WO1996008468A1

WO1996008468A1 - Carbamoyloxy amine compounds

Info

Publication number: WO1996008468A1
Application number: PCT/DK1995/000368
Authority: WO
Inventors: Erik Falch; Ivan Mikkelsen; Povl Krogsgaard-Larsen
Original assignee: H. Lundbeck A/S
Priority date: 1994-09-14
Filing date: 1995-09-14
Publication date: 1996-03-21
Also published as: ZA957746B; IL115305A0; AU3470495A

Abstract

Carbamoyloxypropylamine or carbamoyloxyethylamine compounds of formula (I), wherein A represents CH2 or a bond, R1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or phenyl; and R2 is alkyl, alkenyl, alkynyl, cycloalkyl or phenyl; or R1 and R2 together form a ring; R3 and R4 are hydrogen, alkyl, alkenyl, alkynyl, halogenated alkyl, cycloalkyl, phenyl, or phenylalkyl or R3 and R4 together form a spirojoined C4-7 carbocycle; or when R1 and R2 are not linked, R3 and R2 may form ring; R5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or phenylalkyl or together with R2 form a ring; or R5 together with R4 form a ring; R6 and R7 are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or phenylalkyl; or R6 and R7 together form a ring; are ligands at the central nicotine acetylcholine receptors (nAChRs). The compounds are useful in the treatment of cognitive, neurological or mental disorders in which nAChR dysfunction is involved.

Description

Carbamoyloxy Amine Compounds

The present invention relates to a novel class of carbamoyloxypropylamine or carba- moyloxyethylamine derivatives in which the alkyl backbone contains substituents or is partly incorporated into ring structures. The novel compounds are ligands at the central nicotine acetylcholine receptors (nAChRs) and accordingly useful in the treatment of certain cognitive, neurological and mental disorders.

Background of the invention

There is a rapidly growing interest in nAChRs in the central nervous system (CNS) as pharmacological and therapeutic targets (Williams et al., Drug News & Perspec¬ tives 1994, 7, 205-223.). There is convincing evidence of major impairments of central acetylcholine (ACh) neurotransmission in patients with Alzheimer's disease (Pomera et al., Prog. Neuro-Psychopharmacol. Biol. Psychiat. 1986, 70, 553-569.; Perry, Br. J. Psychiat 1988, 752, 737-740.). Cortical nAChRs are markedly reduced in brain tissues from Alzheimer patients (Giacobini, J. Neurosci Res. 1990, 27, 548- 560; Whitehouse et al., Brain Res. 1986, 371, 146-151 ), reflecting the cholinergic deficit associated with Alzheimer's disease. The parietotemporal cortex is the brain area which is most consistently implicated in the cognitive deficits in Alzheimer patients (Gitelman and Prohovnik,Neιvrot->/o/. Aging., 1992 13, 313-318). Preclinical and clinical data are consistent with the view that nACh receptor agonists are useful in the treatment of Alzheimer's disease (Sahakian et al., Br.J. Psych. 1989, 154, 797-800; Levin, Psychopharmacology 1992 , 708, 417-431).

In addition to its palliative effects on cognitive deficits in animal models and patients, nicotine, the most extensively studied nAChR ligand, also shows neuroprotective effects in models relevant to Parkinson's disease (Owman et al., Prog. Brain Res. 1989, 79, 267-276; Williams et al., supra). Such observations make nACh receptors potential targets for therapeutic intervention in this neurologic disease (Aubert et al., J. Neurochem. 1992, 58, 529-541 ). Similarly, nAChR ligands have therapeutic potential in schizophrenia (Adler et a\.,Biol. Psychiat. 1992, 32, 607-616). Further¬ more, nicotine and other nAChR agonists have shown effects in animal models of anxiety (Brioni et al., Eur.J. Pharmacol. 1993, 238, 1-8) and pain (Qian et al., Eur. J. Pharmacol. 1993, 250, 13-14; Badio and Daly, Mol. Pharmacol. 1994, 45, 563-569).

Tobacco smoke contains a variety of substances, but it is beyond doubt that the addictive nature of smoking is attributable to the content of nicotine. Consequently, nAChR ligands may be useful drugs in therapies for smoking cessation (for referen¬ ces, see Williams et al., supra).

Nicotine is the classical nACh receptor agonist, but the number of nACh receptor agonists and antagonists, synthesized or isolated from natural sources, is rapidly growing (Williams et al., supra).

A number of a analogues of carbamylcholine, including N-methylcarbamylcholine (MCC), (Boksa et al., Eur. J. Pharmacol. 1989, 773, 93-108; Abood et al., Pharma¬ col. Biochem. Behav. 1988, 30, 403-408) and N,N-dimethylcarbamylcholine (DMCC) (Punzi et al., Biochem. Pharmacol. 1991 , 41, 465-467; Sarawati et a\.,Drug Dev. Res. 1994, 31, 142-146) have been synthesized and characterized as nAChR ligands. The compounds synthesized included some N-alkyl-, N,N-dialkyl and cycloalkyl carbamate estes of dimethylethanolamine and the N-methyl carbamate ester of dimethylpropanolamine.

Similar compounds are known from Chemical Abstracts 1961 , 55, No CA p 6375a which discloses a few Λ/-(dimethylcarbamoyloxyalkyl)dialkylamines, i.e. 3-dimethyl- carbamoyloxy-Λ/,Λ/-dimethylpropylamine, 3-dimethylcarbamoyloxy-Λ/,Λ/-diethylpropyl- amine, 2-dimethylcarbamoyloxy-/V,Λ/-diethylpropylamine, 1 -[3-(dimethylcarbamoyl- oxy)propyl]piperidine and 2-dimethylcarbamoyloxy-2-phenyl-1 -methyl- Λ/,/V-dimethyl- ethylamine. These compounds are claimed to exhibit choline esterase activity.

MCC appears to interact with presynaptically localized nAChRs involved in a posi¬ tive feedback of ACh release (Araujo et al., supra; Lapchak et al., J. Neurochem. 1989, 53, 1843-1851). Within the compounds found to be nAChR ligands, the qua¬ ternary analogues, i.e. carbamate esters of choline, showed markedly higher nAChR affinity than the corresponding tertiary amines, i.e. carbamate esters of N,N- dimethylaminoethanol (Abood et al., supra; Punzi et al., supra). Since the former group of analogues are likely to show a limited ability to penetrate the blood-brain barrier it is desired to obtain novel potent nAChR ligands having a good ability to penetrate the blood-brain barrier.

Summary of the invention

It has now been found that a series of novel tertiary amine homologues of DMCC are potent nAChR ligands.

Accordingly the present invention relates to a novel class of carbamoyloxy amine compounds of the formula I

FORMULA

wherein A represents CH₂ or a bond,

R-i is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or phenyl; and R₂ is alkyl, alkenyl, alkynyl, cycloalkyl or phenyl; or R-i and R₂ together with the adjacent nitrogen form a 3 to 7 membered monoazacyclic ring; R₃ and R₄ are the same or different and each represent hydrogen, alkyl, alkenyl, alkynyl, mono- or polyhalogenated lower alkyl, cycloalkyl, phenyl, or phenyl-lower alkyl or R₃ and R₄ together form a spirojoined C₄.₇ carbocycle; or when R-i and R₂ are not linked, R₃ and R₂ may together with the nitrogen and carbon to which they are attached form a 3 to 7 membered monoazacyclic ring; R₅ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or phenyl-lower alkyl; or if R₂ do not form a ring with R-i or R₃, then R₅ and R₂ may together with the nitrogen atom to which R₂ is attached, the carbon atom substituted with R₃ and R₄ and the carbon atom to which R₅ is attached, form a 3 to 7 membered monoazacyclic ring; or if R₃ is not included in a ring and R₅ do not form a ring together with R₂, R₅ and R₄ may together with the carbon atoms to which they are attached form a 3 to 7 membered carbocyclic ring; provided that R₅ is hydrogen when A is a bond; Rβ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or phenyl-lower alkyl; and R₇ is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or phenyl-lower alkyl, provided that R₇ cannot be phenyl or phenyl-lower alkyl when Re is hydrogen; or Re and R₇ together with the adjacent nitrogen form a 5 to 6 membered monoaza- cyclic ring; with the proviso that one of R3 and R₄ must be different from hydrogen when A is a bond, R-i is hydrogen or alkyl and R₂ is alkyl, and that R3 and R₄ may not both be hy¬ drogen when A represents CH₂, Re is hydrogen or methyl, R₇ is methyl and R-i and R₂ are both alkyl or together with the N-atom to which they are attached form a piperidine ring; and pharmaceutically acceptable salts thereof.

The compounds of the invention have been found to have a high affinity for nAChR's. Furthermore, some of the compounds have been found to exhibit nAChR agonist properties. Accordingly, the compounds of the invention are considered use¬ ful in the treatment of cognitive, neurological and mental disorders in which nAChR dysfunction is involved, such as pain, dementia, Alzheimers disease, Parkinsons di¬ sease, impaired learning ability, impaired memory function, psychosis, schizophre¬ nia, pain and anxiety, in particular dementia, Alzheimers disease or impaired lear- ning ability or memory function. Furthermore, they may be used in theraputical treat¬ ment for smoking cessation.

In another aspect the invention provides a pharmaceutical composition comprising at least one novel carbamoyloxy amine compound of formula I in a therapeutically effective amount.

In a further aspect the present invention provides the use of a carbamoyloxy amine compound of formula I for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders and diseases.

Detailed Description of the Invention

Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers as well as any mixture thereof, including the racemic mixtures, are also embraced by the invention.

In the present context, the term alkyl designates C-i-β alkyl which may be straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, tert.butyl, pentyl, hexyl, hep- tyl or octyl. Among the alkyl groups, lower alkyl groups are preferred. The term lower alkyl designates C₁-₄ alkyl which may be a straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, tert.butyl. Similarly, alkenyl and alkynyl, desig¬ nate C2-8 groups having at least one double or tripple bond, respectively, and lower alkenyl and lower alkynyl designate such groups having up to 4 carbon atoms.

The term cycloalkyl designates a saturated carbocyclic ring having 3-7 carbon atoms, inclusive.

The term phenyl-lower alkyl designates a lower alkyl group (as herein defined) which, in turn, is substituted with a phenyl group. Preferred phenyl-lower alkyl are benzyl, 1-and 2-phenylethyl, 1-.2-, and 3-phenylpropyl, and 1 -methyl- 1-phenylethyl.

The term halogen designates F, Cl, Br or I, F being preferred. The term polyhaloge- nated lower alkyl designates lower alkyl, as defined above, substituted with two or more halogen atoms, which may be the same or different. A preferred example of polyhalogenated lower alkyl is trifluoromethyl.

The term a 3 to 7 membered monoazacyclic ring refers to a 3-, 4-, 5-, 6- or 7- membered ring containing one nitrogen atom, such as aziridinyl, azetidinyl, pyrrolidi- nyl, piperidinyl or perhydroazepinyl. Preferred groups are pyrrolidinyl and piperidinyl.

The term 3 to 7 membered carbocyclic ring refers to a 3-, 4-, 5-, 6- or 7-membered carbon ring, for instance cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.

The salts of the compounds of the formula I include any pharmaceutically accept¬ able acid addition salt. This term as used herein generally includes the non-toxic acid addition salts of compounds of the formula I, formed with non-toxic inorganic or organic acids. For example, the salts include salts with non-toxic inorganic acids, such as hydrochloric, hydrobromic, sulphuric, sulphamic, nitric, phosphoric and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, stearic, lactic, malic, pamoic, ascorbic, phenylacetic, glutamic, benzoic, salicylic, sulphonic, sulphanilic, and the like.

In formula I R-i is preferably lower alkyl, most preferably methyl and R₂ is preferably lower alkyl, especially methyl, or designates together with R₃ and the nitrogen and carbon, repectively, to which R₂ and R₃ are attached a pyrrolidinyl ring or R-i and R₂ may together form a pyrrolidinyl ring.

Furthermore, R3 is preferably lower alkyl, or together with R₂ forms a ring, cf above. Most preferably R₃ is lower alkyl, especially methyl.

R₄ is preferably hydrogen and R₅ is preferably hydrogen or together with R₃ forms a ring, cf. above.

Re is preferably hydrogen or lower alkyl, most preferably hydrogen, ethyl or methyl and R₇ is preferably lower alkyl, most preferably ethyl or methyl.

Preferred compounds of the invention are compounds of formula II

FORMULA II

wherein R-i, R_2, R_3, Rε and R₇ are as defined above;

Especially preferred compounds of the invention are compounds of formula

FORMULA

wherein R-i, R₂, Re and R₇ are as defined above;

Another, subclass of preferred compounds of the invention are compounds of formula IV:

Formula IV

wherein R*ι , Re and R₇ are as defined above.

Especially preferred compounds are:

(R,S)-4-Dimethylcarbamoyloxy-2-Λ/,Λ/-dimethylbutylamine

(S)-4-Dimethylcarbamoyloxy-2-Λ/,Λ/-dimethylbutylamine

(R)-4-Dimethylcarbamoyloxy-2-Λ/,Λ/-dimethylbutylamine

Compounds which may also be mentioned are: 4-Dipropylcarbamoyloxy-2-Λ/,Λ/-dimethylbutylamine 4-Ethylmethylcarbamoyloxy-2-/V,Λ/-dimethylbutylamine 4-Methylpropylcarbamoyloxy-2-Λ/,Λ/-dimethylbutylamine

The compounds of the invention are conveniently administered to a patient, via rectal, oral, parenteral or transdermal dosage forms or by inhalation as one or more daily doses, or other time-presented doses. The dose will, of course, depend on the requirements of the individual under treatment.

The effective daily dose of a typical compound is 5.0 μg to 1.5 mg, preferably 10 μg to 1.0 mg, in particular 25 μg to 0.5 mg pr. kg of body weight. Thus, the daily dose is generally in the range of 0.3 to 100 mg, preferably 0.6 to 60mg, usually 1.5 to 40 mg for typical compounds regardless of administration form. The daily dose may be administered in 1 to 3 single doses.

The compounds of the formula I may be administered in the form of tablets, capsules, suspensions, emulsions, solutions, injectables, suppositories, enema, various drug delivery devices and in other suitable form. The route of administration may be rectally, orally, parenterally or transdermally or by inhalation. The formula¬ tion and preparation of any of these dosage forms is well-known to those skilled in the art of pharmaceutical formulation.

In a typical preparation for oral administration e.g. tablet or capsule, any one of the compounds of the present invention in a pharmacologically effective amount is combined with any oral nontoxic pharmaceutically acceptable inert carrier such as lactose, starch and microcrystalline cellulose. Additionally, when required, suitable binders (e.g. gelatin), lubricants (e.g. talc or magnesium stearate) and disintegrating agents (e.g. starch or various cellulose derivatives) are included.

Similarly, in a typical formulation for parenteral application (intravenous, intramus- cular, subcutaneous or the like), a compound of the present invention is dissolved in sterile water in a given concentration and sterilized by e.g. membrane filtration, or radiation. The pH of the solution may, if necessary, be adjusted with e.g. hydrochlo¬ ric acid, sodium hydroxide or a suitable buffer, and a suitable preservative may optionally be added. Similarly, agents like sodium chloride may be added in order to adjust the tonicity of the solution. A suitable parenteral preparation may also consist of the compound formulated as a sterile, solid substance distributed in injection vials. Before dispensing, water for injection is added to dissolve the compound.

For the rectal application of the compounds of the invention, typical dosage forms include suppositories (emulsion and suspension types), rectal gelatin capsules (solutions and suspensions), and enemas or micro-enemas (solutions and suspen¬ sions). Thus, in a typical suppository formulation, a compound of the invention is combined with any pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids (C-io-C-iβ), glycerinated gelatin, and various water- soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters. Various additives like salicylates or surfactant materials may be incorporated. Enemas or micro-enemas of the solution type may simply be prepared by dissolving compounds of this invention in water or in water containing e.g. 0.5% of methylcellulose or another viscosity-increasing agent. The novel and useful compounds of the invention may also be administered by drug delivery systems such as gastrointestinal drug delivery devices and rectally applied osmotic delivery devices, wherein the delivery device is manufactured from naturally occurring or synthetic polymeric materials.

The compounds of the present invention may be prepared by : a) Reacting a compound of the formula V

Formula V

wherein R-j' is as R-i defined above or an amino protecting group, and R2, R3, R4, R5 and A are as defined above, with a compound of the formula VI

Formula VI

wherein R₆' is as defined above for R₆ except that it may not be hydrogen, R₇ is as defined above, and Z is a leaving group; and then, if an amino protecting group has been used, removing the said group;

b) reacting a compound of the formula V as defined above with an isocyanate, R7-N=C=0, wherein R₇ is as defined above and then, if an amino protecting group has been used; or

c) reacting a compound of the formula VII

Formula VII

wherein R-j', R2, R3, R4, R5, Z and n are as defined above, with a compound of the formula VIII

HN Formula VIII

R₇ wherein R₆ and R₇ are as defined above and then, if an amino protecting group has been used, removing the said group.

The reaction is carried out without a solvent or in a solvent, e.g. toluene, tetrahydro- furan, diethylether, acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide, or the like. In a) and c) a base, e.g. sodium hydride, tertiary amine, pyridine, potas¬ sium carbonate, or the like, usually has to be present whereas in b) a base may be present if convenient. In a) and b) the temperature during the reaction is usually be¬ tween 0°C and the boiling point of the mixture and in c) it is usually between -10°C and the boiling point of the mixture The reaction time is normally from 1 to 96 hours.

The compounds formulas V, VI and VIII are either commercially available or may be prepared by standard methods.

One way to obtain the compounds of formula VII may be by reacting a compound of formula V with phosgene.

Suitable leaving groups Z may easily be selected by a person skilled in the art. As examples may be mentioned chlorine, bromine and iodine.

The term amino protecting group designates groups readily removable by hydrolysis or hydrogenation. Suitable protecting groups may easily be selected. As examples of such groups may be mentioned methyloxycarbonyl, ethyloxycarbonyl, tert.butyl- oxycarbonyl, benzyloxycarbonyl, formyl, acetyl, trityl, benzyl, or the like.

The present invention is further illustrated by the following examples which, however, may not be construed to be limiting. Example 1

(S)-2-Dimethylcarbamoyloxymethyl-1-methylpyrrolidine (Comp. (S)-1). Salt with 1.0 equivalent of tartaric acid To a suspension of 80% sodium hydride dispersion (3.52 g; 117.4 mmol) in dry toluene (70 ml) was added a solution of (S)-2-hydroxymethyl-1-methylpyrrolidine (10.00 g; 87.0 mmol ) in dry toluene (30 ml) over a period of 15 min. After 5 hours at 25°C, a solution of dimethylcarbamoyl chloride (11.20 g; 104.4 mmol) in dry toluene (30 ml) was added over a period of 45 min., and the mixture was allowed to stir overnight at 25°C. Water (75 ml) was added, and the two phases were separated. The water phase was extracted with toluene (4 X 75 ml), and the combined organic phases dried with MgSU₄. The solvent was removed under reduced pressure and the crude product (15.8 g) was purified by flash column chromatography on silica gel by use of triethylamine.toluene (1 :20) and an increasing amount of ethyl acetate as eluent. The eluent was removed under reduced pressure and the purified product was obtained as a yellow oil (15.8 g; 98%). Part of the oil (1.40 g ) was dissolved in dry isopropanol (5 ml) and a solution of L(+)-tartaric acid (1.24 g) in isopropanol (20 ml) was added followed by diethylether. After standing 72 hours at 5°C the title compound was isolated by filtration. Recrystallization from isopropanol and diethyl- ether gave the title compound (1.95 g; 77%), mp.: 82-84°C.

Example 2

(S)-2-Ethylcarbamoyloxymethyl-1-methylpyrrolidine (Comp. (S)-2). Salt with 1.0 equivalent of fumaric acid. Ethyl isocyanate (1.23 ml; 15.7 mmol) was added to (S)-2-hydroxymethyl-1-methyl- pyrrolidine (1.50 g; 13.0 mmol) in dry toluene (10 ml) over a period of 5 min.. After 6 hours at 25°C another portion of ethylisocyanate (0.30 ml; 3.93 mmol ) was added. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the crude product (2.22 g; 92%) was purified by flash column chroma- tography on silica gel by use of triethylamine:heptane (1 :20) and an increasing amount of ethyl acetate as eluent. The eluent was evaporated under reduced pressure to give the free base of the title compound (1.96 g; 81%) as an oil. As described in Example 1 , part of the oil (0.50 g) was converted to the fumaric acid salt by using fumaric acid. Recrystallization from isopropanol and diethylether gave the title compound (0.63 g; 77%), mp.: 101.5-102.5°C.

Example 3

(R,S)-4-Dimethylcarbamoyloxy-2-Λ/,Λ/-dimethylbutylamine (Comp. 8). Salt with 1.0

5 equivalent of fumaric acid.

(R,S)-3-Λ/,Λ/-Dimethylamino-1-butanol (4.29 g; 36.7 mmol) was added over a period of 10 min to a suspension of 60% sodium hydride dispersion (1.91 g; 47.7 mmol) in dry DMF (100 ml). After 3 hours at 40°C, dimethylcarbamoyl chloride (5.12 g; 47.7 mmol) was added over a period of 20 min. After another 4 hours at 40°C, the ιo mixture was allowed to stir overnight at 25°C. After removal of the solvent under reduced pressure the residue was taken up in 100 ml water and extrated with diethylether (80 ml +3x30 ml). The combined organic phases were dried with MgSθ₄ and the solvent was removed under reduced pressure, leaving the crude product as a yellow oil (5.69 g; 83%). As described in Example 1 , the oil was

15 converted to the fumaric acid salt by using fumaric acid. Recrystallization from iso¬ propanol and diethylether gave the title compound (5.78 g; 61%), mp.: 91-93.5°C.

Example 4

C/s-Λ/-Methyl-2-dimethylcarbamoyloxymethylcyclopentylamine (Comp. cis-(1 S,2R)-

20 18). Salt with 1.0 equivalent fumaric acid.

Cs,frans-2-(Λ/-benzyl-Λ/-methylamino)cyclopentanemethanol (4.50 g; 18.4 mmol ) was reacted with dimethylcarbamoyl chloride (2.67 g; 24.8 mmol ) as described in Example 2. The crude product (5.55 g; 96%) was purified by flash column chromato¬ graphy on silica gel by use of triethylamine:heptane (1 :20) as eluent. The eluent

25 was evaporated under reduced pressure and the N -benzylated title compound was obtained as an oil (1.85 g; 32%). Part of the oil (1.55 g; 5.34 mmol) was dissolved in acetic acid (50 ml) and hydrogenated with 120 mg prereduced Ptθ₂ at 3 atm.and 25°C for 24 hours. The solvent was removed under reduced pressure, and the crude product (1.09 g; 99%) was purified by flash column chromatography on silica

30 gel by use of triethylamine:heptane (1 :20) as eluent. The eluent was evaporated under reduced pressure to give the free base of the title compound (0.59 g; 54%) as an oil. As described in Example 1 , the oil was converted to the fumaric acid salt. Recrystallization from isopropanol and diethylether gave the title compound (0.54 g; 80%), mp.: 102.5-103.5°C. The following Table 1 lists further examples of the invention. The symbols used in the table refers to formula I. For the purpose of completion the compounds of Examples 1-4 are also included in the table.

The compounds were synthesized by methods analogeous to those described in Examples 1-4. Compounds (S)-8 and (R)-8 were prepared from Comp. 8 by standard resolution methods.

The following optical rotations have been measured, [αfo²⁵ deg.:

Comp. (S)-1 : +3.7; Comp. (R)-1 : -3.7; Comp. cis-(1S,2R)-18: -52.9; and Comp. cis- (1 R,2S)-18: +52.7, Comp. (S)-8 (tartrate): -4.41 , Comp. (R)-8 (tartrate): +4.97, (R)- 30: +4.81 and (S)-30: 4.98.

Table 1 : Examples

Comp. A¹' Ri R₂ R₃ R₄ R₅ R₆ R₇ Mp °C (salt)²-

(S)-1 B Me (CH₂)₃ H H Me Me 130.5-132.5 (T)

(RM B Me (CH₂)₃ H H Me Me 130-132 (B)

(S)-2 B Me (CH₂)₃ H H H Et 101.5-102.5

(S)-3 B Me (CH₂)₃ H H Et Et 102-103

(S)-4 B Me (CH₂)₃ H H H Me 76-77.5

(S)-5 B Et (CH₂)₃ H H Me Me 82-84

6 B Me (CH₂)₄ H H Me Me 123-124.5

7 CH₂ Me (CH₂)₃ H H Me Me 95-96

8 CH₂ Me Me Me H H Me Me 91-93.5

(s)-8 CH₂ Me Me Me H H Me Me 120 dec. (DT)

(R)-8 CH₂ Me Me Me H H Me Me 120 dec. (DT)

9 CH₂ Me Me Et H H Me Me 102-103

10 CH₂ Me Me Me₂CH H H Me Me 96-100

11 CH₂ Me Me CβHn H H Me Me 130-133 Comp. A^* Ri R₂ R₃ R₄ R₅ Re R₇ Mp °C

12 CH₂ Me Me (CH₂)₅ H Me Me 114-115

13 CH₂ H Me Me H H Me Me 66-68

14 CH₂ (CH2)₄ Me H H Me Me 98-99

15 CH₂ (CH2)₅ Me H H Me Me 121-125

16 CH₂ Me Me H H H H Et 84-87

17 CH₂ Me Me H H H Et Et 60-65 cis-18 CH₂ Me Me H (CH₂)₃ Me Me 126-127 trans- 18 CH₂ Me Me H (CH₂)₃ Me Me 122-124.5 cis- CH₂ Me Me H (CH₂)₃ Me Me 146.5-167.5 (T)

(1S2R)18 cis- CH₂ Me Me H (CH₂)₃ Me Me 146.5-167.5 (T)

(1 R,2S)18

19 CH₂ H Me H (CH₂)₃ Me Me 102.5-103.5

20 CH₂ Me Me H (CH₂)₄ Me Me 146-148

21 CH₂ (CH₂)₄ H H H Me Me 103.5-104.5

22 B Me Me Me Me H Me Me 144.5-145.5

23 B (CH₂)₄ H H H Me Me 110-113

24 B (CH₂)₄ H H H H Et 62-64 (M)

25 B (CH₂)₅ H H H Me Me 118-122

26 B (CH₂)₅ H H H H Et 88-93

27 B Me Me Me H H Me Me 112-117

28 CH₂ Me R₂-Rs =(CH₂)₂ ; R₃. 4= H Me Me 84-85

29 CH₂ Me R₂-Rs =(CH₂)₃ ; R₃. R4= H Me Me 112-113

30 CH₂ Me Me Me H H H Me 97-99

(R)-30 CH₂ Me Me Me H H H Me 91-91 (0)

(S)-30 CH₂ Me Me Me H H H Me 91-92 (0)

31 CH₂ Me Me Me H H Et Et 96-97.5 (C)

1): B designates a bond.

2): T designates tartrate, B hydrobromide, DT dibenzoyi tartrate; M maleate, O oxalate and C hydrochloride. The remaining compounds were isolated as fumarates. Pharmacology

The compounds of the invention were tested in the following well recognized and reliable test methods.

L-[³H]Nicotine binding

L-[³H]Nicotine binding to cholinergic receptors in rat brain membranes was per¬ formed essentially as described by Lippiello, P.M. and Fernandes, K.G. Mol. Pharmacol, 1986, 29, 448-454.. Rat brains were homogenized (Ultraturrax) in 10 vol (w/v) buffer consisting of Na₂HP0_4l 8 mM; KH₂P0₄, 1.5 mM; KCI, 3 mM; NaCl, 120 mM; EDTA, 2 mM; HEPES, 20 mM; and iodoacetamide, 5mM (pH 7.4). The homogenate was centrifuged (50.000 x g; 20 min.; 0°C) and the pellet resuspended in 10 vol. cold standard assay buffer with the same composition as the buffer preparation described above, except for the addition of MgCl_2, 1 mM and CaCb, 2 mM, and the elimination of EDTA and iodoacetamide. Aliquots (0.1 mg of tissue) were incubated with 5 nM L-[³H]Nicotine (78 Ci/mmol, Amersham) alone or in the presence of test compound in a total volume of 0.6 ml for 60 min. at 0°C. Incubation was terminated by adding 5 ml of ice-cold sodium potassium phosphate buffer (50 mM, pH 7.4) followed by rapid filtration through Whatman GF/B filters presoaked in 0.1 %polyethyleneimine using a Brandel cell-harvester. Filters were washed with three 5-ml aliquots of cold sodium potassium phosphate buffer, and bound radioac¬ tivity estimated by liquid scintillation counting methods. Each compound was tested in three different concentrations, and nonspecific binding estimated at 0.5 μM nicotine-H-tartrate. All estimations were made in triplicate, and each displacement experiment was repeated at least three times. Table 2: L-[³H] Nicotine Binding Data

Compound ICso-values (μM) Compound ICso-values (μM) No L-[³H] Nicotine No L-[³H] Nicotine

1 0.068 cis-18 0.56

(S)-1 0.52 trans-18 2.3

(S)-2 0.66 cis-(1 S,2R)-18 0.32

(S)-3 0.026 cis-(1 R,2S)-18 0.65

(S)-4 0.30 19 5.4

(S)-5 0.59 20 27

6 11 21 1.8

7 1.6 22 67

8 0.009 23 0.63

(S)-8 0.064 24 2.2

(R)-8 0.003 25 11

9 0.15 26 47

10 2.9 27 2.3

11 80 28 6.0

12 29 29 47

13 1.6 30 0.008

14 33 (R)-30 0.006

16 0.64 (S)-30 0.39

17 0.84 31 0.014

Furthermore, the compounds of the invention have been tested with respect to affini¬ ty for muscarinic receptors by the method of Sauerberg, P. et al., J. Med. Chem. 1988, 31, 1312-1316, and some of compounds were tested with respect to agonistic effect at the nAChRs in the Guinea Pig lleum test as described by Amt et al. Eur. J. Pharmacol. 1992, 218, 159-169 or the Nicotine Cue test as described by L. T. Meltzer et al., Psychopharmacology Q8, 283-286, 1980. Some of the compounds were selective towards the nAChRs as compared to muscarinic receptors whereas the compounds tested in the Guinea Pig lleum test or the Nicotine Cue test were found to act as agonists. Formulation Examples

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art as described above.

Typical examples of recipes for the formulation of the invention are as follows:

1 ) Tablets containing 5.0 mg of active compound calculated as the free base:

Compound cis-(1 S,2R)-18 5.0 mg

Lactose 60 mg

Maize starch 30 mg

Hydroxypropylcellulose 2.4 mg

Microcrystalline cellulose 19.2 mg

Croscarmellose Sodium Type A 2.4 mg

Magnesium stearate 0.84 mg

2) Tablets containing 10 mg of Compound 8 calcu

Compound 8 10 mg

Lactose 46.9 mg

Maize starch 23.5 mg

Povidone 1.8 mg

Microcrystalline cellulose 14.4 mg

Croscarmellose Sodium Type A 1.8 mg

Magnesium stearate 0.63 mg

3) Syrup containing per millilitre:

Compound (S)-1 25 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerol 50 mg

Methyl-paraben 1 mg

Propyl-paraben 0.1 mg

Ethanol 0.005 ml

Flavour 0.05 mg Saccharin natrium 0.5 mg

Water ad 1 ml

4) Solution for injection containing per millilitre: Compound 8 20 mg

Sorbitol 5.1 mg

Acetic acid 0.08 mg

Water for injection ad 1 ml

Claims

PATENT CLAIMS

1. A carbamoyloxypropylamine or carbamoyloxyethylamine compounds of the formula I

FORMULA

wherein A represents Chtø or a bond,

Ri is hydrogen, C-|.β alkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C₃.₇ cycloalkyl or phenyl; and R2 is C₁-₈ alkyl, C₂.₈ alkenyl, C2-8 alkynyl, C₃-₇ cycloalkyl or phenyl; or Ri and R₂ together with the adjacent nitrogen form a 3 to 7 membered monoazacyclic ring;

R3 and R₄ are the same or different and each represent hydrogen, C₁-₈ alkyl, C2-8 alkenyl, C₂-₈ alkynyl, mono- or polyhalogenated C₁.₄ alkyl, C3.₇ cycloalkyl, phenyl, or phenyl-Cι-₄ alkyl or R₃ and R₄ together form a spirojoined C₄-₇ carbocycle; or when Ri and R2 are not linked, R₃ and R₂ may together with the nitrogen and carbon to which they are attached form a 3 to 7 membered monoazacyclic ring;

R₅ is hydrogen, C₁-₈ alkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C₃-₇ cycloalkyl, phenyl, or phenyl-Cι-₄ alkyl; or if R₂ do not form a ring with Ri or R₃, then R₅ and R₂ may together with the nitrogen atom to which R₂ is attached, the carbon atom substituted with R₃ and R₄ and the carbon atom to which R₅ is attached, form a 3 to 7 membered monoazacyclic ring; or if R3 is not included in a ring and R₅ do not form a ring together with R₂, R₅ and

R₄ may together with the carbon atoms to which they are attached form a 3 to 7 membered carbocyclic ring; provided that R₅ is hydrogen when A is a bond; RQ is hydrogen, Cι.₈ alkyl, C₂-₈ alkenyl, C₂.₈ alkynyl, C₃.₇ cycloalkyl, phenyl or phe- nyl-Cι-₄ alkyl; and R is Ci-β alkyl, C₂-₈ alkenyl, C₂-₈ alkynyl, C₃.7 cycloalkyl, phenyl or phenyl-Cι-₄ alkyl, provided that R₇ cannot be phenyl or phenyl-Cι- alkyl when R₆ is hydrogen; or

Re and R₇ together with the adjacent nitrogen form a 5 to 6 membered monoaza- cyclic ring; with the proviso that one of R₃ and R₄ must be different from hydrogen when A is a bond, Ri is hydrogen or Ci-β alkyl and R₂ is Ci-β alkyl, and that R₃ and R₄ may not both be hydrogen when A represents CH2, Re is hydrogen or methyl, R₇ is methyl and Ri and R₂ are both Ci-β alkyl or together with the N-atom to which they are attached form a piperidine ring;

or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 , characterized in that Ri and R are both C₁.₄ alkyl, preferably methyl.

3. A compound of Claim 1 , characterized in that R together with R₃ and the nitrogen and carbon, repectively, to which R2 and R3 are attached, designates a pyrrolidinyl ring.

4. A compound of Claim 1 , characterized in that Ri and R₂ together with the nitrogen atom to which they are attached form a pyrrolidinyl ring.

5. A compound of Claim 1 , characterized in that R₃ is C₁.₄ alkyl, preferably methyl

6. A compound of Claim 1 , characterized in that R₄ together with R₅ and the carbon atoms to which they are attached form a cyclopentyl ring.

7. A compound of Claim 1 , characterized in that R₄ and R₅ are hydrogen.

8. A compound of any of Claims 1 - 7, characterized in that Re is hydrogen or C₁-₄ alkyl, preferably hydrogen, ethyl or methyl and R₇ is C₁-4 alkyl, preferably ethyl or methyl.

9. A compound of any of Claims 1 - 8, characterized in that A is CH₂ and R₄ and R₅ are hydrogen.

10. A compound of Claims 9, characterized in that R₃ is methyl.

11. A compound of Claim 1 , characterized in that R₂ together with R₃ and the nitrogen and carbon, repectively, to which R₂ and R₃ are attached, designates a pyrrolidinyl ring, A represents a bond and R₄ and R₅ are hydrogen.

5

12. A compound of Claim 1 , characterized in that it is selected from the group consisting of:

(S)-2-Dimethylcarbamoyloxymethyl-1-methylpyrrolidine, 4-Dimethylcarbamoyioxy-2-/V,Λ -dimethylbutylamine,

10 (R,S)-4-Dimethylcarbamoyloxy-2-Λ ,Λ/-dimethylbutylamine, (S)-4-Dimethylcarbamoyloxy-2-Λ/,/V-dimethylbutylamine, (R)-4-Dimethylcarbamoyloxy-2-N,Λ/-dimethylbutylamine and C/s-Λ/-Methyl-2-dimethylcarbamoyloxymethylcyclopentylamine; and pharmaceutically acceptable salts thereof.

15

13. A pharmaceutical composition, characterized in that it comprises at least one compound of any of Claims 1 - 12, in a therapeutically effective amount, together with one or more pharmaceutically acceptable carriers or diluents.

20 14. Use of a compound of any of Claims 1 - 12 for the manufacture of a pharma¬ ceutical preparation for the treatment of a cognitive, neurological or mental dis¬ orders in which nAChR dysfunction is involved, preferably pain, dementia, Alzheimers disease, Parkinsons disease, impaired learning ability, impaired memory function, psychosis, schizophrenia, pain or anxiety or for theraputical

25 treatment for smoking cessation.