, dried over sodium sulfate and filtered through a plug of silica gel. The filtrate was evaporated under reduced pressure to provide the title compound 38 in the form of an oil (1.53 g), MS (FAB) m / e 280 (MH) +.

Stage C A solution of 38 (1.53 g) and triphenylphosphine (1.9 g) in dimethylformamide (10 ml) was heated in an oil bath (90 ° C) for 24 hours. The reaction mixture was then evaporated under reduced pressure and the residual product was cormatrographed by evaporative chromatography on silica gel (50 ml). Elution with 10% methanol-dichloromethane affords after evaporation under reduced pressure the title compound 39 in the form of a white powder (1.56 g), MS (FAB) m / e = 446 (M) +.

Stage D A solution of butyl lithium at 2.5 M in hexanes (0.9 ml) was added to a solution of 39 (1.0 g) in tetrahydrodurane (10 ml) at -78 ° C. The solution was then stirred at room temperature for 30 minutes and then the resulting solution was cooled again to -78 °, followed by addition of a solution of the aldehyde (0.38 g) in tetrahydrofuran (5 ml). The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure. The resulting crude product was chromatographied by evaporative chromatography on silica gel (50 ml). Elution with 5% methanol-dichloromethane afforded after evaporation under reduced pressure the title compound 40 as a white powder (0.34 g), MS (FAB) m / e = 264 (MH) +.

Stage E H H A solution of 40 (0.32 g) in ethanol (5 ml) containing PtO (0.085 g) was hydrogenated at atmospheric pressure for 24 hours. Then the catalyst was filtered and the filtrate was evaporated under reduced pressure. The resulting crude product was chromatographed by evaporative chromatography on silica gel (30 ml). Elution with 10% methanol-dichloromethane afforded after evaporation under reduced pressure the title compound 41 in the form of a resinous gum (0.23 g), MS (FAB) m / e = 266 (MH) +.

Stage F Compound 41 (0.1 g) was stirred with 4M HCl in dioxane (2 ml) for 30 minutes and the reaction mixture was then evaporated under reduced pressure. The residual product was dissolved in methanol (2 ml) and the solution was stirred while an ion exchange resin Biorad AG 1-X8 (OH form) was added until the pH of the solution was above 8. The resin was extracted by filtration and the filtrate was then evaporated to obtain the title compound 42 in the form of a resinous gum (0.061 g), MS (Cl) m / e = 165 (MH) +. The R-enantiomer can be obtained in a similar manner.

EXAMPLE 2 Stage A To a MeOH solution (15 mL) of 33 obtained in Step D of Example 1 (600 mg, 1.48 mmol) at room temperature was added methyl acrylate (0.300 mL, 3.33 mmol). The reaction mixture was stirred for 2 hours at room temperature and then heated at 60 ° C overnight. The solvents were evaporated and the residue was chromatographed directly on silica gel (5% MeOH-CH 2 Cl 2 -> 10% MeOH) to obtain 574 mg (78%) of 43 as an off-white solid. LRMS (Cl, M + H) = 494.

Stage B To a solution of toluene (5 ml) of p-chloroaniline (0.160 g, 1.25 mmol) was added trimethylaluminum (0.700 ml)., 2M in toluene) at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes and at room temperature for 40 minutes. Then a solution of toluene-CH2Cl2 of compound 43 (10 ml, 1: 1, v / v) was added at 0 ° C to the aniline complex. After 30 minutes, the mixture was heated at 80 ° C for 3 hours and then at room temperature overnight. The reaction was quenched by the addition of solid Na 2 SO 4 x 10 H20, followed by addition of MeOH. After stirring for 20 minutes. Chromatrography on silica gel (10% MeOH-EtOAc - >; 15% MeOH with 1% NH 4 OH) gave 624 mg (97%) of 44 as a white foam. Irms (Cl, M + H) = 589.

Stage C To a solution of dioxane (10 ml) of compound 44 from the previous step was added a solution of 4M HCl-dioxane (2 x 2 ml) and the mixture was heated at 80 ° C for 6 hours. The mixture was then cooled to room temperature and evaporated under reduced pressure to obtain a rubbery foam. The residue was rinsed with Et20 (3 x 10 mL) and the supernatant was decanted. The product was stored under high vacuum to obtain 45 in the form of a tan solid (400 mg of dichlorohydrate salt). MS (Cl) 347 (M + 1).

EXAMPLE 3 Stage A 0 ° C - Ambient temperature Ethylmagnesium bromide (23 ml, 69.1 mmol, 3M in ether) was added dropwise to a 0 ° C solution of 4-iodo-triphenylmethylmidazole (25.1 g, 57.6 mmol) in methylene chloride (280 ml). The mixture was stirred at 0 ° C for 30 minutes, the cooling bath was removed and the resulting yellow solution was stirred at room temperature for 60 minutes. 4-Pyridinecarboxaldehyde (6.1 ml, 63.4 mmol) was added dropwise. The reaction became very thick. A small aliquot of the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. TLC (5% methanol / methylene chloride) indicated that the starting material had been consumed. The reaction was quenched with saturated ammonium chloride. The reaction mixture was dissolved in methylene chloride (required ~ 1.5 I), transferred to a separatory funnel and extracted with methylene chloride. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated on silica gel sufficiently to obtain a free-flowing powder. The powder was loaded onto a chromatography column preloaded with 10% methanol / methylene chloride. Elution with the same solvent gave 22.5 g (93%) of 47 as a white solid. 1 H NMR (400 MHz, CDCl 3): 8.56 (2H, d, J = 6.0 Hz), 7.47 (1H, d, J = 1.4 Hz), 7.36 (11 H, m), 7.13 (6H, s), 6.63 ( 1 H, s), 5.79 (1 H, s), 4.43 (1 H, s). MS (Cl): 418 (M + 1, 26), 243 (100), 167 (45) Stage B Acetic anhydride (9.7 mL, 51.4 mmol) was added to a room temperature suspension of 47 (21.4 g, 51.1 mmol), triethylamine (35.6 mL, 255.7 mmol) and dimethylaminopyridine (0.13 g, 1.0 mmol) in methylene chloride (800 ml). The suspension was left under stirring overnight. Eventually all the solid dissolved. TLC (10% methanol / methylene chloride) indicated that all the starting material had been consumed. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with a saturated solution of ammonium chloride and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was azeotroped (3 times) with toluene (to remove the acetic anhydride and residual acetic acid) in order to obtain 22.8 g (97%) of 48 as a white solid. 1 H NMR (400 MHz, CDCl 3): 8.61 (2H, d, J = 6.1 Hz), 7.46 (1H, d, J = 1.4 Hz), 7.38 (11H, m), 7.15 (6H, s), 6.83 (1H , s), 6.80 (1H, s), 2.20 (3H, s).

Stage C 48 was dissolved in an acetic acid (100 ml) with heating, transferred to a Parr hydrogenation flask and purged with nitrogen. Platinum oxide (1.13 g, 4.96 mmol) was added. The resulting mixture was hydrogenated in a Parr apparatus at 4218 kg / cm2 overnight. A small aliquot of 1 N NaOH and ethyl acetate was quenched. TLC (10% MeOH / methylene chloride) indicated that the starting material and the formation of the lower Rf products had been consumed. The mixture was again subjected to hydrogenation for a few more days. The TLC indicated that the starting material had been consumed. The mixture was filtered through celite and concentrated. The residue was partitioned between 1 N sodium hydroxide and methylene chloride. Solid sodium chloride was added to increase the separation and the mixture was extracted with methylene chloride. Solid sodium chloride was added to increase the separation and the mixture was extracted with methylene chloride. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated on sufficient silica gel so that the result was a free-flowing powder. This powder was loaded onto a chromatography column preloaded with silica and 10% methanol / methylene chloride. Elution with 5% NH4OH (COncy 0% methanol / (85% dichloromethane gave 15.9 g (79%) of 49 as white crystals.1H-NMR (400 MHz, CDCl3): 7.33 (10H, m), 7.14 (6H, m), 6.51 (1 H, s), 3.04 (2H, m), 2.57 (2H, dd, J = 2.4, 12.1 Hz), 2.44 (2H, d, J = 7.0 Hz), 1.76 ( 1 H, m), 1.66 (2 H, d, J = 12.5 Hz), 1.10 (2 H, dd, J = 3.7, 12.4 Hz) MS (LC / MS): 418 (M +).

Stage D (R is 4-chlorophenyl) 4-Chlorobenzenesulfonyl chloride (0.12 g, 0.56 mmol) was added to a room temperature solution of 49 (0.21 g, 0.51 mmol) and triethylamine (0.11 mL, 0.76 mmol) in methylene chloride ( 3 ml). The resulting mixture was stirred overnight. TLC (10% methanol / methylene chloride) indicated that the starting material had been consumed. The solution was transferred to a separatory funnel, diluted with methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated on sufficient silica gel to obtain a free-flowing powder. . The resulting powder was loaded onto a chromatography column preloaded with silica and methylene chloride. Elution with methylene chloride followed by 10% methanol / methylene chloride gave 0.26 g of 50 as a white solid. 1 H NMR (400 MHz, CDCl 3): 7.68 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.32 (10H, m), 7.12 (6H, m), 6.49 (1 H, s), 3.74 (2H, d, J = 1 1.5 Hz), 2.41 (2H, d, J = 7.0 Hz), 2.24 (2H, dd, J = 2.36, 1.8 Hz), 1.69 (2H, d , J = 13.0 Hz), 1.61 (1 H, m), 1.28 (2H, dd, J = 4.2, 12.8 Hz). MS (LCMS): 582 (M +).

Stage E A mixture of 50 (0.299 g, 0.56 mmol) in methanol (6 ml) and 1 N HCl (3 ml) was heated to 80 ° C. After 3 hours a small aliquot was quenched in 1 N sodium hydroxide and ethyl acetate. TLC (10% methanol / methylene chloride) indicated that the starting material had been consumed. The mixture was cooled to room temperature and concentrated. The residue was dissolved in water and ether and transferred to a separatory funnel. The aqueous layer was washed with ether. The aqueous layer was concentrated to give 0.154 g (75%) of 51 as crystals. 1 H NMR (400 CD3OD): 8.80 (1H, d, J = 1.4 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.32 (1H, s), 3.77 (d, J = 11.8 Hz), 2.66 (2H, d, J = 7.2 Hz), 2.29 (2H, DT, J = 2.5, 12.1 Hz), 1.73 (2H, d, J = 11.7 Hz), 1.60 ( 1 H, m), 1.32 (2H, m). MS (Cl): 340 (M + 1).

EXAMPLE 4 Stage A R is 4-chlorophenyl. 1-3- (Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.20 g, 0.68 mmol) was added to a solution maintained at room temperature of 49 (0.21 g, 0.52 mmol), 4-chlorobenzoic acid (0.07 g, 0.547). mmol), N-methylmorpholine (0.17 ml, 1.56 mmol) and hydroxybenzotriazole (0.08 g, 0.62 mmol) in dimethylformamide (2 ml) and methylene chloride (2 ml). The resulting mixture was stirred overnight. TLC (10% methanol / methylene chloride) indicated that all the starting material had been consumed. The mixture was transferred to a separatory funnel, diluted with methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated over sufficient silica so as to obtain a free-flowing powder. The resulting powder was loaded onto a chromatography column preloaded with silica and 10% methanol / methylene chloride. elution with the same solvent gave 0.26 g of a clear oil. The NMR shows that the product was contaminated with dimethylformamide. The product was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give 0.237 g (83%) of 52. 1 H NMR (400 MHz, CDCl 3): 7.34 (14H , m), 7.13 (6H), 6.52 (1H, s), 4.65 (1H, m), 3.68 (1H, m), 2.98 (1H, m), 2.74 (1H, m), 2.47 (2H, d, J = 7 Hz), 1.96 (1 H, m), 1.70 (2H, m), 1.16 (2H, m). MS (LCMS): 546 (M +).

EXAMPLE 5 Stage A 49 53 R1 is H and R2 is 4-chlorophenyl. A mixture of 49 (2.0 g, 4.9 mmol) and N- (4-chlorophenyl) acrylamide (0.98 g, 5.4 mmol) in toluene (50 mL) was heated to reflux overnight. TLC (10% methanol / methylene chloride) indicated that the starting material had been consumed. The mixture was cooled to room temperature and concentrated on sufficient silica gel to obtain a free-flowing powder. The resulting powder was loaded onto a chromatography column preloaded with silica and 10% methanol / methylene chloride. Elution with 10% methanol / methylene chloride followed by 5% ammonia (concentrate) / 10% methanol / 85% methylene chloride gave 1.17 g of the title compound with a trace of impurity and 1.50 g of pure 53 in the form of oils. The combined yield was 2.67 g (92%). 1 H NMR (400 MHz, CDCl 3): 7.46 (2H, d, J = 11.8 Hz), 7.34 (1 H, s), 7.32 (10H, m), 7.23 (2H, d, J = 11.8 Hz), 7.14 ( 6H, m), 6.55 (1 H, s), 3.04 (2H, d, J = 15.3), 2.68 (2H, m), 2.51 (4H, d, J = 8.3 Hz), 2.07 (2H, t, J = 14.7 Hz), 1.80 (3H, m), 1.28 (2H, m). MS (LCMS): 589 (M +).

EXAMPLE 6 temperature 49 room 54 R is 3,5-dichlorophenyl. 3,5-Dichlorophenyl isocyanate (0.21 g, 1.1 mmol) was added to a solution maintained at room temperature of 49 (0.3 g, 0.74 mmol) in methylene chloride (5 mL). The resulting mixture was stirred overnight. TLC (5% ammonia (concentrate) / 10% methanol / 85% methylene chloride) indicated that the starting material had been consumed. The mixture was concentrated with sufficient silica gel to obtain a free-flowing powder. The resulting powder was loaded onto a chromatography column preloaded with silica and 20% acetone / methylene chloride. Elution with 20% acetone / methylene chloride followed by 5% methanol / methylene chloride gave 0.37 g (83%) of 54 as a white solid. 1 H NMR (400 MHz, CDCl 3): 7.53 (1H, m), 7.36 (10H, m), 7.12 (6H, m), 6.97 (1 H, m), 6.71 (1H, m), 6.56 (1H, s) ), 4.04 (2H, d, J = 17.3), 2.86 (2H, m), 2.52 (2H, d, J = 9.1 Hz), 1.95 (1 H, m), 1.72 (2H, d, J = 17.1 Hz ), 1.16 (2H, m). MS (LC / MS): 596 (M +).

EXAMPLE 7 Stage A Trimethylaluminum (1.2 ml, 2.4 mmol, 2M in tuluene) was added to a 0 ° C solution of 3-chloroanil (0.10 g, 0.8 mmol) in toluene (7.5 ml). After 5 minutes the cooling bath was removed and the mixture was stirred at room temperature for 30 minutes. 55 (0.48 g, 0.1 mmol) in toluene (10 ml) was added through a cannula. The mixture was refluxed overnight. TLC (10% methanol / 85% methyl chloride) indicated that the starting material had been consumed. The mixture was cooled to room temperature, diluted with ethyl acetate and quenched with a saturated solution of sodium sulfate. The resulting mixture was stirred overnight. The mixture was basified with 1 N NaOH (3 ml). The resulting mixture was transferred to a separatory funnel and extracted with ethyl acetate. The extracts were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated on sufficient silica gel to obtain a free-flowing powder. The resulting powder was loaded onto a chromatography column preloaded with silica and 3% methane / methylene chloride. Elution 3-10% methane / methylene chloride gave 0.31 g (66%) of 56 as a white foam. 1 H NMR (400 MHz, CDCl 3): 7.71 (1 H, m), 7.29 (12H, m), 7.14 (6H, m), 7.05 (2H, m), 6.55 (1 H, s), 3.04 (2H, m), 2.68 (2H, m), 2.51 (3H, m), 2.09 (2H, m), 1.81 (2H, m), 1.58 (2H, m), 1.3 (2H, m). MS (LCMS): 589 (M +).

Stage B Compound 56 (0.6 g, 1.0 mmol) in methanol (18 mL) and 1 N HCl (6 mL) was heated to 60 ° C. The progress of the reaction was monitored by cooling a small aliquot of the reaction with 1N sodium hydroxide and with ethyl acetate. TLC (5% ammonia (concentrate) / 10% methanol / 85% methylene chloride) indicated that the starting material had been consumed. The mixture was cooled to room temperature and concentrated. The residue was not completely soluble in ether / water. The residue was basified with 1 N NaOH, diluted with methylene chloride, transferred to a separatory funnel and extracted with methylene chloride. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated on sufficient silica gel to obtain a free-flowing powder. The powder was loaded on a chromatography column preloaded with silica and with 10% methanol / methylene chloride. Elution with 10% methanol / methylene chloride followed by 5% ammonia (concentrate) / 10% methanol / chloride) gave the title compound as a clear oil. The oil was redissolved in methylene chloride and treated with an excess of HCl (4M in dioxane) and concentrated in vacuo to give 0.205 g (44%) of 57 as clear crystals. 1 H NMR (400 CD3OD): 8.85 (1 H, s), 7.50 (2 H, d, J = 11.4 Hz), (7.40 (1 H, s), 7.05 (2 H, d, J = 11.4 Hz), 4.521 (2 H) , s), 4.15 (2H, t, J = 7.5 Hz), 3.46 (2H, d, J = 16.2 Hz), 3.35 (3H, m), 3.02 (2H, t, J = 16.2 Hz) 2.95 (6H, s), 2.74 (2H, d, J = 9.0 Hz), 2.25 (2H, m), 1.93 (2H, d), 1.60 (2H, m), MS (FAB): 357 (M + 1).

EXAMPLE 8 Stage A N-Butyllithium (30.4 mL, 48.6 mmol, 1.6 M in hexane) was added to a solution at -78 ° C of diidopropylamine (6.63 mL, 50.6 mmol) in tetrahydrofuran (75 mL). After 30 minutes 58 (7.5 ml, 40.5 mmol) in tetrahydrofuran (30 ml) was added through a cannula. The reaction was stirred at -78 ° C for 1.5 hours and then N-phenyltrifluoromethanesulfonamide (15.3g, 44.5 mmol) in tetrahydrofuran (50 ml) was added through a cannula. The mixture was allowed to warm to room temperature overnight. TLC (20% ethyl acetate / hexanes) indicated that the starting material had been consumed. Triethylamine (added to prevent acid triflate hydrolysis on the silica gel) was added, and the resulting mixture was concentrated on enough silica gel to obtain a free-flowing powder. The powder was loaded on a chromatography column precharged with silica and with 20% ethyl acetate / hexanes. Elution with the same solvent gave 10.8 g (83%) of 59 in the form of a yellow oil. 1 H NMR (400 MHz, CDCl 3): 7.30 (5H, m), 5.73 (1 H, m), 3.63 (2H, s), 3.13 (2H, dd, J = 3.0, 6.4 Hz), 2.72 (2H, t , J = 5.7 Hz), 2.45 (2H, m).

Stage B Trimethylsilylacetylene (5.9 ml, 42.1 mmol) was added to a room temperature solution of 59 (10.8 g, 33.7 mmol) in a 3: 1 mixture of tetrahydrofuran and diidopropylamine (50 ml). Dichlorobis (triphenylphosphine) palladium (II) and (1.42 g, 2.0 mmol) and copper iodide (I) (1.1 g, 5.7 mmol) were added. The color of the reaction went from red to brown to black. After 1 hour, TLC (5% ethyl acetate / hexanes) indicated that the starting material had been consumed. The reaction was diluted with ethyl ether, transferred to a separatory funnel, washed with water, with 3/1% ammonium chloride / saturated ammonia (concentrated) and brine and dried over anhydrous sodium sulfate, filtered and concentrated enough silica gel to obtain a free flowing powder. The powder was loaded on a chromatography column precharged with silica and with 10% ethyl acetate / hexanes. Elution with the same solvent gave 6.1 g (67%) of 60 as a yellow solid. 1 H NMR (400 MHz, CDCl 3): 7.35 (5H, m), 6.14 (1 H, m), 3.63 (2H, s), 3.08 (2H, m) 2.63 (2H, t, J = 5.7 Hz), 2.33 (2H, m), 0.23 (9H, s).

Stage C 61 Tetrabutylammonium fluoride (27 ml, 27.0 mmol, 1 M in tetrahydrofuran) was added to a solution at room temperature of 60 (6.1 g, 22.5 mmol) in tetrahydrofuran (100 ml). After ~ 2 hours, TLC (20% ethyl acetate / hexanes) indicated that the starting material had been consumed. The reaction mixture was diluted with ethyl acetate, transferred to a separatory funnel, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated on sufficient silica gel to obtain a free-flowing powder. . The powder was loaded on a chromatography column precharged with silica and with 10% ethyl acetate / hexanes. Elution with the same solvent gave 3.4 g (76%) of 61 as a yellow solid. 1 H NMR (400 MHz, CDCl 3): 7.36 (5H, m), 6.17 (1 H, m), 3.65 (2H, s), 3.11 (2H, m) 2.91 (1 H, s), 2.64 (2H, t , J = 5.6 Hz), 2.35 (2H, m).

Stage D 61 62 61 (3.42 g, 17.3 mmol) and 1-triphenylmethyl-4-iodoimidazole were dissolved. 86. 3 g, 14.4 mmol) in tetrahydrofuran (100 ml) and diisopropylamine (40 ml). Dichlorobis (triphenylphosphine) palladium (II) and (1.22 g, 1.7 mmol) and copper iodide (I) (0.4 g, 1.7 mmol) were added. The reaction mixture was allowed to stir at room temperature overnight. TLC (5% methane / methylene chloride) indicated that the starting material had been consumed. The reaction was diluted with methylene chloride, transferred to a separatory funnel, washed with water, with 3/1 saturated ammonium chloride / ammonia (concentrate) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate to give 7.02 g, (98%) of 62 as a light yellow solid. 1 H NMR (400 MHz, CDCl 3): 7.44 (1 H, d, J = 1.1 Hz), 7.40 (14 H, m), 7.18 (6 H, m), 7.06 (1 H, d, J = 1.5 Hz), 6.12 ( 1 H, m) 3.64 (2H, s), 3.12 (2H, m), 2.64 (2H, t, J = 5.7 Hz), 2.39 (2H, m), MS (FAB): 505 (M +).

Stage E 62 63 62 (7.0 g, 14.1 mmol) was dissolved in a mixture of tetrahydrofuran (250 ml), methanol (200 ml) and methylene chloride (100 ml) and purged with nitrogen. 10% palladium on charcoal (1.0 g) was added and the resulting suspension was hydrogenated in a Parr apparatus overnight at 4,218 kg / cm 2. TLC (5% methane / methylene chloride) indicated that a considerable amount of starting material remained. The mixture was filtered through celite, 10% palladium on fresh charcoal was added and the mixture was hydrogenated again in a Parr apparatus at 4,218 kg / cm2 for two days. TLC (5% methanol / methylene chloride) indicated that a considerable amount of starting material remained. 20% palladium hydroxide on carbon (1.0 g) and acetic acid (60 ml) were added and the mixture was hydrogenated again on a Parr apparatus at 4,218 kg / cm2 overnight. The mixture was filtered and concentrated. TLC (5% ammonia (conc) / 10% methanol / methylene chloride) indicated that there was a certain amount of new foci. The residue was redissolved in acetic acid (75 ml) and 20% palladium hydroxide on carbon (1.0 g) was added and the mixture was hydrogenated at 3.515 kg / cm2 for two days. The reaction was filtered through celite, the filter cake was washed well with methanol. The filtrate was concentrated and the residue was azeotroped with toluene (3 times) to remove residual acetic acid. The residue was dissolved with 1 N NaOH and with merylene chloride, transferred to a separatory funnel and extracted with methylene chloride. The extracts were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to provide 6.8 g of an amber oil. Chromatography on silica eluting with 4% ammonia (concentrate) / 10% methanol / 86% methylene chloride gave 0.7 g (10%) of 63. 1H-NMR (400 CD3CI3): 7.29 (15H, m), 7.13 ( 6H, m), 6.49 (1H, s), 3.58 (2H, m), 2.94 (2H, m), 2.54 (2H, t, J = 8.0 Hz), 1.98 (2H), 1.66 (2H, m), 1.54 (3H, m), 1.29 (2H).

Stage F 63 (0.019 g, 0.054 mmol) was dissolved in methanol (1 ml), and 1 M HCl (2 drops) was added. The resulting solution was purged with nitrogen. 10% palladium on charcoal (0.005 g) was added and the mixture was filtered through celite, the filter cake was washed well with methanol and concentrated to give 0.0128 g of a clear oil. The 1 H NMR analysis indicated that no reaction had occurred. The oil was redissolved in methanol (1 ml) and HCl (1 drop) was added. The resulting solution was purged with nitrogen, 20% palladium hydroxide on carbon (0.01 g) was added and the mixture was stirred under a balloon of hydrogen gas overnight. The mixture was filtered through celite, the filter cake was washed well with methanol and concentrated to give 0.0085 g of 64 as a clear oil. 1 H NMR (400 CD3OD): 8.87 (1 H, s), 7.41 (1 H, s), 3.45 (2 H, m), 3.04 (2 H, m), 2.85 (2 H, m), 2.05 (2 H, m), 1.75 (3H, m), 1.53 (3H, m). The compound (64) was then used to produce the compounds of formula I, following for example the procedures of the preceding examples.

EXAMPLE 9 Ethyl isonipecotate obtainable commercially with di-tert-butyl dicarbonate was protected, and the ethyl ester was reduced with lithium aluminum hydride and the intermediate alcohol was converted to the desired iodide 69 with iodine according to the procedure described by A. Villalobos in the Journal of Medicinal Chemistry 1994, 37, 2721-2734.

A 500 ml round bottom flask was charged with iodide 69 (10.0 g, 30.75 mmol), triphenylphosphine (16.9 g, 64.6 mmol) and 150 ml acetonitrile. The solution was refluxed for 16 hours, cooled to room temperature and then concentrated in vacuo to a yellow oil. The crude product was further purified by chromatography on silica gel using a gradient of 4: 1 hexane: ethyl acetate to 100% ethyl acetate and with a final elution of 95: 5 methylene chloride: methanol to provide the salt of phosphonium 70 (7.13 g) with a yield of 40%. A 500 ml round bottom flask was charged with phosphonium salt 70 (7.13 g, 12.14 mmol), n-trityl-imidazole-4-carboxaldehyde (4.5 g, 13.14 mmol) and 250 ml of dry tetrahydrofuran, and the reaction mixture was cooled to 4 ° C. Potassium t-butoxide (14 ml in 1 M dioxane, 14 mmol) was added dropwise and the solution was allowed to cool slowly to room temperature and then the disappearance of the aldehyde was controlled by TLC. Additional potassium t-butoxide was added after 4 hours (2.4 ml, 2.4 mmol) and the reaction was allowed to stir at room temperature. After a total of 16 hours elapsed the reaction was filtered and the filtrate was concentrated to an oil. Elution on a column of silica gel with hexanes: ethyl acetate gave the pure alkene 72 (3.2 g) in 51% yield as a mixture of E / Z isomers.

A 500 ml round bottom flask was charged with alkene 72 (3.2 g), Pt02 (0.75 g) and 150 ml of methanol and adhered to a three-way device with a hydrogen ampule. The heterogeneous reaction was stirred under hydrogen for 2 hours. The catalyst was filtered and the filtrate was concentrated to an oil (3.2 g). The crude intermediate was redissolved in 180 ml of dioxane and treated at room temperature with 1 M TFA in dioxane (20 ml, 20 mmol) for 24 hours. The pH of the reaction mixture was adjusted to more than 8 with sodium hydroxide (1M), ethyl acetate was added and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to a semi-solid. The crude product was purified by chromatography (methylene chloride: methanol eluent) to provide pure 73 (1.8 g, 69% yield).

EXAMPLE 10 c To a flask containing the phosphonium salt 39 (3.5 g, 6.11 mmol) was added dry THF (30 ml) under a nitrogen atmosphere. The mixture was cooled to 0 ° C and t-BuOK (1.0 M solution, 8 g, 8 mmol) was added by dripping through a syringe. The resulting yellow-colored mixture was stirred for 20 minutes and then the 3-carbon-aldehyde (2.4 g, 6.55 mmol) in 8 ml of THF was added through a syringe. The reaction mixture was stirred for 24 hours at 25 ° C and then quenched by the addition of an NH 4 Cl solution. The aqueous portion was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO, filtered and concentrated. Chromatography on silica gel (40% EtOAc-hexane -> 60% EtOAc) provided 74.6.6 g (71%) of material. MS (electrospray, M + H) = 534. To compound 74 (2.3 g, 4.3 mmol) dissolved in MeOH was added Pt02 (0.4 g). A hydrogen balloon was placed over the reaction mixture and stirring was continued for 2-3 hours at 25 ° C. The reaction mixture was then chromatographed on Si02 (100% hexane which was increased to 75% EtOAc-hexane) to remove the catalyst and to obtain the pure product 75.2.24 g (97%). MS (electrospray, M + H) = 536. To a dioxane solution of compound 75 (2.0 g, 3.7 mmol) was added a 4M solution of dioxane-HCl (10 mL) at 25 ° C. The mixture was stirred for about 6 hours and then cooled to 0 ° C and 5% NaOH was added to bring the pH to 7. The mixture was extracted with EtOAc and the combined organics were washed with brine, dried over MgSO 4. filtered and concentrated to give 1.14 g (100%) of compound 76. MS (electrospray, M + H) = 436. Treatment of 76 (200 mg, 0.46 mmol) again with 4M dioxane-HCl (5 ml) at 80 ° C for 4 hours gave 140 mg of compound 77. MS (Cl, M + H) = 194. The following compounds were prepared following procedures similar to those described above. twenty twenty , twenty twenty Mass spectrometry data The compounds of this invention are agonists or antagonists of the histamine H3 receptor. The affinity of adhesion of the compounds of the invention to the H3 receptor can be demonstrated by the procedure described below: H3 receptor adhesion assay The source of H3 receptors in this experiment consisted of guinea pig brain. The animals used weighed 400-600 g. The tissue was homogenized using a Polytron in a 50 mM Tris solution, pH 7. 5, the final tissue concentration in the homogenization buffer was 10% w / v. The homogenates were centrifuged at 1000 x g for 10 minutes in order to eliminate lumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000 x g for 20 minutes in order to pellet the membranes, which were then washed three times in the homogenization buffer (50,000 x g for 20 minutes each). The membranes were frozen and stored at -70 ° C until needed. All the test compounds were dissolved in DMSO and then diluted in the adhesion buffer (50 mM Tris., pH 7.5) so that the final concentration was 2 μg / ml with 0.1% DMSO. Then the membranes (400 μg of protein) were added to the reaction tubes. The reaction was initiated by the addition of 3 nm [3 H] R -methylhistamine (8.8 Ci / mmol) or [3 H] N-α-methylhistamine (80 Ci / mmol) and incubated at 30 ° C for minutes. Adherent ligand was removed from the non-adhered ligand by filtration, and the radioactive ligand capacity adhered to the membranes was quantified by liquid scintillation spectrometry. All incubations were carried out in duplicate and the standard error was less than 10% in all cases. The compounds of inhibited more than 70% of the specific adhesion of the radioactive ligand to the receptor, were serially diluted to determine a Ki (nM). Compounds 45, 78, 79, 81-97 and 113-118 had a Ki in the range of 0.1 to 220 nM. Compounds 45, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 91, 94, 96 and 116 had a Ki in the range of 0.1 to 20 nM.

The compounds described in this invention are pharmaceutically acceptable inert carriers which may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. The powders and tablets may be comprised of from about 5 to about 70% active ingredient. Suitable solid carriers are known in the art, they are constituted for example by magnesium carbonate, magnesium stearate, sugar and lactose. The tablets, powders, seals and capsules can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a low melting point wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and then the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into molds of a convenient size and allowed to cool and then solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example, aqueous or water-propylene glycol solutions for parenteral injection may be mentioned. The liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form which may be in combination with a pharmaceutically acceptable carrier such as an inert tablet. Also included are preparations in solid form that are intended to be converted shortly from their use to liquid form preparations for oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal matrix dressing or reservoir type that are conventional in the art for the purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In such form the preparation is subdivided into unit doses containing the appropriate quantities of the active component, for example and an effective amount to achieve the desired purpose. The amount of active compound in unit dose of the preparation can be varied or adjusted to from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 500 mg, according to a particular application. The actual dosage used may vary depending on the requirements of the patient and the severity of the disease being treated. The determination of the appropriate dosage for each particular situation is within the skill of the person skilled in the art. In general, treatment starts with smaller dosages that are less than the optimal dose of the compound. Next, the dosage is increased in small increments until the optimum effect is reached under the circumstances. For reasons of convenience the total daily dosage can be divided and administered in portions during the day if desired. The amount of administration frequency of the compounds of the invention and their pharmaceutically acceptable salts will be regulated according to the opinion of the attending physician considering the factors such as the age, condition and weight of the patient as well as the severity of the the symptoms that are being treated. A typical recommended dosage regimen is oral administration of from 1 mg to 2000 / day, preferably 10 to 1000 / day in one to four divided doses to obtain relief of symptoms. The compounds are non-toxic when administered within this dosage range. Following are examples of pharmaceutical dosage forms containing a compound of the invention. As used herein, "active compound" is used to designate one of the compounds of formula I or a salt thereof. The scope of the invention in its pharmaceutical composition aspect is not limited to the examples provided. Examples of pharmaceutical dosage forms EXAMPLE A Tablets Manufacturing method Items Nos. 1 and 2 are mixed in an appropriate mixer for 10-15 minutes. The mixture is granulated with item No. 3. The wet granules are crushed through a coarse screen (for example a quarter of an inch, 0.63 cm) if necessary. The wet granules are dried. Dry granules are sieved if necessary and mixed with item No. 4 and mixed for 10-15 minutes. Item No. 5 is added and mixed for 1-3 minutes. The mixture is compressed to the appropriate size and weight in an appropriate tabletting machine.

EXAMPLE B Capsules Manufacturing method Items Nos. 1, 2 and 3 are mixed in an appropriate mixer for 10-15 minutes. Item No. 4 is added and mixed for 1-3 minutes. The mixture is filled into 2-piece hard gelatin capsules, suitable in a suitable encapsulated machine. While the present invention has been described in conjunction with the specific embodiments set forth above, many of the alternatives, modifications thereof will be apparent to those skilled in the art. All said alternatives, modifications and variations are within the spirit and scope of the present invention.

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula: or pharmaceutically acceptable salts or solvates thereof, wherein: X is a straight chain alkyl group having 1 to 7 carbon atoms or an alkene or alkylene group with 2 to 4 carbon atoms; wherein said alkyl or alkene groups are optionally substituted with up to two R7 groups; n is 0, 1 or 2, m is 0 to 4; p is 0 to 4; when m is 0 to 4, Y represents -SO2-; -CS-; -CO-; -CONR5-; -CO (CH2) wO- (being W 1 to 4); -COO-; -CON (OR5) -; -C (NR5) NR5-; -S02NR5- or -CSNR5; when m is 2 to 4, Y represents all the preceding groups in which m is 0 to 4 and in addition, Y represents -COR5-; -OR-; -NR5CONR5-; -NR5CO-; -NR5-; -OCONR5-; -NR5C (NR5) NR5-, -NR5CSNR5; -NR5CS- or -NR5SO2-; -NR5C (O) O-; O-CSNR2; each R 5 independently represents hydrogen, alkyl or benzyl; R6 is selected from: (1) aryl, (2) heteroaryl, (3) a 3-7 membered heterocyclic group, (4) substituted aryl having 1-3 substituents independently selected from alkyl, halogen, trihalomethyl, CN, N02 , OR10 or NR10R11, wherein R10 and R11 are independently selected from H, alkyl or trihalomethyl, (5) substituted heteroaryl having 1-3 substituents independently selected from alkyl, halogen, trihalomethyl, CN, N02, OR10 or NR10r11, where R10 and R11 are as defined above; or (6) substituted heterocyclic having 1-3 substituents independently selected from alkyltriahalomethyl or NR10R11, wherein R10 and R11 are as defined above, said substituents being attached to the carbon atoms in the ring such that the total amount of substituents in the ring is from 1 to 3; and wherein the heterocyclic ring contains substitutable nitrogen atoms and said nitrogen atoms being optionally substituted with lower alkyl; when Y is -S0- then R6 in addition to the preceding groups also represents alkyl having 1 to 7 carbon atoms or a group -NR10R11 wherein R10 and R11 are as previously defined; each R1 is independently selected from hydrogen, alkyl or trihalomethyl; each R7 is independently selected from hydrogen, alkyl, trihalomethyl, CN, N02, OR10R11, where R10 and R11 are as previously defined.

2. The compound of claim 1 having the formula in which: q is 1 to 7; m is 0 to 4; n is 0 to 1; p is 0 to 4; when m is 0 to 4, Y is selected from -S02-, -S02NH-, -CONH-, -CO-, -C (NH) NH-, or -CO (CH2) wO-; and when m is 2 to 4, Y represents all the preceding groups when m is 0 to 4 and further Y represents -NHCONH-, -O- or -NHC (NH) NH-; and w, R1, R6 and R7 are as previously defined.

3. The compound of claim 2, wherein q is 1 to 4; m is 0 to 3; p is 0, 1 or 2; And it is -CONH-, -S02- or -CO-; R6 is phenyl or substituted phenyl; each R1 is independently selected from H or alkyl; and each R7 is independently selected from H or alkyl.

4. The compound of claim 3 wherein (1) n is 0; (2) Y is -CONH- or -S02; (3) R6 is (a) monosubstituted phenyl wherein said substituent is in the 3 or 4 position and said substituent is selected from fluoro, chloro, methoxy or trifluoromethoxy, or (b) disubstituted phenyl wherein said substituents are in the 3-position , And said substituents are the same and are selected from fluorine, chlorine, methoxy or trifluoromethoxy; and (4) R1 and R7 are H.

5. The compound of claim 4 wherein q is 2.

6. The compound of claim 1 which is selected from:

7. - The compound of claim 2 wherein n is 1; Y is selected from -S02-, -CONH-, -CO-, or -CO (CH2) wO-; and, when m is 2 to 4, and in addition to the preceding groups, it is also selected from -NHCONH- or -O-.

8. The compound of claim 7, wherein (1) q is 1 or 2; (2) n is 1; (3) m is 0 to 3; (4) p is 0, 1 or 2; (5) Y is -CONH- or -S02-; (6) R6 is (a) monosubstituted phenyl wherein said substituent is in the 3 or 4 position and said substituent is selected from fluorine, chlorine, methoxy or trifluoromethoxy, or (b) disubstituted phenyl wherein said substituents are in the 3,5-position and said substituents are the same and are selected from fluorine, chlorine, methoxy or trifluoromethoxy; and R1 and R7 are H.

9. The compound of claim 8 wherein q is 2.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound or a salt or solvate thereof, according to claim 1.

11. The use of a compound or salt or solvate thereof, according to claim 1 for the manufacture of a medicament for treating allergy, inflammation, cardiovascular diseases, hypotension, glaucoma, sleep disorders. , diseases of the Gl tract, states of hyper- and hypomotility of the gastrointestinal tract, disorders of the central nervous system, hyper- and hypoactivity of the central nervous system, Alzheimer's disease, schizophrenia, obesity and migraine.

12. The use of the compound, or salt or solvate thereof, according to claim 1, for the manufacture of a medicament that is used in combination with a drug manufactured to be used as a hystamine receptor antagonist Hi, said combination being useful in the treatment of allergic responses of the upper respiratory tract.

13. The use of claim 12, wherein said Hi antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine, cetiricin.

14. The method of claim 12 wherein said Hi antagonist is selected from: loratadine or descarboethoxyloratadine.