Heteroaryl Derivatives

Background of the Invention

Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family of peptides and is one of the most abundant and widely distributed peptides at the central and peripheral nervous system. NPY acts as a neurotransmitter playing an important role in the regulation of various diseases. Intensive evaluations lead to the finding that multiple NPY receptors are existing being responsible for different physiological and pharmacological activities. Recently, a new NPY receptor subtype has been characterized and cloned, designated as Y5 receptor. It has been demonstrated that the pharmacological function associated with Y5 relates, for example, to obesity and eating disorders. Accordingly, the provision of compounds which act as antagonists of this receptor subtype represents a promisable approach in the regulation of diseases or disorders, such as obesity and eating/food intake disorders.

Summary of the Invention

The invention relates to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5, to pharmaceutical compositions and to new compounds having Y5 antagonistic properties.

Detailed Description of the Invention

The present invention relates to a method of prophylaxis and treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm¬ blooded animal, including man, in need of such treatment a therapeutically effective amount of a compound of formula (I)

in which

alki and alk , independently of one another, represent, independently of one another, a single bond or lower alkylene,

R, represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, C ₃ -C _β -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

R ₂ represents (i) hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkynyl, C ₃ -C ₈ - cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, by lower alkoxy, by ammo, by substituted ammo, by carboxy, by lower alkoxycarbonyl, by (carbocyclic or heterocyclic) aryl-lower alkoxycarbonyl, by carbamoyl, or by N-substituted carbamoyl,

(n) am o or substituted am o,

(in) hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, C ₃ -C ₈ -cycloalkoxy, C ₃ -C ₈ -cycloalkyl-lower alkoxy, (carbocyclic or heterocyclic) aryl-lower alkoxy, lower alkoxycarbonyl-oxy, (carbocyclic or heterocyclic) aryl- lower alkoxycarbonyl-oxy, aminocarbonyl-oxy, or N-substituted aminocarbonyl-oxy, (iv) carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, (v) carbamoyl or N-substituted carbamoyl,

(vi) a group selected from -CH(OH)-R, -CO-R, -NR CO-0-R, -NR,-CO-R, -NRrCO-NR^R, - NRrSOs-R, -NR^SOz-NR R, -SO _z -R, -S0 ₂ -NR R, or -SOs-NR^CO-R, [R being as defined below and Ri being as defined above, or the group -N(R)(R represents am o which is di- substituted by lower alkylene {which may be interrupted by O, S(O) _n or NR ₀ } or which is di- substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

(vn) an element of formula -Xι(X ₂ )(Xs) wherein, (a) if X, is -CH-, X ₂ together with X3 represent a structural element of formula -X ₄ -(CO) _P -(CH ₂ ) ₀ -, -(CH ₂ )q-X4-(CO) _p -(CH ₂ ) _r -, or -(CH ₂ ) _s -X ₄ -CO-(CH ₂ ),-; or, (b) if Xi is -N-, X ₂ together with X ₃ represent a structural element of formula -CO-(CH ₂ ) _u -; being -CH ₂ -, -N(Ri)- or -0-, the integer o is 3-5; the integer p is 0 or 1 , the integer q is 1 or 2, the integer r is 1 , the integer s is 1 or 2, the integer t is 1 or 2; the integer u is 3-5;],

R ₃ and R ₄ , independently of one another, represent

(i) hydrogen, lower alkyl, lower alkenyl, lower alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl- lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (II) lower alkyl which is substituted by a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, ammo, substituted am o, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, N-substituted carbamoyl, and -S(O) _n -R,

R ₃ and R ₄ together represent lower alkylene [which may be mterruDted by O, S(O) _n , NRo] or represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring,

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -O-, -S(O)n-, -CO- or- -C(OR') ₂ -, one of R' being hydrogen or both being each lower alkyl or being together lower alkylene, wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, lower alkenyl, lower alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, (carbocyclic or heterocyclic) aroyl, nitro, cyano

(ii) lower alkyl which is substituted by a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryi, ammo, substituted ammo, carboxy, lower alkoxy-carbonyl, lower alkoxy- lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(in) lower alkoxy which is substituted by a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryi, ammo, substituted am o, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyciic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl, (iv) amino, substituted am o,

(v) carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxv-carboπvi

(vi) carbamoyl and N-substituted carbamoyl, wherein, in each case, the substituted ammo group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by lower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C ₈ - cycloalkyi-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (n) di-substituted by lower alkylene [which may be interrupted by O, S(O) _n or NRo] or is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (in) mono-substituted or, in the second line, independently of one another, di-substituted by -CO-(O) _v -R and the integer v is 0 or 1 , wherein, in each case, the integer n is 0, 1 or 2, wherein, in each case, R ₀ represents hydrogen, lower alkyl, lower alkenyl, lower alkmyl, (carbocyclic or heterocyclic) aryl, (caroocyclic or heterocyclic) aryl-lower alkyl, lower alkanoyl, (carbocyclic or heterocyclic) aroyl, -S0 ₂ -R, or lower alkyl which is substituted by halogen, by hydroxy, or by lower alkoxy, wherein, in each case, R represents hydrogen, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ - cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl- lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, or by lower alkoxy, or a pharmaceutically accetable salt thereof, and relates to new compounds of formula (I) or a salt thereof, to pharmaceutical compositions, and to the manufacture of new compounds of formula (I) and salts thereof

The compounds I can be present as salts, in particular pharmaceutically acceptable salts If the compounds (I) have, for example, at least one basic centre, they can form acid addition salts These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as d-C ₄ -alkanecarboxylιc acids which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid such as ammo acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as C ₁ -C ₄ -alkane- or arylsuifonic acids which are unsubstituted or substituted, for example by halogen for example methane- or o-toluenesulfonic aciα

Corresponding acid addition salts can also be formed having, if desired, an additionally present basic centre The compounds (I) having at least one acid group (for example COOH) can also form salts with bases Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amme, such as morphoiine, thiomorpholme, piperidine, pyrrolidme, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, trioutyl- or dimethylpropylamme, or a mono-, di- or tnhydroxy lower alkylamine, for example mono-, di- or triethanolamine Corresponding internal salts may furthermore be formed, if a compound of formula compπses e g both a carboxy and an ammo group Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds (I) or their pharmaceutically acceptable salts, are also included

(Carbocyclic or heterocyclic) aryl in (carbocyclic or heterocyclic) aryl or aryloxy, respectively, represents, for example, phenyl, biphenylyl, naohthyl or an appropriate 5- or 6-membered and monocyclic radical or an appropriate bicyclic heteroaryl radical which, in each case, have up to four identical or different hetero atoms, such as nitrogen, oxygen or sulfur atoms, preferably one, two, three or four nitrogen atoms, an oxygen atom or a sulfur atom Appropriate 5-membered heteroaryl radicals are, for example, monoaza-, diaza-, tπaza-, tetraaza-, monooxa- or monothia-cyclic aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl and thienyi, while suitable appropriate 6-membered radicals are in particular pyridyl Appropriate bicyclic heterocyclic aryls are, for example, indolyl, mdazolyl, benzofuryi, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, or qumazolinyl Appropriate aromatic radicals, including ring A, are radicals which may be monosubstituted or polysubstituted, for example di- or trisubstituted, for example by identical or different radicals, for example selected from the group as given above Preferred substituents of corresponding aryl radicals (including of ring A) are, for example, halogen, lower alkyl, halo- lower alkyl, lower alkoxy, oxy-lower alkylene-oxy, hydroxy, hydroxy-lower alkoxy, and lower alkoxy-lower alkoxy

(Carbocyclic or heterocyclic) aroyl is in particular benzoyl, naphthoyl, furoyl, thenoyl, or pyπdoyl

(Carbocyclic or heterocyclic) aryl-lower alkanoyl in (carbocyclic or heterocyclic) aryl-lower alkanoyloxy or (carbocyclic or heterocyclic) aryl -lower alkanoyl is in particular phenyl-lower alkanoyl, naphthyl-lower alkanoyl, or pyndyl-lower alkanoyl,

(Carbocyclic or heterocyclic) aryl-lower alkyl is in particular phenyl-, naphthyl- or pyndyl- lower alkyl

(Carbocyclic or heterocyclic) aryl-lower alkoxycarbonyl is in particular phenyl-, naphthyl- or pyndyl-lower alkoxy.

Lower alkyl which substituted by halogen, hydroxy, lower alkoxy, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, or ammo is in particular halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyloxy-, naphthyloxy- or pyπdyloxy- lower alkyl, phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower alkyl, ammo-lower alkyl, or corresponding N- or N,N- substituted ammo-lower alkyl.

An ammo group which is mono-substituted by lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl- lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl is in particular lower alkylamino, C ₃ -C ₈ -cycloalkyl-amιno, C ₃ -C ₈ -cycloalkyl-loweralkyl-amιno, phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-amiÏ€o, phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower alkylamino.

An ammo group which is, independently of one another, di-substituted by lower alkyl, C ₃ -C ₈ - cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl is in particular di-lower alkylamino, dι-C ₃ -C ₈ -cycloalkyl-amιno, dι-(C ₃ -C ₈ -cycloaikyl-lower aikyl)-amιno, di-(pheny)-, naphthyl-, furyl-, thienyl-, or pyÏ€dyl)- amino, dι-(phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower alkyl)-amιno, lower alkyl-C ₃ -C ₈ - cycloalkyl-amino, lower alkyl-(C ₃ -C ₈ -cycloalkyl-lower alkyl)-amιπo, lower alkyl-(phenyl-, naphthyl-, furyl-, thienyl-, or pyrιdyl)-amιno, lower alkyl-(phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower aikyi)-amιno

Lower alkyl which is substituted by carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl,

carbamoyl in which the amino group is mono-substituted or, independently of one another, di-substituted by lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, and carbamoyl in which the amino group is di-substituted by lower alkylene [which may be interrupted by O, S(O) _n , NR ₀ , the integer n being 0, 1 or 2 and R ₀ being hydrogen, lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, lower alkanoyl, (carbocyclic or heterocyclic) aroyl, -SO ₃ H, -SO ₂ -R and R being lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ - cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl- lower alkyl] is in particular carboxy-lower alkyl, lower alkoxy-carbonyl-lower alkyl, lower alkoxy-lower alkoxy-carbonyl-lower alkyl, (phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)-lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, or corresponding N- or N, N-substituted carbamoyl-lower alkyl.

Lower alkoxy which substituted by halogen, hydroxy, lower alkoxy, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, or amino is in particular halo-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyloxy-, naphthyloxy- or pyridyloxy-lower alkyl, phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-lower alkoxy, amino- lower alkoxy, or corresponding N- or N,N- substituted amino-lower alkoxy.

Lower alkoxy which is substituted by carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, carbamoyl in which the amino group is mono-substituted or, independently of one another, di-substituted by lower alkyi, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, and carbamoyl in which the amino group is di-substituted by lower alkylene [which may be interrupted by O, S(0) _n , NR ₀ , the integer n being 0, 1 or 2 and R ₀ being hydrogen, lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, lower alkanoyl, (carbocyclic or heterocyclic) aroyl, -S0 ₃ H, -S0 ₂ -R and R being lower alkyl, C ₃ -C _β -cycloalkyl, C ₃ -C ₈ - cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl- lower alkyl] is in particular carboxy-lower alkoxy, lower alkoxy-carbonyl-lower alkoxy, lower alkoxy-lower alkoxy-carbonyl-lower alkoxy, (phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)- lower alkoxycarbonyl-lower alkoxy, carbamoyl-lower alkoxy, or corresponding N- or N,N- substituted carbamoyl-lower alkoxy.

Substituted lower alkyl or lower alkoxy, respectively, is mono- or poly-substituted, e.g. di- or tπ-substituted.

The group of formula -N(R ₃ )(R ₄ ) in which R ₃ and R ₄ together represent lower alkylene which is condensedat two adjacent carbon atoms with a benzene ring represents, for example, lower alkylene-phenylene-lower alkylene-amino, such as 3,4-dihydro-1 H-ιsoquιnolιn-2-yl

The general definitions used above and below, unless defmed differently, have the following meanings:

The expression "lower" means that corresponding groups and compounds, in each case, in particular comprise not more than 7, preferably not more than 4, carbon atoms.

Halogen is in particular halogen of atomic number not more than 35, such as fluorine, chlorine or bromine, and also includes iodine

Lower alkyl is in particular CrC ₇ - alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and also includes corresponding pentyl, hexyl and heptyl radicals. C C ₄ -alkyl is preferred.

Lower alkenyl is in particular C ₃ -CÏ„-alkenyl and is, for example, 2-propenyl or 1-, 2- or 3-butenyl. C ₃ -C ₅ -alkenyl is preferred.

Lower alkynyl is in particular C ₃ -C -alkynyl and is preferably propargyl.

Lower alkoxy is in particular and is, for example, methoxy, ethoxy, n- propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals C,^- alkoxy is preferred

Lower alkenyloxy is in particular C ₃ -C ₇ -alkenyloxy, preferably allyloxycarbonyl, while lower alkynyloxy is in particular C ₃ -C ₅ -alkynyloxy, such as propargyloxy

Oxy-lower alkylene-oxy is in particular oxy-C ₄ -alkylene-oxy, preferably oxy- methylene-oxy or oxy-ethylene-oxy

Lower alkanoyloxy is in particular C ₂ -C ₇ -alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy. C ₂ -C ₅ -alkanoyloxy is preferred

Lower alkanoyl is in particular C ₂ -C ₇ -alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl. C ₂ -C ₅ -alkanoyl is preferred.

NaphthoyI is 1- or 2-naphthoyl, furoyl 2- or 3-furoyl, thenoyi 2- or 3-thenyl, and pyndoyi 2-, 3-, or 4-pyridoyl

C ₃ -C ₈ -Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

C ₃ -C ₈ -Cycloalkyl-lower alkyl is in particular C ₃ -C ₈ -cycloalkyl-d-C ₄ -alkyl, in particular C ₃ -C ₆ - cycloalkyl-d-C ₂ -alkyl. Preferred is cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl.

C ₃ -C ₈ -Cycloalkoxy is, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy Cyclopentyloxy and cyclohexyloxy are preferred.

C ₃ -C ₈ -Cycloalkyl-lower alkoxy is in particular C ₃ -C ₈ -cycloalkyl-Cι-C ₄ -alkoxy, in particular C ₃ - C ₆ -cycloalkyl-d-C ₂ -alkoxy. Preferred is cyclopropylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy.

Lower alkylene is in particular d-d-alkylene, in particular d-d-alkylene, and is straight-chain or branched and is in particular methylene, ethylene, propylene and butylene and also 1 ,2-propyiene, 2-methyl-1 ,3-propylene, 3-methyl-1 ,5-pentylene and 2,2-dιmethyl-1 ,3-propylene. C ₃ -C ₅ -alkylene is preferred. In case of alk, or alk ₂ , respectively, lower alkylene preferably is -(CH ₂ ) _P - the integer p being 1-3 Lower alkylene in an substituted am o group preferably is 1 ,2-ethyleÏ€e, 1 ,3-

propylene, 1 ,4-butylene, 1 ,5-pentylene, 1 ,6-hexylene, 2-methyl-1 ,3-propylene, or 2-methyl-butylene, or 3-methyl-1 ,5-pentylene

Ammo which di-substituted by lower alkylene is in particular C ₃ -C ₇ -alkyleneamιno, preferably 1 -azιdιno, 1 -pyrrolιdιno or 1-pιpeÏ€dιno.

Ammo which di-substituted by lower alkylene which is interrupted by O, S(O) _n or NR ₀ is in particular morpholmo, thiomorpholmo or the mono- or di-oxide thereof, or 4-R ₀ -pιperazιno.

Lower alkanesulfonyl is in particular d-d-alkoxy-Ci-d-alkoxycarbonyl, preferably ethoxyethoxycarbonyl, methoxyethoxycarbonyl and isopropyloxyethoxycarbonyl.

Lower alkoxycarbonyl is in particular C ₂ -C ₈ -alkoxycarbonyl and is, for example, methoxy-, ethoxy-, propyloxy- or pivaloyloxy-carbonyl C ₂ -C ₅ -alkoxycarbonyl is preferred

Lower alkoxy-lower alkoxy-carbonyl is in particular d-C ₄ -alkoxy-C ₂ -C ₃ - alkoxycarbonyl and is, for example, methoxy- or ethoxy-ethoxy-alkoxycarbonyl

Hydroxy-lower alkyl is in particular hydroxy-d-C ₄ -alkyl, such as hydroxymethyl, 2- hydroxyethyl or 3-hydroxypropyl Furthermore, hydroxy-lower alkyl may exhibit two hydroxy groups, such as 3-hydroxy-1 -hydroxymethyl-propyl.

Hydroxy-lower alkoxy is in particular hydroxy-d-d-alkoxy, such as hydroxymethyl, 2- hydroxyethyl or 3-hydroxypropyl

Lower alkoxy-lower alkoxy is in particular C C ₄ -alkoxy-C rd-alkoxy and is, for example, 2- methoxyethoxy, 2-ethoxyethoxy, 2-n-propyloxyethoxy or ethoxymethoxy

Ammo which di-substituted by lower alkylene and ts condensed at two adjacent carbon atom with a benzene Ï€ng is in particular C ₂ -C ₆ -cyc!oalkylenemιno which is is condensed at

two adjacent carbon atom with a benzene ring Preferred is ιndolιn-1 -yl or 1 ,2,3,4- tetrahydro-quιnolιn-1 -yl

Halo-lower alkyl is in particular halo-Cι-C -alkyl, such as trifluoromethyl, 1 ,1 ,2- trifluoro-2-chloroethyl or chloromethyl

Halo-lower alkoxy is in particular halo-Cι-C -alkoxy, such as tπfluoromethoxy, 1 ,1 ,2-trιfluoro- 2-chloroethoxy or chloromethoxy.

Phenyloxy-, naphthyloxy- or pyπdyloxy-lower alkyl is in particular phenyloxy-, naphthyloxy- or pyπdyloxy-d-d-alkyl, such as phenoxy-methyl, 2-phenoxy-ethyl, 1 - or 2-naphthyloxy- methyl, or 2-, 3-, or 4-pyπdyloxy-methyl

Phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower alkyl is in particular phenyl-, naphthyl- or pyridyl-d-d-alkyl, such as phenyl-methyl, 2-phenyl-ethyl, 1 - or 2-naphthyl-methyl, or 2-, 3-, or 4-pyπdyl-methyl

Naphthyl is in particular 1 - or 2-naphthyl; furyl 2- or 3-furyl; thienyl 2- or 3-thιenyl; pyridyl 2-, 3- or 4-pyrιdyl, indolyl, indazolyl e g 6-1 (H)-ιndazolyl, benzofuryl e g 2-, 3- or 5- benzofuranyl, benzothienyl e g. 2-, 3-, or 5-benzothιenyl, benzimidazolyl e g 1-, 2- or 5- benzimidazolyl, quinolinyl e.g 2- 4- 5-, 6-, 7-, or 8-αuιnolιnyl, isoquinolinyl e.g 1 -, 3-, 4-, or 6-ιsoquιnolyl, or qumazolinyl e.g 2-, 4-, 5-, 6-, 7-, or 8-quιnazolιnyl.

Ammo-lower alkyl is in particular amtno-Cι-C ₇ -alkyl, preferably amιno-Cι-C ₄ -alkyl, such as ammomethyl, 2-amιnoethyl or 3-amιnopropyl

Lower alkylamino is in particular d-C ₇ -alkylamιno and ts, for example, methyl-, ethyl-, n-propyl- and isopropyl-ammo Cι-C ₄ -alkylamιno is preferred

C ₃ -C ₈ -Cycloalkyl-amιno is in particular C ₃ -C ₆ -cycloalkyl-amιno and is, for example, cyclopropyl-, cyclopentyl and cyclohexyi-amino

C ₃ -C ₈ -Cycloa!kyl-lower alkylamino is in particular C ₃ -C _β -cycloalkyl-d C ₇ alkylamino and is for example cyclopropylmethyl-amino or cyclohexylmethyl

amino. C ₃ -C ₈ -Cycloalkyl-C ₁ -C ₄ -alkylamino is preferred.

Phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-lower alkyl-amino is in particular phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-d-C ₄ -alkyl)-amino, preferably benzyl-amino, 2- phenethyl-amino, 1- or 2-naphthylmethyl-amino, or 2-, 3-, or 4-pyridylmethyl-amino.

Di-lower alkylamino is in particular di-C C ₄ -alkylamino, such as dimethyl-, diethyl-, di-n- propyl-, methylpropyl-, methylethyl-, methylbutyl-amino and dibutylamino.

Di-C ₃ -C ₈ -cycloalkyl-amino is in particular di-C ₃ -C ₆ -cycloalkylamino, preferably cyclopropylamino, cyclopentylamino or cyclohexylamino.

Di-(C ₃ -C ₈ -cycloalkyl-lower alkyl)-amino is in particular di-(C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl)-amino, preferably cyclopropylmethyl-amino, cyclopentylmethyl-amino or cyclohexylmethyl-amino.

Di-(phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-lower alkyl)-amino is in particular di-(phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-Cι-C ₄ - alkyi)-amino, preferably di-benzyl-amino, di-(2- phenethyl)-amino, di-(1- or 2-naphthylmethyl)-amino, or di-(2-, 3-, or 4-pyridylmethyl)-amino.

Lower alkyl-C ₃ -C ₈ -cycloalkyl-amino is in particular d-C -alkyl-C ₃ -C ₆ -cycloalkyl-amino, preferably nethyl-cyclopropyl-amino, methyl-cyclopentyl-amino or methyl-cyclohexyl-amino.

Lower alkyl-(C ₃ -C ₈ -cycloalkyl-lower alkyl)-amino is in particular Cι-C ₄ -alkyl-(C ₃ -C ₆ -cycloalkyl- Cι-C ₄ -alkyl)amino, preferably nethyl-cyclopropylmethyl-amino, methyl-cyclopentylmethyl- amino or methyl-cyclohexylmethyl-amino.

Lower alkyl-(phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)- ammo is in particular d-d-alkyl- (phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl)- am o, such as (m)ethyl-phenyl-amino.

Lower alkyl-(phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower alkyl)-amιno is in particular Cι-C ₄ -alkyl-(phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl-d-C.-alkylJ-amino, such as (m)ethyl-benzyl-amino or (m)ethyl-(2-phenethyl)-amιno.

Carboxy-lower alkyl is in particular carboxy-C ₁ -C ₄ -alkyl, such as carboxy-methyl, 2-carboxy- ethyl, or 3-carboxy-propyl.

Lower alkoxy-carbonyl-lower alkyl is in particular C ₂ -C ₅ -alkoxycarbonyl-d-C -alkyl, such as (m)ethoxycarbonyl-methyl, 2-(m)ethoxycarbonyl-ethyl or 2-pιvaloyl-ethyl.

Lower alkoxy-lower alkoxy-carbonyl-lower alkyl is in particular d-C -alkoxy-C ₂ -C ₅ - alkoxycarbonyl-d-C ₄ -alkyl, such as 2-methoxy-ethoxycarbonyl-methyl or 2-(2-ethoxy- ethoxycarbonyl)-ethyl

(Phenyl-, naphthyl-, furyl-, thienyl-, or pyrιdyl)-lower alkoxycarbonyl-lower alkyl is in particular (phenyl-, naphthyl-, furyl-, thienyl-, or pyridyl) -C ₂ -C ₅ -alkoxycarbonyl-d-C ₄ -alkyl, such as benzyloxycarbonyl-methyl or 2-(2-phenethyloxy-carbonyl)-ethyl

Carbamoyl-lower alkyl is in particular carbamoyl-Cι-C -alkyi, such as carbamoyl-methyl, 2- carbamoyl-ethyl or 3-carbamoyl-propyl

Hydroxy-lower alkoxy is in particular hydroxy-Ci-djalkoxy, such as hydroxymethoxy, 2- hydroxyethoxy or 3- hydroxy pro poxy

Phenyloxy-, naphthyloxy- or pyndyloxy-lower alkoxy is in particular phenyloxy-, naphthyloxy- or pyπdyloxy-d-C -alkoxy, such as phenoxy-methoxy, 2-phenoxy-ethoxy, 1 - or 2- naphthyloxy-methoxy, or 2-, 3-, or 4-pyπdyloxy-methoxy.

Phenyl-, naphthyl-, furyl-, thienyl-, or pyndyl-lower alkoxy is in particular phenyl-, naphthyl- or pyπdyl-d-d-alkoxy, such as phenyi-methoxy, 2-phenyl-ethoxy, 1 - or 2-naphthyl- methoxy, or 2-, 3-, or 4-pyrιdyl-methoxy

Ammo-lower alkoxy is in particular amιno-d-d-alkoxy, such as aminomethoxy, 2- ammoethoxy, or 3-amιno-propoxy

Carboxy-lower alkoxy is in particular carboxy-d-C ₄ -alkoxy, such as carboxy-methoxy, 2- carboxy-ethoxy, or 3-carboxy-propyloxy

Lower alkoxy-carbonyl-lower alkoxy is in particular C ₂ -C ₅ -alkoxycarbonyl-d-C -alkoxy, such as (m)ethoxycarbonyl-methoxy, 2-methoxycarbonyl-ethyl, or 2-(2-ethoxycarbonyl)-ethyl

Lower alkoxy-lower alkoxy-carbonyl-lower alkoxy is in particular Ci-d-alkoxy-d-Cs- alkoxycarbonyl-Cι-C ₄ -alkoxy, such as (m)ethoxymethoxycarbonyl-methoxy, 2-ethoxy- methoxycarbonyl-ethyl, or 2-[(2-ethoxy-ethoxycarbonyl)]-ethyl

(Phenyl-, naphthyl-, furyl-, thienyl-, or pyrιdyl)-lower alkoxycarbonyl-lower alkoxy is in particular (Dhenyl-, naphthyl-, furyl-, thienyl-, or pyrιdyl)-C ₂ -C ₅ -alkoxycarbonyl-d-C ₄ -alkoxy, such as benzyloxycarbonyl-methoxy, phenethyloxycarbonyl-methoxy, 2- (benzyloxycarbonyl)-ethoxy, or 2-(2-phenethyloxycarbonyl)-ethoxy

Carbamoyl-lower alkoxy is in particular carbamoyl-Cι-C ₄ -alkoxy, such as carbamoyl- methoxy, 2-carbamoyl-ethoxy, or 3-carbamoyl-propyloxy

Obesity, for example, is a wide-spread phenomena which e g causes a variety of pathological symptoms or influences the overall state of health Also associated therewith are considerable socio-economic investments and a heavy financial burden for managed health care organisations The problem to be solved is to present an approach to systemically treat obesity or related diseases or disorders Surprisingly, it has been manifested that the modulation of the NPY receptor subtype Y5 leads to a control of the eating behavior

Extensive pharmacological investigations have shown that the comDOunds (I) and their pharmaceutically acceptable salts, for example, are useful as antagonists of the neuropeptide Y5 receptor subtype

Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family with wide-spread distribution throughout the mammalian nervous system NPY and its relatives (peptide YY or PYY, and pancreatic polypeptide or PP) elicit a broad range of physiological effects through activation of at least five G protein-coupled receptor subtypes known as Y1 , Y2, Y3, Y4 (or PP), and the "atypical Y1 " The role of NPY as the most powerful stimulant of feeding behavior yet described is thought to occur primarily through activation of the hypothalamic "atypical Y1 "

receptor. This receptor is unique in that its classification is based solely on feeding behavior data, rather than radioligand binding data, unlike the Y1 , Y2, Y3, and Y4 (or PP) receptors, each of which are described previously in both radioligand binding and functional assays. ^12S I-PYY- based expression cloning technique may be used to isolate a rat hypothalamic cDNA encoding an "atypical Y1 " receptor referred to herein as the Y5 subtype. Y5 homolog may be isolated and characterized of from human hippocampus. Protein sequence analysis reveals that the Y5 receptor belongs to the G protein- coupled receptor superfamiiy. Both the human and rat homolog display < 42% identity in transmembrane domains with the previously cloned "Y-type" receptors. Rat brain localization studies using in situ hybridization techniques verify the existence of Y5 receptor mRNA in rat hypothalamus. Pharmacological evaluation reveals the following similarities between the Y5 and the "atypical Y1 " receptor. 1 ) Peptides bind to the Y5 receptor with a rank order of potency identical to that described for the feeding response: NPY ³ NPY ₂ -36 = PYY = [Leu ³¹ , Pro^NPY » NPY13.se. 2) The Y5 receptor is negatively coupled to cAMP accumulation, as has been proposed for the "atypical Y1 " receptor. 3) Peptides activate the Y5 receptor with a rank order of potency identical to that described for the feeding response. 4) The reported feeding "modulator" [D-Trp ^3a ]NPY binds selectively to the Y5 receptor and subsequently activated the receptor. 5) Both the Y5 and the "atypical Y1 " receptors are sensitive to deletions or modifications in the midregion of NPY and related peptide ligands.

The peptide neurotransmitter neuropeptide Y (NPY) is a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system. NPY is considered to be the most powerful stimulant of feeding behavior yet described (Clark, J.T., Kalra, P.S., Crowley, W.R., and Kalra, S.P. (1984). Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115: 427-429, 1984; Levine, A.S., and Morley, J.E. (1984). Neuropeptide Y: A potent inducer of consummatory behavior in rats. Peptides 5: 1 025-1029; Stanley, B.G., and Leibowitz, S.F. ; (1984) Neuropeptide Y: Stimulation of feeding and drinking by injection into the paraventricular nucleus. Life Sci. 35: 2635-2642). Direct injection into the hypothalamus of satiated rats, for example, can increase food intake up to 10-fold over a 4-hour period (Stanley, B.G., Magdalin, W., Seirafi, A., Nguyen, M.M., and Leibowitz, S.F. (1992). Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y, receptor mediating this peptide's effect. Peptides 13: 581-587). The role of NPY in normal and abnormal eating behavior, and the ability to interfere with NPY-dependent pathways as a means to appetite and weight control, are areas of great interest in pharmacological and pharmaceutical research (Sahu and Kalra, 1993;

Dryden, S , Frankish, H , Wang, Q., and Williams, G (1994) Neuropeptide Y and energy balance one way ahead for the treatment of obesity ⁷ Eur J Clm Invest.24: 293-308). Any credible means of studying or controlling NPY-dependent feeding behavior, however, must necessarily be highly specific as NPY can act through at least 5 pharmacologically defined receptor subtypes to elicit a wide variety of physiological functions (Dumont, Y., J.-C. Martel, A. Fournier, S. St-Pierre, and R. QuiÏ€on. (1992). Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues. Progress in Neurobioloαv 38.125-167). It is therefore vital that knowledge of the molecular biology and structural diversity of the individual receptor subtypes be understood as part of a rational drug design approach to develop subtype selective comDounds. A brief review of NPY receptor pharmacology is summarized below and also in Table 1

TABLE 1. Pharmacologically defined receptors for NPY and related pancreatic polypeptides

Rank orders of affinity for key peptides (NPY, PYY, PP, [Leu ³¹ Pro^NPY, NPY ₂₃₆ , and NPY,^) are based on previously reported binding and functional data (Schwartz, TW..J Fuhlendorff, L.L.K _j e s, M.S KÏ€stensen, M Vervelde, M. O'Hare, J.L. Krstenansky, and B. Bjornholm. (1990) Signal epitopes in the three-dimensional structure of neuropeptide Y. Ann. N Y Acad. Sci.611 : 35-47, Wahlestedt, C , Karoum, F., Jaskiw, G., Wyatt, R J , Larhammar, D., Ekman, R., and Reis, D J (1991) Cocaine-induced reduction of brain neuropeptide Y synthesis dependent on medial prefrontal cortex Proc Natl. Acad Sci.882978-2082, Dumont, Y., J.-C. Martel, A Fournier, S. St-Pierre, and R QuiÏ€on (1992). Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues Progress in Neurobioloov 38.125-167; Wahlestedt, C, and D.J Reis. (1993) Neuropeptide Y-Related Peptides and Their Receptors-Are the Receptors Potential Therapeutic Targets? Ann. Rev, Pharmacol. Tox.32309-352). Missing peptides in the series reflect a lack of published information.

TABLE 1

NPY Receptor Pharmacology

NPY receptor pharmacology has historically been based on structure/activity relationships within the pancreatic polypeptide family. The entire family includes the namesake pancreatic polypeptide (PP), synthesized primarily by endocrine cells in the pancreas; peptide YY (PYY), synthesized primarily by endocrine cells in the gut; and NPY, synthesized primarily in neurons (Michel, M.C. (1991). Receptors for neuropeptide Y: multiple subtypes and multiple second messengers. Trends Pharmacol.: 12: 389-394; Dumont et al. , 1992; Wahlestedt and Reis, 1993). All pancreatic polypeptide family members share a compact structure involving a "PP-fold" and a conserved C-terminal hexapeptide ending in Tyr ³⁶ (or Y ³⁶ in the single letter code). The striking conservation of Y ³⁶ has prompted the reference to the pancreatic polypeptides' receptors as "Y-type" receptors (Wahlestedt, d, L. Edvmsson, E. Ekblad, and R. Hakanson. Effects of neuropeptide Y at sympathetic neuroeffector junctions: Existence of Y, and Y ₂ receptors. In: Neuronal messengers in vascular function, Fernstrom Symp. No 10., pp 231 -242. Eds A. Nobm and C H. Owman. Elsevier: Amsterdam (1987)), all of which are proposed to function as seven transmembrane-spanning G protein-coupled receptors (Dumont et al., 1992).

The Y1 receptor recognizes NPY = PYY » PP (Grundemar et al., 1992). The receptor requires both the N- and the C-terminal regions of the peptides for optimal recognition. Exchange of Gin ³⁴ in NPY or PYY with the analogous residue from PP (Pro ³⁴ ), however, is well-tolerated. The Y1 receptor has been cloned from a variety of species including human, rat and mouse (Larhammar, D., A.G. Blomqvist, F. Yee, E. Jazin, H. Yoo, and C. Wahlestedt. (1992). Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J. Biol. Chem. 267: 10935-10938; Herzog, H , Y.J. Hort, H . Ball, G. Hayes, J. Shine, and L. Selbie. (1992). Cloned human neuropeptide Y receptor couples to two different second messenger systems Proc. Natl. Acad. Sci. USA 89, 5794-5798, Eva, C , Oberto, A., Sprengel, R. and E. Genazzani (1992). The murine NPY-1 receptor gene: structure and delineation of tissue specific expression FEBS left. 314: 285-288, Eva, C , Keinanen, K., Monyer, H., Seeburg, P , and Sprengel, R. (1990) Molecular cloning of a novel G protein- coupled receptor that may belong to the neuropeptide receptor family FEBS Lett. 271 , 80-84) The Y2 receptor recognizes PYY ~ NPY » PP and is relatively tolerant of N-terminal deletion (Grundemar, L and Rl Hakanson (1994) Neuropeptide Y effector systems

perspectives for drug development. Trends. Pharmacol. 15:153-159) . The receptor has a strict requirement for structure in the C-terminus (Arg ³³ -Gln ³⁴ -Arg ³⁵ -Tyr ³⁶ -NH ₂ ); exchange of Gin ³⁴ with Pro ³⁴ , as in PP, is not well tolerated. The Y2 receptor has recently been cloned. The Y3 receptor is characterized by a strong preference for NPY over PYY and PP (Wahlestedt, C, Karoum, F., Jaskiw, G., Wyatt, R.J., Larhammar, D., Ekman, R., and Reis, D.J. (1991). Cocaine-induced reduction of brain neuropeptide Y synthesis dependent on medial prefrontal cortex. Proc. Natl. Acad. Sci. 88: 2978-2082). [Pro ³⁴ ]NPY is reasonably well tolerated even though PP, which also contains Pro ³⁴ , does not bind well to the Y3 receptor This receptor (Y3) has not yet been cloned The Y4 receptor binds PP > PYY > NPY. Like the Y1 , the Y4 requires both the N- and the C-terminal regions of the peptides for optimal recognition. The "atypical Y1 " or "feeding" receptor is defined exclusively by injection of several pancreatic polypeptide analogs into the paraventricular nucleus of the rat hypothalamus which stimulates feeding behavior with the following rank order: NPY _{2 36} > NPY - PYY ~ [Leu^.Pro^NPY > NPY ₁₃ .36 (Kalra, S.P., Dube, M.G., Fournier, A., and Kalra, P.S. (1991). Structure-function analysis of stimulation of food intake by neuropeptide Y: Effects of receptor agonists. Physiology & Behavior 50: 5-9; Stanley, B.G., Magdalm, W., Seirafi, A., Nguyen, M.M., and Leibowitz, S.F. (1992). Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Yi receptor mediating this peptide's effect. Peptides 13: 581 - 587). The profile is similar to that of a Y1-like receptor except for the anomalous ability of NPY _2-36 to stimulate food intake with potency equivalent or better than that of NPY. A subsequent report by Balasubramaniam, A., Sheriff, S., Johnson, M E , Prabhakaran, M., Huang, Y., Fischer, J.E., and Chance, W.T. (1994). Y: A competitive antagonist of NPY in rat hypothalamus. J. Med. Chem. 37: 31 1-815 showed that feeding can be regulated by [D-Trp ³² ]NPY While this peptide is presented as an NPY antagonist, the published data at least in part support a stimulatory effect of [D-Trp ³² ]NPY on feeding. [D- Trp ³² ]NPY thereby represents another diagnostic tool for receptor identification

This plasmid (pcEXV-hY5) was deposited on November 4, 1994 with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorgansims for the Purposes of Patent Procedure and was accorded ATCC Accession No 75943

The plasmid which comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to the DNA encoding the rat Y5 receptor as to permit expression thereof has been designated as pcEXV-rY5 (ATCC Accession No. 75944)

This plasmid (pcEXV-rY5) was deposited on November 4, 1994 with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorgansims for the Purposes of Patent Procedure and was accorded ATCC Accession No CRL 75944

A method for determining whether a ligand can specifically bind to a Y5 receptor comprises contacting a cell transfected with and expressing DNA encoding the Y5 receptor with the ligand under conditions permitting binding of ligands to such receptor, detecting the presence of any such ligand specifically bound to the Y5 receptor, and thereby determining whether the ligand specifically binds to the Y5 receptor

A method for determining whether a ligand is a Y5 receptor antagonist comprises contacting a cell transfected with and expressing DNA encoding a Y5 receptor with the ligand in the presence of a known Y5 receptor agonist, such as PYY or NPY, under conditions permitting the activation of a functional Y5 receptor response, detecting a decrease in Y5 receptor activity, and thereby determining whether the ligand is a Y5 receptor antagonist.

In an embodiment of the above-described methods, the cell is non-neuronal in origin In a further embodiment, the non-neuronal cell is a COS-7 cell, 293 human embryonic kidney cell, NIH-3T3 cell or L- (TK-) cell

The cell lines are transfected with a vector which is adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the DNA in the mammalian cell operatively linked to the DNA encoding the mammalian Y5 receptor as to permit expression thereof

For example, such plasmid which comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to the DNA encoding the human

Y5 receptor as to permit expression thereof designated pcEXV-hY5 (ATCC Accession No. 75943)

Experimental Details

MATERIALS AND METHODS

cDNA Cloning

Total RNA was prepared by a modification of the guanidine thiocyanate method (Kingston, 1987), from 5 grams of rat hypothalamus (Rockland, Gilbertsville, PA). Poly A ⁺ RNA was purified with a FastTrack kit (Invitrogen Corp., San Diego, CA) Double stranded (ds) cDNA was synthesized from 7 mg of poly A ⁺ RNA according to Gubler and Hoffman (Gubler, U abd B.J Hoffman (1983). A simple and very efficient method for generating cDNA libraries. Gene. 25, 263-269), except that ligase was omitted in the second strand cDNA synthesis. The resulting DS cDNA was ligated to BstxI/EcoRI adaptors (Invitrogen Corp ), the excess of adaptors was removed by chromatography on Sephacryl 500 HR (Pharmacιa®-LKB) and the ds-cDNA size selected on a Gen-Pak Fax HPLC column (Millioore Corp , Milford, MA) High molecular weight fractions were ligated in pEXJ.BS (A cDNA cloning expression vector derived from pcEXV-3; Okayama, H. and P. Berg (1983) A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells Mol Cell Biol 3 280-289, Miller, J and Germain, R.N. (1986). Efficient cell surface expression of class II MHC molecules in the absence of associated invariant chain. J. Exp. Med 164: 1478-1489) cut by Bstxl as described by Aruffo and Seed (Aruffo, A. and Seed, B (1987). Molecular cloning of a CD28 cDNA by a high efficiency COS cell expression system. PNAS. 84, 8573-8577) The ligated DNA was electroporated in E Coli MC 1061 F ⁺ (Gene Pulser, Biorad) A total of 3 4 x 10 ⁶ independent clones with an insert mean size of 2.7 kb could be generated The library was plated on Petri dishes (Ampicillin selection) in pools of 6 9 to 8 2 x 10 ³ independent clones After 18 hours amplification, the bacteria from each pool were scraped, resuspended in 4 ml of LB media and 1 5 ml processed for plasmid purification with a QIAprep-8 plasmid kit (Qiagen Inc, Chatsworth, CA) 1 ml aliquots o ^f each bacterial oool were stored at -85°C in 20% glycerol

Isolation of a cDNA clone encoding an atypical rat hypothalamic NPY5 receptor

DNA from pools of » 7500 independent clones was transfected into COS-7 cells by a modification of the DEAE-dextran procedure (Warden, D. and H.V. Thome. (1968). Infectivity of polyoma virus DNA for mouse embryo cells in presence of diethylaminoethyl-dextran. J. Gen. Virol. 3, 371 ). COS-7 cells were grown in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum, 100 U/ml of penicillin, 100 mg/ml of streptomycin, 2 mM L-glutamine (DMEM-C) at 37°C in 5% C0 ₂ . The cells were seeded one day before transfection at a density of 30,000 cells/cm ² on Lab-Tek chamber slides (1 chamber, Permanox slide from Nunc Inc., Naperville, IL). On the next day, cells were washed twice with PBS, 735 ml of transfection cocktail was added containing 1/10 of the DNA from each pool and DEAE-dextran (500 mg/ml) in Opti-MEM I serum free media (Gibco®BRL LifeTechnologies Inc. Grand Island, NY). After a 30 min. incubation at 37°C, 3 ml of chloroquine (80 mM in DMEM-C) was added and the cells incubated a further 2.5 hours at 37°C. The media was aspirated from each chamber and 2 ml of 10% DMSO in DMEM-C added. After 2.5 min. incubation at room temperature, the media was aspirated, each chamber washed once with 2 ml PBS, the cells incubated 48 hours in DMEM-C and the binding assay was performed on the slides. After one wash with PBS, positive pools were identified by incubating the cells with 1 nM (3x10 ⁶ cpm per slide) of porcine [ ¹²⁵ I]-PYY (NEN; SA=2200 Ci/mmole) in 20 mM Hepes-NaOH pH 7.4, CaCI2 1.26 mM, MgSO4 0.81 mM, KH ₂ P0 ₄ 0.44 mM, KCL 5.4, NaCI 10 mM, .1 % BSA, 0.1 % bacitracin for 1 hour at room temperature. After six washes (three seconds each) in binding buffer without ligand, the monolayers were fixed in 2.5% glutaraldehyde in PBS for five minutes, washed twice for two minutes in PBS, dehydrated in ethanol baths for two minutes each (70, 80, 95, 100%) and air dried. The slides were then dipped in 100% photoemulsion (Kodak® type NTB2) at 42°C and exposed in the dark for 48 hours at 4°c in light proof boxes containing drierite. Slides were developed for three minutes in Kodak® D19 developer (32 g/l of water), rinsed in water, fixed in Kodak® fixer for 5 minutes, rinsed in water, air dried and mounted with Aqua-Mount (Lerner Laboratories, Pittsburgh, PA). Slides were screened at 25x total magnification. A single clone, CG-18, was isolated by SIB selection as described (Mc Cormick, 1 987). DS-DNA was sequenced with a Sequenase kit (US Biochemical , Cleveland, OH) accordmg to the manufacturer. Nucleotide and peptide sequence analysis were performed with GCG programs (Genetics Computer group, Madison, WI).

Isolation of the human Y5 homolog

Using rat oligonucleotide primers in TM 3 (sense primer, position 484-509 in SEQ ID NO:1) and in TM 6 (antisense primer; position 1219-1243 in SEQ ID NO: 1), a human hippocampal cDNA library has been screened using the polymerase chain reaction 1 μl (4 x 10 ⁶ bacteria) of each of 450 amplified pools containing each »5000 independent clones and representing a total of 2.2 x 10 ⁶ was subjected directly to 40 cycles of PCR and the resulting products analyzed by agarose gel electrophoresis One of three positive pools was analyzed further and by sib selection a single cDNA clone was isolated and characterized. This cDNA turned out to be full length and in the correct orientation for expression. DS- DNA was sequenced with a sequenase kit (US Biochemical, Cleveland, OH) according to the manufacturer

Cell Culture

COS-7 cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penιcιllιn/100 mg/ml streptomycin) at 37°C, 5% C0 ₂ . Stock plates of COS-7 cells were trypsmized and split 1 :6 every 3-4 days. Human embryonic kidney 293 cells were grown on 150 mm plates in D-MEM with supplements (minimal essential medium) with Hanks' salts and supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penιcιllιn/100 mg/ml streptomycin) at 37 °C, 5% C0 ₂ . Stock plates of 293 cells were trypsmized and split 1 :6 every 3-4 days. Mouse fibroblast LMT(k)- cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penιcιllιn/100 mg/ml streptomycin) at 37 °C, 5% C0 ₂ . Stock plates of COS-7 cells were trypsmized and split 1 :10 every 3-4 days

Stable Transfection

Human Y5 and rat Y5 receptors were co-transfected with a G-418 resistant gene into mouse fibroblast LMT(k)- cells by a calcium phosphate transfection method (Cullen, B

(1987). Use of eurkaryotic expression technology in the functional analysis of cloned genes Methods Enzymol. 152: 685-704). Stably transfected cells were selected with G-418.

EXPERIMENTAL RESULTS

cDNA Cloning

In order to clone a rat hypothalamic "atypical" NPY receptor subtype, applicants used an expression cloning strategy in COS-7 cells (Gearing et al, 1989; Kluxen, F.W., Bruns, C. and Lubbert H. (1992). Expression cloning of a rat brain somatostatin receptor cDNA. Proc. Natl. Acad. Sci. USA 89. 4618-4622; Kieffer, B , Befort, K., Gaveπaux-Ruff, C and Hirth, C.G (1992) The

6-opιoιd receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proc natl. Acad. Sci. USA 89, 12048-12052). This strategy was chosen for its extreme sensitivity since it allows detection of a single "receptor positive" cell by direct microscopic autoradiograpny. Since the "atypical" receptor has only been described in feeding behavior studies involving injection of NPY and NPY related ligands in rat hypothalamus (see introduction), applicants first examined its binding profile by running competitive displacement studies of ¹²³ I-PYY and ¹²⁵ I-PYY ₃ . ₃₆ on membranes prepared from rat hypothalamus. The competitive displacement data indicate: 1 ) Human PP is able to displace 20% of the bound ¹²⁵ !-PYY with an IC ₅₀ of 1 1 nM (Fig. 1 and Table 2). As can be seen in table 5, this value does not fit with the isolated rat Y1 , Y2 and Y4 clones and could therefore correspond to another NPY/PYY receptor subtype. 2) [Leu ₃₁ , Pro^] NPY (a Y1 specific ligand) is able to displace with high affinity (IC ₅₀ of 0.38) 27% of the bound ¹²⁵ l- PYY336 ligand (a Y2 specific ligand) (Fig. 2 and table 2). These data provide the first evidence based on a binding assay that rat hypothalamic membranes could carry an NPY receptor subtype with a mixed Y1 Y2 pharmacology (referred to as the "atypical" subtype) which fits with the pharmacology defined in feeding behavior studies

TABLE 2 Pharmacological profile of the rat hypothalamus

Binding data reflect competitive displacement of ¹² I -PYY and ^2a I-PYY _{3 36} from rat hypothalamic membranes Peptides were tested at concentrations ranging from 0.001 nM to 00 nM unless noted The IC ₅ o value corresponding to 50% displacement, and the

percentage of displacement relative to that produced by 300 nM human NPY, were determined by nonlinear regression analysis Data shown are representative of at least two independent experiments TABLE 2

Peptide ICso Values, nM (% NPY-produced displacement)

¹²⁵ I-PYY ¹²⁵ I-PYY _{3 36}

human NPY 0.82 (100%) | 1 5 (100%)

human NPY _{2 36} 2 3 (100%) 1 2 (100%)

human 0 21 (44%) 340 (56%) 0 38 (27%) 250 (73%) [Leu ³¹ ,Pro ³⁴ ]NPY

human PYY 1.3 (100%) 0.29 (100%)

human PP 1 1 (20%) untested

Based on the above data, a rat hypothalamic cDNA library of 3 x 1 0 independent recombmants with a 2 7 ko average insert size was fractionated into 450 pools of »7500 independent clones All pools were tested in a binding assay with ¹²⁵ I-PYY as described (Y2 patent) Seven pools gave rise to positive cells in the screening assay (# 81 , 92, 147, 246, 254, 290, 312). Since Y1 , Y2, Y4 and Y5 receptor subtypes (by PCR or binding analysis) are expressed in rat hypothalamus, applicants analyzed the DNA of positive pools by PCR with rat Y1 , Y2 and Y4 specific primers Pools # 147, 246, 254 and 312 turned out to contain cDNAs encoding a Y1 receptor, pool # 290 turned out to encode a Y2 subtype, but pools # 81 and 92 were negative by PCR analysis Ï„or Y1 , Y2 and Y4 and therefore likely contained a cDNA encoding a new rat hypothalamic NPY receptor (Y5) Pools # 81 and 92 later turned out to contain an identical NPY receptor cDNA Pool 92 was subjected to sib selection as described until a single clone was isolated (designated CG-18)

The isolated clone carries a 2 8 kb cDNA This cDNA contains an open reading frame between nucleotides 779 and 2146 that encodes a 456 ammo acid protein The long 5'

untranslated region could be involved in the regulation of translation efficiency or mRNA stability. The flanking sequence around the putative initiation codon does not conform to the Kozak consensus sequence for optimal translation initiation (Kozak, M. (1989). The scanning model for translation: an update. J. Cell Biol. 108, 229-241 ; Kozak, M. (1991 ). Structural features in eukaryotic mRNAs that modulate the initiation of translation. J. Biol. Chem. 266, 19867-19870). The hydrophobicity plot displayed seven hydrophobic, putative membrane spanning regions which makes the rat hypothalamic Y5 receptor a member of the G-protein coupled superfamiiy. The nucleotide and deduced amino acid sequences are shown in SEQ ID NOS: 1 and 2, respectively.

Localization studies show that the Y5 mRNA is present in several areas of the rat hippocampus. Assuming a comparable localization in human brain, applicants screened a human hippocampal cDNA library with rat oligonucleotide primers which were shown to yield a DNA band of the expected size in a PCR reaction run on human hippocampal cDNA. Using this PCR screening strategy (Gerald et al, 1994, submitted for publication), three positive pools were identified. One of these pools was analyzed further, and an isolated clone was purified by sib selection. The isolated clone (CG-19) turned out to contain a full length cDNA cloned in the correct orientation for functional expression (see below). The human Y5 nucleotide and deduced amino acid sequences are shown in SEQ ID NOS 3 and 4, respectively. When compared to the rat Y5 receptor the human sequence shows 84.1% nucleotide identity and 87.2% amino acid identity. The rat protein sequence is one amino acid longer at the very end of both amino and carboxy tails of the receptor when compared to the rat. Both pharmacological profiles and functional characteristics of the rat and human Y5 receptor subtype homologs may be expected to match closely.

When the human and rat Y5 receptor sequences were compared to other NPY receptor subtypes or to other human G protein-coupled receptor subtypes, both overall and transmembrane domain identities are very low, showing that the Y5 receptor genes are not closely related to any other previously characterized cDNAs.

The compounds according to the present invention and their pharmaceutically acceptable salts have proven to exhibit pronounced and selective affinity to the Y5 receptor subtype (shown in Y5 binding test) and in vitro and in vivo antagonistic properties. These properties are shown in vitro by their ability to inhibit NPY-induced calcium increase in stable

transfected cells expressing the Y5 receptor and in vivo by their ability to inhibit food intake induced by intracerebroventricular application of NPY or 24 h food deprivation in conscious rats.

Binding experiments

The selective affinity of the compounds according to the present invention to the Y5 receptor is detected in a Y5 binding assay using LM(tk-)-h-NPY5-7 cells which stably express the human NPY Y5 receptor or HEK-293 cells stably expressing the rat NPY Y5 receptor.

The following buffers are used for the preparation of membranes and for binding assay: a) buffer 1 (homogenisation buffer, pH 7.7 at 4°C) contains Tris-HCl [FLUKA, Buchs, Switzerland] (20 mM) and ethylenediamine tetraacetate (EDTA) [FLUKA, Buchs, Switzerland] (5 mM); b) buffer 2 (suspension buffer, pH: 7.4 at room temperature) contains N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) [Boehringer Mannheim, Germany] (20 mM), NaCI (10 mM), CaCI ₂ (1.26 mM), MgS0 ₄ (0.81 mM) and KH ₂ P0 ₄ (0.22 mM); buffer 3 (binding buffer, pH 7.4 at room temperature) contains HEPES (20 mM), NaCI (10 mM), CaCI ₂ (1.26 mM), MgS0 ₄ (0.81 M), KH ₂ P0 ₄ (0.22 mM) and 1 mg/ml bovine serum albumin [FLUKA],

Cells are washed in phosphate buffered saline and harvested using a rubber policeman. The cells are homogenised using a Polytron homogeniser (3 bursts of 8 seconds) in ice- cold hypotonic buffer (buffer 1 , pH 7.7 at 4°C ). The homogenate is centrifuged at 32,000 x g for 20 min at 4°C. The pellets are resuspended in the same buffer and recentrifuged. The final pellets are suspended in buffer 2. Protein concentration is measured by the method of Bradford using the Pierce reagent [PIERCE, Rockford, USA], with bovine serum albumin as standard. The crude membrane preparation is aliquoted, flash-frozen in liquid nitrogen and stored at -80°C. Before use, 0.1 % (1 mg/ml) bovine serum albumin is added. ^{1 25} l-[Pro ³ ]hPYY (60 pM, Anawa, Wangen, Switzerland) dissolved in buffer 3 is used as radioligand. All test compounds are dissolved in dimethyl sulfoxide (DMSO) at 10 ^"2 M and diluted to 10 ^{~ 3} M in buffer 3. Subsequent dilutions are in buffer 3 plus 10% DMSO. Incubations are performed in Millipore Multiscreen FC filter plates [Millipore, Bedford, USA]. The filters in each well are pretreated with 2% polyethyleneimine for 30 min and rinsed once with 300 microL buffer 3 before use. The following are pipetted into each well: 20 microL buffer 3, 25 microL ^{1 25} l-[Pro ³⁴ ]hPYY [SAXON, Hannover, Germany] (600 pM); 25 microL

test compound (or binding buffer for the controls); 180 microL crude membrane suspension (approximately 5 microg protein). Incubations are performed at room temperature for 2h. Non-specific binding is defined as the binding remaining in the presence of 1 microM [Pro ³⁴ ]hPYY. The incubations are terminated by rapid filtration and washing four times with 300microL phosphate buffered saline. The filters are removed from the wells, placed into plastic tubes and assayed for radioactivity in a gamma counter [Gammamaster, WALLAC, Finland].

The IC50 values of the compounds according to this invention at the human Y5 receptor range especially between about 0.1 nM and about 10 microM.

Measurements of calcium transient

For the determination of in vitro antagonistic properties of the compounds according to the present invention, stably transfected LM(tk-)-hY5-7 cells are used in which a NPY-induced calcium transient is measured as described below. Cells are harvested in a medium containing EDTA (0.5 mM) and phosphate buffered saline (PBS). Cells are then washed in phosphate buffered saline solution and loaded for 90 min at room temperature and pH 7.4 with 10 microM FLUO-AM (fluoro-3-acetoxy methylester, supplemented with pluronic acid as suggested by the manufacturer, Molecular Probes Inc., Eugene, Oregon, USA) in a cell culture buffer of the following composition (NaCI 120 mM, MgCI ₂ 1 mM , KCl 5.4 mM , NaH P0 ₄ 0.33 mM, glucose 11 mM, taurine 5 mM, pyruvate 2 mM, glutamine 1.5 mM HEPES 10 mM, insulin 10 U/l, BSA 0.1% at for 90 min at room temperature. After centrifugation the cells are resuspended in the cell culture buffer at a concentration of 3-4 million cells/ml and supplemented with 200 microM sulfinpyrazone.

Calcium transients are measured at room temperature in a millititer plate using a Cytofluor 2350 (Millipore) with wavelength settings at 485 nm for excitation and 530 nm for emission. 180 microL of cells suspension are preincubated in the presence of various amounts of compounds dissolved in 2 microL DMSO in triplicates ( or 2 microL DMSO for the controls) for 5 min and then NPY is added at a final concentration of 100 nM. The compound concentrations giving 50% inhibition of the maximum of the Ca transients are then calculated.

In this cell system, NPY induces Ca transients with an EC50 of 50 nM. The data are analyzed using a Microsoft Excel software. The concentrations which cause a 50% inhibition

of the initial control values are given as IC50 values The IC50 values are determined for the compounds according to the present invention and their pharmaceutically acceptable salts.

The property of the com pounds according to the present invention and their pharmaceutically acceptable salts to inhibit NPY-mduced increase intracellular calcium indicates their antagonistic properties with IC50 values ranging especially between about 0.1 nM and about 10 microM Representatives are, for example, the final products of working examples 3, 4 and 1 1 , for which following IC50 values [μM/L] were determined: 0.02 (Ex. 3); 0 1 (Ex. 4), 0.32 (Ex 1 1 )

Measurements of NPY-mduced food intake in conscious rats

In addition this antagonistic property of the Y5 receptor subtype is also observed in-vivo in conscious rats by their ability to inhibit NPY-mduced food intake For these determinations food intake is measured in normal satiated rats after intracerebroventπcular application (i.c.v ) of neuropeptide Y [BACHEM, Feincnemikalien, Bubendorf, Switzerland] in the presence or absence of the compounds according to the present invention. Male Sprague- Dawley rats weighing 180-220 g are used for all experiments They are individually housed in stainless steel cages and maintained on a 1 V13 h light-dark schedule (lights off at 1800 h) under controlled temperature (21 -23 °C) at all times Water and food (NAFAG lab chow pellets) [NAFAG, Gossau, Switzerland] are available ad libitum

Under pentobarbital [ VETERINARIA AB, Zurich, Switzerland] anesthesia, all rats are implanted with a stainless steel guide cannula targeted at the right lateral ventricle. Stereotaxic coordinates, with the incisor bar set -2.0 mm below mteraural line, are : -0.8 mm anterior and +1.3 mm lateral to bregma The guide cannula is placed on the dura. Injection cannulas extended the guide cannulas -3.8 mm ventrally to the skull surface. Animals are allowed at least 4 days of recovery postoperatively before being used in the experiments Cannula placement is checked postoperatively by testing all rats for their drinking response to a 50 ng intracerebroventncular (icv) injection of angiotensin II Only rats which drink at least 2.5 ml of water within 30 mm after angiotensin II injection are used in the feeding studies Injections are made in the morning 2 hours after light onset Peptides are injected in artificial cerebrospinal fluid (ACSF) [FLUKA, Buchs, Switzerland] in a volume of 5 μl The ACSF contains NaCI 124 mM, KCl 3 75 mM, CaCI ₂ 2 5 mM, MgS0 ₄ 2 0 mM, KH ₄ P0 ₄ 0.22 mM, NaHC0 ₃ 26 mM and glucose 1 0 mM NPY (300 pmole) is administered by the

intracerebroventπcular route 10-60 minutes after administration of compounds or vehicle DMSO/water (10%, v/v) or cremophor/water (20%,v/v) [SIGMA, Buchs, Switzerland].

Food intake is measured by placing preweighed pellets into the cages at the time of NPY injection. Pellets are removed from the cage subsequently at each time point indicated in the figures and replaced with a new set of preweighed pellets.

All results are presented as means ±SEM. Statistical analysis is performed by analysis of variance using Student-Newman-Keuls test.

The compounds according to the present invention inhibit NPY-mduced food intake in rats in a range especially of about 0.01 to about 100 mg/kg after oral, intraperitoneal, subcutaneous or intravenous administration

Measurements of food intake in 24 hours food deprived rats

Based on the observation that food deprivation induces an increase in the hypothalamic NPY levels, it is assumed that NPY mediates food intake induced by food deprivation. Thus, the compounds according to the present invention are also tested in rats after 24 hours food deprivation. These experiments are conducted with male Sprague-Dawley (CIBA-GEIGY AG, Sisseln, Switzerland] rats weighing between 220 and 250 g. The animals are housed in individual cages for the duration of the study and allowed free access to normal food together with tap water. The animals are maintained in room with a 12 h light/dark cycle (8 a.m. to 8.00 p.m. light) at 24°C and monitored humidity. After placement into the individual cages the rats undergo a 2-4 days equilibration period, during which they are habituated to their new environment and to eating a powdered or pellet diet [NAFAG , Gossau , Switzerland]. At the end of the equilibration period, food is removed from the animals for 24 hours starting at 8.00 a.m At the end of the fasting period the animals are injected intraperitoneally, intravenously or orally either with the compounds according to the present invention or an equivalent volume of vehicle DMSO/water (10%, v/v) or cremophor/water (20%, v/v) and 10-60 mm later the food is returned to them. Food intake at various time periods is monitored over the following 24 hour period. Inhibition of food intake by the compounds according to the present invention is given in percentage of the respective control vehicle-treated rats

The compounds according to the present invention inhibit food intake in this food deprived rat model in a range especially of about 0 01 to about 100 mg/kg after oral, intraperitoneal, subcutaneous or intravenous administration Representatives are, for example, the final

products of working examples 1 and 2, for which an inhibition of food intake of 57% or 46%, respectively, versus the respective control vehicle-treated animals after i.p. application of 30 mg/kg was determined.

Measurements of food intake in obese Zucker rats

The antiobesity efficacy of the compounds according to the present invention can also be shown in Zucker obese rats, an art-known animal model of obesity. These studies are conducted with male Zucker fatty rats (fa/fa) [HARLAN CPB, Austerlitz, NL] weighing between 480 and 500 g. Animals are individually housed in metabolism cages for the duration of the study and allowed free access to powdered food together with tap water. The animals are maintained in a room with a 12 hour light/dark cycle (8 a.m. to 8.00 p.m. light) at 24°C and monitored humidity. After placement into the metabolism cages the rats undergo a 6 day equilibration period, during which they are habituated to their new environment and to eating a powdered diet. At the end of the equilibration period, food intake during the light and dark phases is determined. After a 3 day control period, the animals are treated with the compounds according to the present invention or vehicle DMSO/water (10% , v/v) or cremophor/water (20%, v/v).

The compounds according to the present invention inhibit food intake in Zucker obese rats in a range especially of about 0.01 to about 100 mg/kg after oral, intraperitoneal, subcutaneous or intravenous administration.

The above experiments clearly demonstrate that the Y5 receptor subtype is the primary mediator of NPY-induced feeding and that corresponding antagonists can be used for the treatment of obesity and related disorders [Nature, Vol. 382, 168-171 (1996)].

The compounds according to the present invention can inhibit food intake induced either by intracerebroventricular application of NPY or by food deprivation or as well as spontaneous eating in the Zucker obese rat. Thus, the compounds according to the present invention can especially be used for the prophylaxis and treatment of disorders or diseases associated with the Y5 receptor subtype, especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain and additionally in the treatment of sexual/reproductive

disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea

The compounds according to the present invention act as antagonists of neuropeptide Y (NPY) binding at the Y5 receptor subtype. By virtue of their Y5 receptor antagonistic property, the compounds of the formula (1) and their pharmaceutically acceptable salts can therefore be used, for example, as pharmaceutical active ingredients in pharmaceutical compositions which are employed, for example, for the prophylaxis and treatment of diseases and disorders associated with NPY Y5 receptor subtype, especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea.

The invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described hereinbefore and hereinafter for the manufacture of a pharmaceutical composition for the prophylaxis and treatment of diseases or disorders associated with NPY Y5 receptor subtype, especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea

The invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt tnereof as described hereinbefore and hereinafter for the prophylaxis and treatment of diseases or disorders associated with NPY Y5 receptor subtype, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and

additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea.

The invention relates especially to a method of prophylaxis and treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm¬ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk-, and alk ₂ , independently of one another, represent a single bond or lower alkylene;

Ri represents hydrogen, lower alkyl, lower alkenyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

R ₂ represents (i) hydrogen, halogen, cyano, nitro, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by lower alkoxy, by substituted ammo, by lower alkoxycarbonyl, or by N-substituted carbamoyl; (ii) substituted ammo;

(iii) hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, C ₃ -C ₈ -cycloalkyl-lower alkoxy, (carbocyclic or heterocyclic) aryl-lower alkoxy, lower alkoxycarbonyl-oxy, or N-substituted aminocarbonyl-oxy;

(iv) lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl; (v) N-substituted carbamoyl;

(vi) a group selected from -CH(OH)-R, -CO-R, -NR,-CO-0-R, -NR CO-R, -NR^O-NR^R, - NRTSO _JΓ R, [R being as defined below and Ri being as defined above, or the group -N(R)(R,) represents amino which is di- substituted by lower alkylene {which may be interrupted by O, S(0) _n or NR ₀ } or which is di- substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

(vii) an element of formula -Xι(X ₂ )(Xs) wherein, (a) if X, is -CH-, X ₂ together with X ₃ represent a structural element of formula -X--(CO) _p -(CH ₂ ) ₀ - ₁ -(CH ₂ ) _q -X ₄ -(CO) _p -(CH ₂ ) _r - _I or -(CH ₂ ) _s -X4-CO-(CH ₂ ),-; or, (b) if X, is -N-, X ₂ together with X ₃ represent a structural element of formula -CO-(CH ₂ ) _u -; [XA being -CH ₂ -, -N^)- or -0-; the integer o is 3-5; the integer p is 0 or 1 ; the integer q is 1 or 2; the integer r is 1 ; the integer s is 1 or 2; the integer t is 1 or 2; the integer u is 3-5; with the proviso that, if the integer p is 0, X ₄ is different from -CH ₂ -,],

R ₃ and R ₄ , independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (II) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, ammo, substituted ammo, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, N- substituted carbamoyl, and -S(0) _n -R;

R ₃ and R together represent lower alkylene [which may be interrupted by O, S(0) _n , or NR ₀ ] or represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring;

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, -CO- or- (OR') ₂ -; one of R' being hydrogen or both being each lower alkyl or being together lower alkylene, wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the beÏ€zo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, lower alkoxy, lower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano;

(II) lower alkyl which is substituted by a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, ammo, substituted ammo, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(in) lower alkoxy which is substituted by a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, ammo, substituted ammo, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(iv) am o, substituted ammo,

(v) carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, (vi) carbamoyl and N-substituted carbamoyl,

wherem, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, is derived and selected from the group consisting of phenyl, biphenylyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, pyridyl, indolyl, mdazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, quinolinyl, isochmolyl, or quinazolmyl, wherein, in each case, the substituted ammo group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by lower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C ₈ - cycloalkyl-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (n) di-substituted by lower alkylene [which may be interrupted by O, S(0) _n or NRo] or is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (in) mono-substituted or, in the second line, independently of one another, di-substituted by -C0-(O) _v -R and the integer v is 0 or 1 , wherein, in each case, tne integer n is 0, 1 or 2, wherein, in each case, R ₀ represents hydrogen or lower alkyl; wherein, in each case, R represents hydrogen, lower alkyl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, or by lower alkoxy

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ , independently of one another, represent a single bond or lower alkylene, Ri represents hydrogen, lower alkyl, lower alkenyl, or lower alkoxy-lower alkyl; R ₂ represents (i) hydrogen, halogen, cyano, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by lower alkoxy, by substituted ammo, by lower alkoxycarbonyl, or by N-substituted carbamoyl, (II) substituted ammo,

(in) lower aikoxy or lower alkoxy-lower alkoxy,

(iv) lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl,

(v) N-substituted carbamoyl;

(vi) a group selected from -CH(OH)-R, -NR CO-R, -NR,-S0 ₂ -R, -NR ₁ -S0 ₂ -NRι-R, -S0 ₂ -R, - S0 ₂ -NR R, or -S0 ₂ -NR CO-R, [R being as defined below and R being as defined above, or the group -N(R)(R!) represents amino which is di-substituted by lower alkylene {which may be interrupted by O or NR ₀ } or which is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or (vii) an element of formula -X^X;,)^) wherein, (a) if X is -CH-, X ₂ together with X ₃ represent a structural element of formula -X ₄ -(CO) _p -(CH ₂ )o-, -(CH ₂ )q-X ₄ -(CO) _p -(CH ₂ ) _r - ₎ or -(CH ₂ ) _s -X ₄ -CO-(CH ₂ ) _r ; or, (b) if X is -N-, X ₂ together with g represent a structural element of formula -CO-(CH ₂ ) _u -; PC being -CH ₂ -, -N^)- or -0-; the integer o is 3-5; the integer p is 0 or 1 ; the integer q is 1 or 2; the integer r is 1 ; the integer s is 1 or 2; the integer t is 1 or 2; the integer u is 3-5; with the proviso that, if the integer p is 0, X, is different from -CH ₂ -;];

R ₃ and R ₄ , independently of one another, represent (i) hydrogen, lower alkyi, lower alkenyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

(ii) lower alkyl which is substituted by a substituent selected from the group consisting of: lower alkoxy, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, and N-substituted carbamoyl;

R ₃ and R ₄ together represent lower alkylene [which may be interrupted by O, S(0) _n , or NRo};

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, -CO- or- (OR') ₂ -; one of R' being hydrogen or both being each lower alkyl or being together lower alkylene; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, lower alkoxy, lower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano;

(ii) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(lii) lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, ammo, substituted am o, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl,

(carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(iv) substituted ammo;

(v) lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl;

(vi) carbamoyl and N-substituted carbamoyl; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, is derived and selected from the group consisting of phenyl, biphenylyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, pyridyl, indolyl, mdazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, quinolinyl, isochmolyl, or αumazolinyl; wherein, in each case, the substituted amino group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by lower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C ₈ - cycloalkyl-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (ii) di-substituted by lower alkylene [which may be interrupted by O, S(0) _n or NRo] or is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (iii) mono-substituted or, in the second line, independently of one anotner, di-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ; wherein, in each case, the integer n is 0, 1 or 2; wherein, in each case, R ₀ represents hydrogen or lower alkyl; wherein, in each case, R represents hydrogen, lower alkyl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, or by lower alkoxy

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ , independently of one another, represent a single bond or lower alkylene;

Ri represents hydrogen or lower alkyl;

R ₂ represents (i) hydrogen, halogen, cyano, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by lower alkoxy, by substituted amino, by lower alkoxycarbonyl, or by N-substituted carbamoyl; (ii) substituted amino;

(iii) hydroxy, lower alkoxy or lower alkoxy-lower alkoxy;

(iv) lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl; (v) N-substituted carbamoyl;

(vi) a group selected from -CH(OH)-R, -CO-R, -NR CO-R, -NR S0 ₂ -R, -NR^SOa-NR^R, - S0 ₂ -R, -S0 ₂ -NRι-R, or -S0 ₂ -NR CO-R, [R being as defined below and R, being as defined above, or the group -N(R)(Rι) represents amino which is di-substituted by lower alkylene {which may be interrupted by O or NR ₀ } or which is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

R ₃ represents (i) hydrogen, lower alkyl, lower alkenyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

(ii) lower alkyl which is substituted by a substituent selected from the group consisting of: lower alkoxy, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, and N-substituted carbamoyl;

R ₄ represents hydrogen;

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, or -CO-; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryi, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, C ₃ -C _B -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, lower alkoxy, lower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano;

(ii) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, substituted amino, carboxy, lower alkoxy-carbonyl, lower

alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(in) lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, ammo, substituted am o, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl,

(carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(iv) substituted ammo;

(v) lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl;

(vi) carbamoyl and N-substituted carbamoyl, wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, is derived from phenyl, naphthyl, pyrrolyl, imidazolyl, or pyridyl, wherein, in each case, the substituted ammo group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by lower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C ₈ - cycloalkyl-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (n) di-substituted by lower alkylene [which may be interrupted by O, S(0) _n or NRo] or is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (in) mono-substituted or, in the second line, independently of one another, di-substituted by -CO-(0) _v -R and the integer v is 0 or 1 , wherein, in each case, the integer n is 0, 1 or 2, wherein, in each case, R ₀ represents hydrogen or lower alkyl, wherein, in each case, R represents hydrogen, lower alkyl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, or by lower alkoxy

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound oÏ„ formula (I) or a pharmaceutically acceptable salt thereof in wnich alk, and alk ₂ independently of one another, represent a single bond or lower alkylene,

R, represents hydrogen or lower alkyl;

R ₂ represents (i) hydrogen, halogen, cyano, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycIoalkyl-lower alkyl, phenyl, phenyl-lower alkyl, or lower alkyl which is substituted by di-lower alkylamino; (ii) amino which is mono-substituted by lower alkyl, phenyl or pyridyl, or which is disubstituted by lower alkyl or by C ₂ -C ₆ -alkylene;

(iii) hydroxy or lower alkoxy which is unsubstituted or substituted by C ₃ -C ₈ -cycloalkyl, or by phenyl;

(iv) a group selected from -NR1-CO-R, -NR1-SO2-R, - R^SOa-NR R, -S0 ₂ -R, or -S0 ₂ -NR R, [R being lower alkyl, halo-lower alkyl, phenyl, pyridyl, or naphthyl, R-, being as defined above, or the group -N(R)(R represents amino which is mono-substituted by lower alkyl, by hydroxy-lower alkyl, or by naphthyl, or which is di-substituted by lower alkyl or by C ₂ -C ₆ - alkylene {which may be interrupted by O or NR ₀ , R ₀ being hydrogen or lower alkyl}];

R ₃ represents hydrogen, lower alkyl or lower alkyl which is substituted by lower alkoxy or di-lower alkyl-amino;

R ₄ represents hydrogen;

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, or -CO-; wherein any aryl moiety, if not designated otherwise and the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy-lower alkoxy, and lower alkoxy-lower alkoxy.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which aik ₁ and alk ₂ , independently of one another, represents a single bond; or d-d- alkylene;

Ri represents hydrogen or lower alkyl;

R ₂ represents (i) hydrogen, halogen, cyano, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ - cycloalkyl-lower alkyl, phenyl, or phenyl-lower alkyl;

(ii) amino which is mono-substituted by lower alkyl, phenyl or pyridyl, or which is disubstituted by lower alkyl or by C ₂ -C ₆ -alkylene;

(iii) hydroxy or lower alkoxy which is unsubstituted or substituted by C ₃ -C ₈ -cycloalkyl, or by phenyl;

(iv) a group selected from -NR CO-R, -NR^SOa-R, -NRrSOj-NR R, -S0 ₂ -R, or -S0 ₂ -NR,-

R, [R being lower alkyl, halo-lower alkyl, phenyl, pyridyl, or naphthyl, R, being as defined above, or the group -N(R)(R represents amino which is mono-substituted by lower alkyl, by hydroxy-lower alkyl, or by naphthyl, or which is di-substituted by lower alkyl or by C ₂ -C ₆ - alkylene {which may be interrupted by O or NR ₀ , R ₀ being hydrogen or lower alkyl}];

R ₃ represents hydrogen, lower alkyl, lower alkyl which substituted by lower alkoxy or di-lower alkylamino, or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, lower alkyl, lower alkoxy, and oxy- lower alkylene-oxy;

R ₄ represents hydrogen;

X represents a single bond, 1 ,2-ethenylene, or -CO-; wherein any aryl moiety, if not designated otherwise and the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy-lower alkoxy, and lower alkoxy-lower alkoxy.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ , independently of one another, represent C ₂ -C ₄ -alkylene;

Ri represents hydrogen;

R ₂ represents (i) hydrogen, halogen, cyano, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ - cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, or pyrrolyl, imidazolyl; (ii) amino, amino which is mono-substituted by C ₃ -C ₆ -cycloalkyl, amino which is disubstituted by lower alkyl or by C ₄ -C ₆ -alkylene or amino which is mono-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ; or

(iii) a group selected from -NR S0 ₂ -R , -S0 ₂ -R, or -SO^NR R, [R, being hydrogen; R being d-C -alkyl, or naphthyl, and the group -NR^R) represents amino which is mono¬ substituted by Cι-C ₄ -alkyl, by hydroxy-Cι-C ₄ -alkyl, or by naphthyl, or which is di-substituted by d-d-alkyl or by C ₂ -C ₆ -alkylene {which may be interrupted by O or NR _0l R ₀ being hydrogen or Cι-C ₄ -alkyl}];

and, in each case,

R ₃ represents hydrogen, lower alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl-lower alkyl, phenyl-lower alkyl, or lower alkyl which is substituted by lower alkoxy or by di-lower alkylamino; and

R ₄ represents hydrogen;

X represents a single bond, 1 ,2-ethenylene or -0-; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂ , independently of one another, represent C ₂ -C ₄ -alkylene;

Ri represents hydrogen;

R ₂ represents a group -NH-S0 ₂ -R or -NH-S0 ₂ -N(R)(R ₁ )[R being d-C ₄ -alkyl, or naphthyl, or the group -N(R)(Rι) represents amino which is mono-substituted by Cι-C ₄ -alkyl, by phenyl, or by naphthyl, or which is di-substituted by d-C ₄ -alkyl or by C ₂ -C ₆ -alkyiene {which may be interrupted by NR ₀ , R ₀ being d-d-alkyl}]; and, in each case,

R ₃ represents hydrogen, lower alkyl or lower alkyl which is substituted by loewr alkoxy or di-lower alkylamino; and

R ₄ represents hydrogen;

X represents a single bond or 1 ,2-ethenylene; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂ , independently of one another, represents a single bond; or Cι-C ₄ - alkylene;

Ri represents hydrogen;

R ₂ represents (i) hydrogen, halogen, cyano, lower alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ - cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, or pyrrolyl, imidazolyl;

(n) ammo, am o which is mono-substituted by C ₃ -C ₆ -cycloalkyl, ammo which is disubstituted by lower alkyl or by C ₄ -C ₆ -alkyleÏ€e or ammo which is mono-substituted by -CO-(0) _v -R and the integer v is 0 or 1 , (in) a group selected from -NR^SO^R, R being lower phenyl or naphthyl,

R ₃ represents hydrogen, C ₃ -C ₆ -cycloalkyl-lower alkyl, phenyl-lower alkyl, lower alkyl which substituted by di-lower alkylamino, d-C ₆ -cycloalkyl, or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of" halogen, cyano, lower alkyl, lower alkoxy, and oxy-lower alkylene-oxy;

R ₄ represents hydrogen;

X represents a single bond or -O-; wherein any aryi moiety, if not designated otherwise and the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, and oxy-lower alkylene-oxy.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 compÏ€sing administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ represent C ₂ -C ₄ -alkylene,

R ₂ represents -S0 ₂ -R or -S0 ₂ -NH-R and R being Cι-C ₄ -alkyl, especially methyl, or naphthyl, and, in each case,

Ri represents hydrogen,

R ₃ represents hydrogen,

R represents hydrogen; and

X represents a single bond or ethenylene, wherein the benzo ring A is unsubstituted or substituted by Cι-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazolme ring

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of Tormula (I) or a pharmaceutically acceptable salt thereof in which alk-, and alk ₂ represent C ₂ -C ₄ -alkylene

R ₂ represents (i) phenyl which is substituted by halogen, especially 4-halo-phenyl, or pyrrolyl, especially 1 -pyrrolyl or (ii) -NH-S0 ₂ -R and R being naphthyl; and, in each case,

Ri represents hydrogen;

R ₃ represents hydrogen;

R ₄ represents hydrogen; and

X represents a single bond; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazolme ring.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alkÏ„ represents ethylene; alk ₂ represent C ₂ -C ₃ -alkylene;

R ₂ represents -S0 ₂ -NH-R and R being naphthyl, especially 1 - or 2-naphthyl;

Ri represents hydrogen;

R ₃ represents hydrogen;

R represents hydrogen; and

X represents a single bond; wherein the benzo ring A is unsubstituted or substituted by Cι-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazolme ring.

The invention relates especially to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alkÏ„ and alk ₂ represent C ₂ -C ₄ -alkylene;

R ₂ represents phenyl which is substituted by halogen, especially 4-chloro-phenyl, or pyrrolyl, especially 1 -pyrrolyl; and, in each case,

Ri represents hydrogen,

R ₃ represents hydrogen,

R ₄ represents hydrogen; and

X represents a single bond; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.

The invention likewise relates to a new compound of formula (I) or a salt thereof as described hereinbefore or hereinafter.

The present invention relates to a new compound of formula (I) or a salt thereof, e.g. in which alkÏ„ and alk ₂ , independently of one another, represent, independently of one another, a single bond or lower alkylene;

R represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

R ₂ represents (ii) amino or substituted amino;

(iii) hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, C ₃ -C ₈ -cycloalkoxy, C ₃ -C ₈ -cycloalkyl-lower alkoxy, (carbocyclic or heterocyclic) aryl-lower alkoxy, lower alkoxycarbonyl-oxy, (carbocyclic or heterocyclic) aryl- lower alkoxycarbonyl-oxy, aminocarbonyl-oxy, or N-substituted aminocarbonyl-oxy; (iv) carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl; (v) carbamoyl or N-substituted carbamoyl;

(vi) a group selected from -CH(OH)-R, -CO-R, -NR CO-0-R, -NR CO-R, -NRrCO-NRrR, - NR^SOs-R, -NRι-S0 ₂ -NRrR, -S0 ₂ -R, -S0 ₂ -NR R. or -S0 ₂ -NR CO-R, [R being as defined below and Ri being as defined above, or the group -N(R)(R ₁ ) represents amino which is di¬ substituted by lower alkylene {which may be interrupted by O, S(0) _n or NR ₀ } or which is di¬ substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

(vii) an element of formula -Xι(X ₂ )(Xs) wherein, (a) if X, is -CH-, X ₂ together with X^ represent a structural element of formula -(CH ₂ ) _q -X ₄ -(CO)p-(CH ₂ )r-, or -(CH ₂ ) _s -X4-CO-(CH ₂ ) _r ; or, (b) if Xi is -N-, X ₂ together with X ₃ represent a structural element of formula -CO-(CH ₂ ) _u -; [X _* being -CH ₂ -, -N(Rι)- or -O-; the integer o is 3-5; the integer p is 0

or 1 ; the integer q is 1 or 2; the integer r is 1 ; the integer s is 1 or 2; the integer t is 1 or 2; the integer u is 3-5; with the proviso that, if the integer p is 0, X ₄ is different from -CH ₂ -;];

R ₃ and R , independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, lower alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl- lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (ii) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, N-substituted carbamoyl, and -S(0) _n -R;

R ₃ and R ₄ together represent lower alkylene [which may be interrupted by O, S(0) _n , NRo] or represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring;

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, -CO- or- (OR') ₂ -; one of R' being hydrogen or both being each lower alkyl or being together lower alkylene; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryi, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, lower alkenyl, lower alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, (carbocyclic or heterocyclic) aroyl, nitro, cyano;

(ii) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy- lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(iii) lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(iv) ammo, substituted ammo;

(v) carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl;

(vi) carbamoyl and N-substituted carbamoyl; wherein, in each case, the substituted amino group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by lower alkyl, by C ₃ -C ₈ -cycioalkyl, by C ₃ -C ₈ - cycloalkyl-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (ii) di-substituted by lower alkylene [which may be interrupted by O, S(0) _n or NRo] or is di -substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (iii) mono-substituted or, in the second line, independently of one another, di-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ; wherein, in each case, the integer n is 0, 1 or 2; wherein, in each case, R ₀ represents hydrogen, lower alkyl, lower alkenyl, lower alkmyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, lower alkanoyl, (carbocyclic or heterocyclic) aroyl, -S0 ₂ -R, or lower alkyl which is substituted by nalogen, by hydroxy, or by lower alkoxy; wherein, in each case, R represents hydrogen, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ - cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl- lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, or by lower alkoxy.

The invention relates especially to a new compound of formula (I) or a salt thereof in which alkÏ„ and alk ₂ , independently of one another, represent a single bond or lower alkylene; Ri represents hydrogen, lower alkyl, lower alkenyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, or (carbocyclic or heterocyclic) aryl-lower alkyl; R ₂ represents

(ii) substituted ammo;

(in) hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, C ₃ -C ₈ -cycloalkyl-lower alkoxy,

(carbocyclic or heterocyclic) aryl-lower alkoxy, lower alkoxycarbonyl-oxy, or N-substituted aminocarbonyl-oxy;

(iv) lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl,

(v) N-substituted carbamoyl,

(vi) a group selected from -CH(OH)-R, -CO-R, -NR ₁ -CO-O-R, -NRrCO-R, -NR ₁ -CO-NR ₁ -R, - NR,-S0 ₂ -R, [R being as defined below and R _T being as defined above, or the group -N(R)(R _! ) represents ammo which is di¬ substituted by lower alkylene {which may be interrupted by O, S(0) _n or NR ₀ } or which is di¬ substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

(vii) an element of formula wherein, (a) if Xi is -CH-, X ₂ together with X ₃ represent a structural element of formula -X ₄ -(CO)p-(CH ₂ ) ₀ -, -(CH ₂ ) _q -X ₄ -(CO) _p -(CH ₂ ) _r -, or -(CH ₂ ) _s -X ₄ -CO-(CH ₂ ) _r ; or, (b) if Xi is -N-, X ₂ together with Xs represent a structural element of formula -CO-(CH ₂ ) _u -; PC being -CH ₂ -, -NfR,)- or -0-; the integer 0 is 3-5; the integer p is 0 or 1 ; the integer q is 1 or 2; the integer r is 1 ; the integer s is 1 or 2; the integer t is 1 or 2; the integer u is 3-5; with the proviso that, if the integer p is 0, X ₄ is different from -CH ₂ -;];

R ₃ and R ₄ , independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (n) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, ammo, substituted ammo, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, N- substituted carbamoyl, and -S(0) _n -R;

R ₃ and R ₄ together represent lower alkylene [which may be interrupted by 0, S(0) _n , or NRo] or represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring;

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, -CO- or- (OR') ₂ -; one of R' being hydrogen or both being each lower alkyl or being together lower alkylene; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of

(I) halogen, lower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C _e -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, lower alkoxy, lower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano,

(II) lower alkyl which is substituted by a substituent selected from the group consisting of halogen, hydroxy, lower alkoxy, ammo, substituted am o, carboxy, lower alkoxy-carbonyl,

lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(iii) lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, amino, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl,

(carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(iv) amino, substituted amino;

(v) carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl;

(vi) carbamoyl and N-substituted carbamoyl; wherein, in each case, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl represents (phenyl-, naphthyl- or pyridyl)-lower alkoxy-carbonyl; wherein, in each case, (carbocyclic or heterocyclic) aryl-lower alkyl represents phenyl-, naphthyl- or pyridyl-lower alkyl; wherein, in each case, (carbocyclic or heterocyclic) aryl-oxy represents phenoxy, naphthyloxy, or pyridyloxy; wherein, in each case, (carbocyclic or heterocyclic) aryl-loweralkanoyl represents (phenyl-, naphthyl- or pyridyl)-lower alkanoyl; wherein, in each case, the substituted amino group of substituted amino, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by lower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C ₈ - cycloalkyl-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (ii) di-substituted by lower alkylene [which may be interrupted by O, S(0) _n or NRo] or is di-substituted by lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (iii) mono-substituted or, in the second line, independently of one another, di-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ; wherein, in each case, the integer n is 0, 1 or 2; wherein, in each case, R ₀ represents hydrogen or lower alkyl; wherein, in each case, R represents hydrogen, iower alkyl, (carbocyclic or heterocyclic) aryl-lower alkyl, or Iower alkyl which is substituted by halogen, by hydroxy, or by Iower alkoxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂₎ independently of one another, represent a single bond or Iower alkylene;

Ri represents hydrogen, Iower alkyl, Iower alkenyl, or Iower alkoxy-lower alkyl;

R ₂ represents (ii) substituted amino;

(iii) Iower alkoxy or Iower alkoxy-lower alkoxy;

(iv) Iower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl; (v) N-substituted carbamoyl;

(vi) a group selected from -NR^CO-R, -NRι-S0 ₂ -R, -NRι-S0 ₂ -NRι-R, -S0 ₂ -R, -SOz-NR^R, or -S0 ₂ -NRι-CO-R, [R being as defined below and Ri being as defined above, or the group -N(R)(R ) represents amino which is di-substituted by Iower alkylene {which may be interrupted by O or NR ₀ } or which is di-substituted by Iower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

(vii) an element of formula -Xι(X ₂ )(Xs) wherein, (a) if X, is -CH-, X ₂ together with X3 represent a structural element of formula -X ₄ -(CO) _p -(CH ₂ ) ₀ -, or -(CH ₂ ) _s -X ₄ -CO-(CH ₂ )t-; or, (b) if Xi is -N-, X ₂ together with X ₃ represent a structural element of formula -CO-(CH ₂ ) _u -; PC being -CH ₂ -, -N(R,)- or -0-; the integer o is 3-5; the integer p is 0 or 1 ; the integer q is 1 or 2; the integer r is 1 ; the integer s is 1 or 2; the integer t is 1 or 2; the integer u is 3-5; with the proviso that, if the integer p is 0, X4 is different from -CH ₂ -;];

R ₃ and R , independently of one another, represent (i) hydrogen, Iower alkyl, Iower alkenyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

(ii) Iower alkyl which is substituted by a substituent selected from the group consisting of: Iower alkoxy, substituted amino, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, and N-substituted carbamoyl;

R ₃ and R together represent Iower alkylene [which may be interrupted by O, S(0) _n , or NRo];

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethyÏ€ylene, -0-, -S(0)n-, -CO- or- (OR') ₂ -; one of R' being hydrogen or both being each Iower alkyl or being together iower alkylene;

wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, Iower alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, Iower alkoxy, Iower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, Iower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, Iower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano,

(II) Iower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, substituted ammo, carboxy, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(in) Iower alkoxy which is substituted by a substituent selected from the group consisting of halogen, hydroxy, Iower alkoxy, C ₃ -C ₈ -cycioalkyl, (carbocyclic or heterocyclic) aryloxy, ammo, substituted ammo, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(iv) substituted ammo,

(v) Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, (vi) carbamoyl and N-substituted carbamoyl; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryi, aroyl, or aryloxy, respectively, is derived and selected from the group consisting of phenyl, biphenylyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, pyridyl, indolyl, benzofuryl, benzothiophenyl, benzimidazolyl, quinolinyl, isochmolyl, or quinazolmyl, wherein, in each case, the substituted ammo group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by Iower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C ₈ - cycloalkyl-lower aikyl, by (carbocyclic or heterocyclic) aryl, by (caroocyclic or heterocyclic) aryl-lower alkyl, or is (n) di-substituted by Iower alkylene [which may be interrupted by 0, S(0) _n or NRo] or is di-substituted by Iower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (in) mono-substituted or, in the second line, independently of one another, di-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ,

wherein, in each case, the integer n is 0, 1 or 2, wherein, in each case, R ₀ represents hydrogen or Iower alkyl; wherein, in each case, R represents hydrogen, Iower alkyl, (carbocyclic or heterocyclic) aryl-lower alkyl, or Iower alkyl which is substituted by halogen, by hydroxy, or by Iower alkoxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂ , independently of one another, represent a single bond or Iower alkylene;

Ri represents hydrogen or Iower alkyl;

R ₂ represents (II) substituted ammo;

(in) hydroxy, Iower alkoxy or Iower alkoxy-lower alkoxy,

(iv) Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, or (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, (v) N-substituted carbamoyl,

(vi) a group selected from -CH(OH)-R, -CO-R, -NR,-CO-R, - RvSOa-R, - S0 ₂ -R, or -S0 ₂ -NRrCO-R, [R being as defined below and R, being as defined above, or the group -N(R)(Rι) represents ammo which is di-substituted by Iower alkylene {which may be interrupted by O or NR ₀ } or which is di-substituted by Iower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or

R ₃ represents (i) hydrogen, lower alkyl, Iower alkenyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl;

(ii) Iower alkyl which is substituted by a substituent selected from the group consisting of Iower alkoxy, substituted ammo, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, and N-substituted carbamoyl,

R ₄ represents hydrogen,

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, or -CO-, wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, Iower alkyl, C ₃ -C _B -cycloalkyl, C ₃ -C ₈ -cycloalkyl-lower alkyl, Iower alkoxy, Iower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, Iower alkanoyloxy, (carbocyclic or heterocyclic)

aryl-lower alkanoyloxy, Iower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano;

(ii) Iower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, substituted ammo, carboxy, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;

(iii) Iower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, C ₃ -C ₈ -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, ammo, substituted ammo, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl,

(carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl,

(iv) substituted ammo;

(v) Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl;

(vi) carbamoyl and N-substituted carbamoyl; wherein, in each case, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl represents (phenyl-, naphthyl- or pyridyl) -Iower alkoxy-carbonyl; wherein, in each case, (carbocyclic or heterocyclic) aryl-lower alkyl represents phenyl-, naphthyl- or pyridyl-lower alkyl; wherein, in each case, (carbocyclic or heterocyclic) aryl-oxy represents phenoxy, naphthyloxy, or pyÏ€dyloxy, wherein, in each case, (carbocyclic or heterocyclic) aryl-lower alkanoyl represents (phenyl-, naphthyl- or pyÏ€dyl)-lower alkanoyl; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, is derived from phenyl, naphthyl, pyrrolyl, imidazolyl, or pyridyl; wherein, in each case, the substituted ammo group of substituted ammo, of N- substituted carbamoyl, and of N-substituted aminocarbonyl-oxy is (i) mono-substituted or, independently of one another, di-substituted by Iower alkyl, by C ₃ -C ₈ -cycloalkyl, by C ₃ -C _B - cycloalkyl-lower alkyl, by (carbocyclic or heterocyclic) aryl, by (carbocyclic or heterocyclic) aryl-lower alkyl, or is (n) di-substituted by Iower alkylene [which may be interrupted by O, S(0) _n or NR ₀ ] or is di-substituted by Iower alkylene which is condensed at two adjacent carbon atoms with a benzene ring, or is (in) mono-substituted or, in the second line, independently of one another, di-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ;

wherein, in each case, the integer n is 0, 1 or 2; wherein, in each case, R ₀ represents hydrogen or Iower alkyl; wherein, in each case, R represents hydrogen, Iower alkyl, (carbocyclic or heterocyclic) aryl-lower alkyl, or Iower alkyl which is substituted by halogen, by hydroxy, or by Iower alkoxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂ independently of one another, represent a single bond or Iower alkylene;

R, represents hydrogen or Iower alkyl;

R ₂ represents (ii) amino which is mono-substituted by Iower alkyl, phenyl or pyridyl, or which is disubstituted by Iower alkyl or by C ₂ -C ₆ -alkylene;

(iii) hydroxy or Iower alkoxy which is unsubstituted or substituted by C ₃ -C ₈ -cycloalkyl, or by phenyl;

(iv) a group selected from -NR CO-R, -NRι-S0 ₂ -R, -NRι-S0 ₂ -NR R, -S0 ₂ -R, or -S0 ₂ -NR R, [R being Iower alkyl, halo-lower alkyl, phenyl, pyridyl, or naphthyl, Ri being as defined above, or the group -N(R)(Rι) represents amino which is mono-substituted by Iower alkyl, by hydroxy-lower alkyl, or by naphthyl, or which is di-substituted by Iower alkyl or by C ₂ -C ₆ - alkylene {which may be interrupted by O or NR ₀ , R ₀ being hydrogen or Iower alkyl}];

R ₃ represents hydrogen, Iower alkyl or Iower alkyl which is substituted by Iower alkoxy or di-lower alkyl-amino;

R ₄ represents hydrogen;

X represents a single bond, 1 ,2-ethenylene, 1 ,2-ethynylene, -0-, -S(0)n-, or- -CO-; wherein the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, Iower alkyl, Iower alkoxy, hydroxy, hydroxy-lower alkoxy, and Iower alkoxy-lower alkoxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alkÏ„ and alk ₂ , independently of one another, represents a single bond; or C -C ₄ - alkylene;

Ri represents hydrogen or Iower alkyl;

R ₂ represents (ii) ammo which is mono-substituted by lower alkyl, phenyl or pyridyl, or which is disubstituted by lower alkyl or by C ₂ -C ₆ -alkylene;

(in) hydroxy or Iower alkoxy which is unsubstituted or substituted by C ₃ -C ₈ -cycloalkyl, or by phenyl;

(iv) a group selected from -NR^CO-R, -NR S0 ₂ -R, -NRι-S0 ₂ -NRrR, -S0 ₂ -R, or -S0 ₂ -NR R, [R being Iower alkyl, halo-lower alkyl, phenyl, pyridyl, or naphthyl, R _T being as defined above, or the group -N(R)(Rι) represents ammo which is mono-substituted by Iower alkyl, by hydroxy-lower alkyl, or by naphthyl, or which is di-substituted by Iower alkyl or by C ₂ -C ₆ - alkylene {which may be interrupted by O or NR ₀ , R ₀ being hydrogen or Iower alkyl}];

R ₃ represents hydrogen, Iower alkyl, C ₃ -C ₃ -cyc!oalkyl, C ₃ -C ₃ -cycloalkyl-lower alkyl, phenyl-lower alkyl, Iower alkyl which substituted by lower alkoxy or di-lower alkylamino, or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, Iower alkyl, Iower alkoxy, and oxy-lower alkylene-oxy;

R ₄ represents hydrogen;

X represents a single bond, 1 ,2-ethenylene, or -CO-; wherein the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, Iower alkyl, Iower alkoxy, hydroxy, hydroxy-lower alkoxy, and Iower alkoxy-lower alkoxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk and alk ₂ , independently of one another, represents a single bond; or d-C ₄ - alkyiene;

R, represents hydrogen;

R ₂ represents (i) hydrogen, halogen, cyano, Iower alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ - cycloalkyl-lower alkyl, phenyl-lower alkyl, phenyl, pyrrolyl, or imidazolyl; (II) ammo, ammo which is mono-substituted by C ₃ -C ₆ -cycloaikyl, am o which is disubstituted by Iower alkyl or by C ₄ -C ₆ -alkylene or ammo which is mono-substituted by -CO-(0) _v -R and the integer v is 0 or 1 ; (in) a group selected from -NRι-S0 ₂ -R, R being Iower phenyl or naphthyl,

R ₃ represents hydrogen, C ₃ -C ₆ -cycloalkyl-lower alkyl, phenyl-lower alkyl, Iower alkyl which substituted by di-lower alkylamino, C ₃ -C ₆ -cycloalkyl, or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, Iower alkyl, Iower alkoxy, and oxy-lower alkylene-oxy;

R ₄ represents hydrogen;

X represents a single bond or -0-; wherein any aryl moiety, if not designated otherwise and the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, Iower alkyl, Iower alkoxy, and oxy-lower alkylene-oxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂ , independently of one another, represent C -C ₄ -alkylene;

R represents hydrogen;

R ₂ represents am o which is disubstituted by by C ₂ -C ₆ -alkylene, especially pentylene, or Ci-d-alkoxy, especially methoxy; or a group selected from -NH-S0 ₂ -R , -S0 ₂ -R, or -S0 ₂ - NH-R, [R being Cι-C ₄ -alkyl, or naphthyl, or the group -NH(R) represents ammo which is mono-substituted by d-C -alkyl, by hydroxy-Cι-C -alkyl, or by naphthyl, or which is di¬ substituted by Cι-C ₄ -alkyl or by C ₂ -C ₆ -alkylene {which may be interrupted by O or NR ₀ , Ro being hydrogen or Cι-C ₄ -alkyl}]; and, in each case,

R ₃ represents hydrogen, Iower alkyl, or Iower alkyl which is substituted by Iower alkoxy or by di-lower alkylamino; and

R ₄ represents hydrogen,

X represents a single bond or 1 ,2-ethenylene; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ represent C ₂ -C ₄ -aikylene,

R ₂ represents (i) phenyl which is substituted by halogen, especially 4-halo-phenyl, or pyrrolyl, especially 1 -pyrrolyl or (n) -NH-S0 ₂ -R and R being naphthyl; and, in each case,

Ri represents hydrogen,

R ₃ represents hydrogen; R represents hydrogen; and X represents a single bond; wherein the benzo ring A is unsubstituted or substituted by Cι-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazolme ring.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ , independently of one another, represent C ₂ -C ₄ -alkylene;

Ri represents hydrogen;

R ₂ represents a group -NH-S0 ₂ -R or -NH-S0 ₂ -N(R)(R ₁ )[R being Cι-C ₄ -alkyl, or naphthyl, or the group -N(R)(R ₁ ) represents ammo which is mono-substituted by Cι-C -alkyl, by phenyl, or by naphthyl, or which is di-substituted by Cι-C ₄ -alkyl or by C ₂ -C ₆ -alkylene {which may be interrupted by NR ₀ , R ₀ being d-C -alkyl}]; and, in each case,

R ₃ represents hydrogen, Iower alkyl or Iower alkyl which is substituted by loewr alkoxy or di-lower alkylamino; and

R represents hydrogen;

X represents a single bond or 1 ,2-ethenylene; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy.

The invention relates especially to a new a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ represent C ₂ -C ₄ -alkylene;

R ₂ represents -S0 ₂ -R or -S0 ₂ -NH-R and R being Cι-C ₄ -alkyl, especially methyl, or naphthyl; and, in each case,

Ri represents hydrogen;

R ₃ represents hydrogen;

R ₄ represents hydrogen; and

X represents a single bond or ethenylene; wherein the benzo ring A is unsubstituted or substituted by Cι-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazolme ring.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk, and alk ₂ represent C ₂ -C ₄ -alkylene;

R ₂ represents (i) phenyl which is substituted by halogen, especially 4-halo-phenyl, or pyrrolyl, especially 1 -pyrrolyl or (ii) -NH-S0 ₂ -R and R being naphthyl; and, in each case,

Ri represents hydrogen;

R ₃ represents hydrogen;

R ₄ represents hydrogen; and

X represents a single bond; wherein the benzo ring A is unsubstituted or substituted by Cι-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki and alk ₂ represent C ₂ -C ₄ -alkylene;

R ₂ represents phenyl which is substituted by halogen, especially 4-chloro-phenyl, or pyrrolyl, especially 1 -pyrrolyl; and, in each case,

Ri represents hydrogen;

R ₃ represents hydrogen;

R represents hydrogen; and

X represents a single bond; wherein the benzo ring A is unsubstituted or substituted by d-C ₄ -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.

The invention relates especially to a new compound of formula (I) or a pharmaceutically acceptable salt thereof in which alki represents ethylene; alk ₂ represent C ₂ -C ₃ -alkylene;

R represents -S0 ₂ -NH-R and R being Ï€aphthyi, especially 1 - or 2-naphthyl;

Ri represents hydrogen;

R ₃ represents hydrogen;

R ₄ represents hydrogen; and

X represents a single bond;

wherein the benzo ring A is unsubstituted or substituted by Cι-C -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.

The invention relates in particular to the novel compounds shown in the examples and to the modes of preparation described therein.

The invention relates to processes for the preparation of the compounds according to the invention. The preparation of new compounds of the formula (I) and their salts comprises, for example, (a) reacting a compound of formula (lla) or a salt thereof

in which Z , represents a leaving group, with a compound of formula (Mb) or a salt thereof

(lib) or

(b) reacting a compound of formula (Ilia) or a salt thereof

in which Z ₂ is a leaving group with a compound of formula HN(R ₃ )(R ₄ ) (lllb) or a salt thereof,

and, if desired, converting a compound I obtainable according to the process or in another manner, in free form or in salt form, into another compound I, separating a mixture of isomers obtainable according to the process and isolating the desired isomer and/or converting a free compound I obtainable according to the

process into a salt or converting a salt of a compound I obtainable according to the process into the free compound I or into another salt.

The reactions described above and below in the variants are carried out in a manner known per se, for example in the absence or, customarily, in the presence of a suitable solvent or diluent or a mixture thereof, the reaction, as required, being carried out with cooling, at room temperature or with warming, for example in a temperature range from about -80°C up to the boiling point of the reaction medium, preferably from about -10° to about +200°C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions. The person skilled in the pertinent art is especially referred to the methods as outlined in the working examples based upon which the person skilled in the art is enabled to carry out the manufacture of the compounds of formula (I).

Salts of starting materials which have at least one basic centre, for example of the formula lllb, are appropriate acid addition salts, while salts of starting materials which have an acidic group, for example of the formula (Mb), are present as salts with bases, in each case as mentioned above in connection with corresponding salts of the formula I.

A leaving group Zi or Z ₂ , respectively, is, for example, reactive esterified hydroxy, or is R'-S(0) _p - [the integer u being 0, 1 or 2 and R' being Iower alkyl, halo-lower alkyl or aryl, such as methyl, trifluoromethyl or p-toluyl], or is Iower alkoxy. Reactive esterified hydroxyl Z4 is in particular hydroxyl esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyioxy, C -d,-alkane-sulfonyloxy which is unsubstituted or substituted, for example by halogen, for example methane- or trifluoromethanesulfonyloxy, C ₅ -C ₇ cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or benzenesulfonyloxy which is unsubstituted or substituted, for example by C^C alkyl or halogen, for example p-brorÏ€obenzene- or p-toluenesulfonyloxy. Preferred Z1 or Z ₂ is chloro, bromo or iodo, methanesulfonyloxy or trifluoromethanesulfonyloxy, or p-toluenesulfonyloxy, or

methylthio or methoxy

The reactions of process variants (a) and (b) are carried out, if necessary, in the presence of a base. Suitable bases are, for example, alkaii metal hydroxides, hydrides, amides, alkanolates, carbonates, tπphenylmethylides, di-lower alkylamides, aminoalkylamides or Iower alkylsilylamides, naphthaleneamines, Iower alkylammes, basic heterocycles, ammonium hydroxides, and carbocyclic amines. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium tert- butoxide, potassium carbonate, lithium tπphenylmethylide, lithium diisopropylamide, potassium 3-(amιnopropyl)amιde, potassium bts(trιmethylsilyl)amιde, dimethylaminonaphthalene, di- or triethylamine, or ethyldnsopropylamine, N-methylpipeπdine, pyridine, benzyltπmethylammonium hydroxide, 1 ,5-dιazabιcyclo[4.3.0]non-5-ene (DBN) and 1 ,8-dιaza- bιcyclo[5.4.0]undec-7-ene (DBU)

The starting material of fomulae (lla), (lib), (Ilia), and (lllb) is essentially known or is accessible analogously to preparation processes known per se

Starting material of the formula (lla) is, for example, described, for example, in US Patent No 5,064,833

The starting material of formula (lib) in which R ₂ represents N-acylated or N- alkylated ammo, such as a group of formula -NR CO-0-R, -NR CO-R, -NR ₁ -CO- NR ₁ -R, -NRι-S0 ₂ -R,-NR S0 ₂ -NRι-R, or N-substituted ammo, is accessible, for example, by N-acylatmg or by N-alkylatmg, respectively, a, preferably N- protected, compound of the formula NH(R ₁ )-alkι-X-alk ₂ -Z ₃ (He) in which Z ₃ represents a group which is convertable to R ₂ , such as ammo, carboxy, or hydroxy Conventional protecting groups may be used, for example, t- butoxycarbonyl which will be splitt off after the N-acylation or the N-alkylation, respectively The starting material of formula (lib) in which R ₂ represents carbamoyl or N-substituted carbamoyl, or esterified carboxy, can be manufactured starting from a compound of formula (He) in which Z ₃ represents carboxy The esteÏ€fication or amidation can be carried out in a manner known per

se. Starting fom a compound of formula (He) in which Z ₃ is hydroxy, corresponding etherified or esterified deÏ€vatices are accessible using etherification or esteÏ€faction methods known in the art

The starting material of formula (Ilia) is accessible, for example, by selectively converting the 4-Z _? -group into a group which is desactivated, for example, by selectively hydrolyz g a compound of formula (lllc)

or a salt thereof to form a corresponding 4-hydroxy-compound which is in the next step reacted with a compound of formula (lib) to introduce the correspondmg side chain into position 2 of the qumazolm ring. Reactivation of the 4-posιtιon, for example, by reaction with a halogenatmg agent, such as POCI ₃ , leads to corresponding compounds of formula (Ilia)

The invention likewise relates to pharmaceutical preparations which contain the compounds according to the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for their preparation

The pharmaceutical preparations according to the invention which contain the compound according to the invention or pharmaceutically acceptable salts thereof are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded anιmal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier The daily dose of the active ingredient depends on the age and the individual condition and also on the manner of administration

The novel pharmaceutical preparations contain, for example, from about 10 % to about 80%, preferably from about 20 % to about 60 %, of the active ingredient Pharmaceutical preparations according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated

tablets, tablets, capsules or suppositories, and furthermore ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate; auxiliaries are primarily glidants, flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may be added to the tablets or sugar-coated tablet coatings.

Other orally utilizable pharmaceutical preparations are hard gelatin capsules, and also soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules may contain the active ingredient in the form of granules, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or

suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible to add stabilizers.

Suitable rectally utilizable pharmaceutical preparations are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules which contain a combination of the active ingredient with a base substance may also be used. Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water- soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers.

The dose of the active ingredient depends on the warm-blooded animal species, the age and the individual condition and on the manner of administration. In the normal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated in the case of oral administration for a patient weighing approximately 75 kg .

The following examples illustrate the invention described above; however, they are not intended to limit its extent in any manner. Temperatures are indicated in degrees Celsius.

Solvent systems (v/v/v):

A 1 : 1 :1 hexanes/ethylacetate

A2: 2:1 hexanes/ethylacetate

A3 90:10: 1 dichloromethane / methanol / ammonium hydroxide A4 80:20: 4 dichloromethane / methanol / ammonium hydroxide A5 180:20:2:1 dichloromethane / methanol / water / acetic acid B1 9:1 dichloromethane/methanol B2 10:1 toluene / ethyl acetate C1 90:10:1 dichloromethane/methanol/ammonium hydroxide C2 80:20:2 dichloromethane/methanol/ammonium hydroxide C3 2:1 hexanes / ethyl acetate C4 1 :1 hexanes / ethyl acetate D1 6:3:1 ethyl acetate / ethanol / ammonium hydroxide E1 9:1 ethyl acetate / methanol

Abbreviations:

HCl hydrochloric acid ml milliliter

NaOH sodium hydroxide

RaNi Raney Nickel

Pd/C Palladiunm on charcoal min minute(s) h hour(s) m.p. melting point

ESI-MS: electro-spray ionization mass spectroscopy

FAB-MS Fast Atom Bombardment Mass Spectroscopy

Rf retention factor on a thin layer chromatography plate

Example 1 : Naphthalene-1 -sulfonic acid [7-(4-amino-guinazolin-2-ylamino)-heptyll-amide hydrochloride

A solution of 0.298 g of naphthalene-1 -sulfonic acid (7-amino-heptyl)-amide and 0.167 g of 2-chloro-quinazoiin-4-ylamine (see: US 3,956,495) in 16 ml of isopentylalcohol is heated up

to 120 °C for 15 hours. Concentration of the reaction mixture followed by chromatography on silica gel (B1) gives 0.192 g of product, which is taken up in dichloromethane and treated at 0 °C with 3 ml of a 4 N HCl solution in dioxane. After concentration in vacuo, naphthalene-1 -sulfonic acid [7-(4-amino-quinazolin-2-ylamino)-heptyl]-amide is obtained as its hydrochloride salt, melting at 100-1 10 °C. Rf(B1) 0.27; FAB-MS: (M+H) ⁺ = 464.

a) [7-(Naphthalene-1-sulfonylamino)-heptyl1-carbamic acid te/f-butyl ester

A solution of naphthalene-1 -sulfonylchloride (3.00 g) and diisopropylethylamine (4.53 ml) in 80 ml of acetonitrile is cooled to 0 °C and treated with (7-amino-heptyl)-carbamic acid tert- butyl ester (3.04 g) in acetonitrile (20 ml). The reaction mixture is stirred at ambient temperature until completion of the reaction. The solution is concentrated and the residue is partitioned between dichloromethane and water. The organics are dried over magnesium sulfate and concentrated to an oil. Chromatography on silica gel (A2) provides [7- (naphthalene-1-sulfonylamino)-heptyl]-carbamic acid fert-butyl ester as a white powder and melting at 79-81 °C. Rf(A2) 0.32.

b) Naphthalene-1 -sulfonic acid (7-amino-heptyl)-amide

A solution of [7-(naphthalene-1 -sulfonylamino)-heptyl]-carbamic acid te/f-butyl ester (4.70 g) in dichloromethane (30 ml) is treated at 0 °C by slow addition of a 4 N HCl solution in dioxane (30 ml). Under completion, the reaction mixture is concentrated in vacuo, the residue is taken up in a 1 N sodium hydroxide solution and is extracted with dichloromethane. The organics are dried over magnesium sulfate and concentrated to yield naphthalene- 1 -sulfonic acid (7-amino-heptyl)-amide as a white powder and melting at 67-68 °C. Rf(C1 ) 0.26.

Example 2: Naphthalene- 1 -sulfonic acid [8-(4-amino-quinazolin-2-ylamino)-octyl)-amide

A solution of naphthalene-1 -sulfonic acid (8-amino-octy!)-amide (0.334 g) and 2-chloro- quinazolin-4-ylamine (0.180 g) in 20 ml of isopentylalcohol is heated up to 120 °C for 15

hours. Concentration of the reaction mixture followed by chromatography on silica gel (B1) gives naphthalene-1 -sulfonic acid [8-(4-amino-quinazolin-2-ylamino)-octyl]-amide as a yellow powder and melting at 80-85 °C. Rf(Bl ) 0.24; FAB-MS: (M+H) ⁺ = 478.

a) [8-(Naphthalene-1-sulfonylamino)-octyl]-carbamic acid tert-butyl ester

Following the procedure described in Example 1 a, (8-amino-octyl)-carbamic acid tert-butyl ester (3.00 g) and naphthalene- 1 -sulfonylchloride (4.1 7 g) are converted to [8- (naphthalene-1-sulfonylamino)-octyl]-carbamic acid tert-butyl ester as an oil. Rf(A2) 0.27.

b) Naphthalene-1 -sulfonic acid (8-amino-octyl)-amide [8-(Naphthalene-1-sulfonylamino)-octyl]-carbamic acid tert-butyl ester (4.55 g) is converted according to Example 1 b to naphthalene-1 -sulfonic acid (8-amino-octyl)-amide as a brown oil. Rf(C2) 0.29.

Example 3: Naphthalene-1 -sulfonic acid [6-(4-amino-guinazolin-2-ylamino)-hexyl]-amide

Following the procedure described in Example 2, naphthalene-1 -sulfonic acid (6-amino- hexyl)-amide (0.450 g) and 2-chloro-quinazolin-4-ylamine (0.264 g) yield naphthaleÏ€e-1 - sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hexyl]-amide as a white powder, melting at 98-101 °C. Rf(B1) 0.28; FAB-MS: (M+H) ⁺ = 450.

Example 4: Naphthalene-2-sulfonic acid f6-(4-amino-quinazolin-2-ylamino)-hexyl]-amide

Following the procedure described in Example 2, naphthalene-2-sulfonιc acid (6-amιno- hexyl)-amιde (0.350 g) and 2-chloro-quinazo n-4-ylamιne (0.205 g) yield naphthalene-2-

sulfonic acid [6-(4-amιno-quιnazolιn-2-ylamιno)-hexyl]-amιde as a white powder, melting at 93-96 °C Rf(B1 ) 0.18; FAB-MS: (M+H) ⁺ = 450.

Example 5 Naphthalene-2-sulfonιc acid f8-(4-amιno-guιnazolin-2-ylamιno)-octyll-amιde hydrochoπde

Following the procedure described in Example 1 , naphthaleπe-2-sulfonιc acid (8-amιno- octyl)-amιde (0.350 g) and 2-chloro-quιnazolιn-4-ylamme (0.188 g) yield naphthalene-2- sulfonic acid [8-(4-amιno-quιnazolιn-2-ylamιno)-octyl]-amιde hydrochoπde melting at 80-86

°C. Rf(B1) 0.22, FAB-MS: (M+H) ⁺ = 478

a) f8-(Naphthalene-2-sulfonylamιno)-octyll-carbamιc acid tert-butyl ester

Following the procedure described in Example 1a, (8-amιno-octyl)-carbamιc acid tert-butyl ester (3 00 g) and naphthalene-2-sulfonylchlorιde (4 17 g) are converted to [8- (naphthalene-2-sulfonylamιno)-octyl]-carbamιc acid tert-butyl ester melting at 91 -92 °C Rf(A2) 0 20

b) Naphthalene-2-sulfonιc acid (8-amιno-octyl)-amιde [8-(Naphthalene-2-sulfonylamιno)-octyl]-carbamιc acid tert-butyl ester (5.00 g) is converted according to Example 1 b to naphthaiene-2-sulfonιc acid (8-amιno-octyl)-amιde as a tan powder melting at 70-71 °C Rf(C1 ) 0.07

Example 6: Naphthalene-2-sulfonιc acid [7-(4-amιno-quιnazolιn-2-ylamιno)-heptyll-amιde hydrochloride

HCl

Following the procedure described in Example 1 , naphthalene-2-sulfonic acid (8-amino- octyl)-amide (0.300 g) and 2-chloro-quinazolin-4-ylamine (0.168 g) yield naphthalene-2- sulfonic acid [7-(4-amino-quinazolin-2-ylamino)-heptyl]-amide hydrochloride melting at 88-96 °C. Rf(B1) 0.22; FAB-MS: (M+H) ⁺ = 464.

a) [7-(Naphthalene-2-sulfonylamino)-heptyll-carbamic acid tert-butyl ester

Following the procedure described in Example 1 a, (7-amino-heptyl)-carbamic acid tert-butyl ester (2.03 g) and 2-naphthalene sulfonylchloride (2.00 g) are converted to [7- (naphthalene-2-sulfonylamino)-heptyl]-carbamic acid tert-butyl ester melting at 62-63 °C. Rf(A1) 0.42.

b) Naphthalene-2-sulfonic acid (7-amino-heptyl)-amide [7-(Naphthalene-2-sulfonylamino)-heptyl]-carbamic acid tert-butyl ester (2.07 g) is converted according to Example 1 b to naphthalene-2-sulfonic acid (7-amino-heptyl)-amide melting at 81 -84 °C . Rf(Cl) 0.07.

Example 7: In a manner analogous to that described hereinbefore it is also possible to manufacture following compounds:

Naphthalene-1 -sulfonic acid [5-(4-amino-quinazolin-2-ylamino)-3,3-dimethyl-pentyl]-amide ; naphthalene-1 -sulfonic acid {3-{1 -[3-(4-amino-quinazolin-2-ylamino)-propyl]-cyclopentyl}- propyl}-amide; naphthalene-1 -sulfonic acid {5-[1 -(4-amino-quinazolin-2-ylamino)-cyclopentyl}-pentyl}- amide; naphthalene-1 -sulfonic acid [6-(4-amino-quinazo!in-2-ylamino)-6-methyl-heptyl]-amide; trans-naphthalene- 1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hex-3-enyl]-amide; c/s-naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hex-3-enyl]-amide; naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hex-3-ynyl]-amide; naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-5-methoxy-hexy!]-amide; naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-7-methoxy-heptyl]-amide; naphthalene-1 -sulfonic acid [5-(4-amino-quinazolin-2-ylamino)-3,3-dimethyl-pentyl]-amide ; naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-6-methyl-heptyl]-amide; naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hex-3-ynyl]-amide; c/s-Naphthalene-1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hex-3-eπyl]-amide;

trans-naphthalene- 1 -sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hex-3-enyl]-amide; naphthalene-1 -sulfonic acid [7-(4-amino-quinazolin-2-ylamino)-4,4-dimethyl-heptyl]-amide ; trans-naphthalene- 1 -sulfonic acid [8-(4-amino-quinazolin-2-ylamino)-oct-4-enyl]-amide; benzenesulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hexyl]-amide;

N-[6-(4-amino-quinazolin-2-yl-amino)-hexyl]-(N,N-dimethyl amino)-sulfonamide;

N-[6-(4-amino-quinazolin-2-yl-amino)-hexyl]-(piperidin1-y l)-sulfonamide;

N-[6-(4-amino-quinazolin-2-yl-amino)-hexyl]-(4-methyl-pip erazin-1 -yl)-sulfonamide;

N-[6-(4-amino-quinazolin-2-yl-amino)-hexyl]-(N-methylamin o)-sulfonamide; naphthalene-1 -sulfonic acid [6-(4-amino-8-methoxy-quinazolin-2-ylamino)-hexyl]-amide; naphthalene-2-sulfonic acid [6-(4-amino-8-methoxy-quinazolin-2-ylamino)-hexyl]-amide;

N-[6-(4-amino-8-methoxy-quinazolin-2-yl-amino)-hexyl]-(N, N-dimethylamino)-sulfonamide;

N-[6-(4-amino-8-methoxy-quinazolin-2-yl-amino)-hexyl]-(pi peridin1-yl)-sulfonamide; naphthalene-1 -sulfonic acid {6-[4-(2-methoxy-ethylamino)-quinazolin-2-yl-amino]-hexyl}- amide; naphthalene-1 -sulfonic acid {6-[4-(2-dimethylamino-ethylamino)-quinazolin-2-yl-amino]- hexyl}-amide; naphthalene-1 -sulfonic acid [6-(4-methylamino-quinazolin-2-yl-amino)-hexyl]-amide; naphthalene-1 -sulfonic acid [6-(4-dimethylamino-quinazolin-2-yl-amino)-hexyl]-amide; naphthalene-1 -sulfonic acid [6-(4-methylamino-8-methoxy-quinazolin-2-yl-amino)-hexyl]- amide; naphthalene-1 -sulfonic acid {6-[4-(2-dimethylamino-ethylamino)-8-methoxy-quinazolin-2-yl - amino]-hexyl}-amide; naphthalene-2-sulfonic acid [6-(4-amino-quinazolin-2-ylamino)-hexyl]-methyl-amide; naphthalene-1 -sulfonic acid {6-[(4-methylamino-quinazolin-2-yl)-methyl-amino]-hexyl}- amide; naphthalene-1 -sulfonic acid {6-[(4-amino-8-methoxy-quinazolin-2-yl)-methyl-amino]-hexyl} - amide.

Example 8: Naphthalene-1 -sulfonic acid {6-[4-(3-diethylamino-propylamino)-ouinazolin-2- ylamino]-hexyl}-amide hydrochloride

A solution of N(2)-(6-amino-hexyl)-N(4)-(3-diethylamino-propyl)-quinazolin e-2,4-diamine (0.47 g) and diisopropylethylamine (0.22 ml) in acetonitrile (8 ml) at 0 °C is treated with 1 - naphthalene-sulfonylchloride (0.115 g) in acetonitrile (2 ml). Upon completion, the reaction mixture is concentrated, the residue is partitioned between dichloromethane and brine. The organic phase is dried over sodium sulfate, concentrated and chromatographed (silica gel, C1). Treatment of the resulting material in dichloromethane (10 ml) at 0 °C with 4N HCl in dioxane (2 ml) followed by evaporation of the solvent gives naphthalene-1 -sulfonic acid {6- [4-(3-diethylamino-propylamino)-quinazolin-2-ylamino]-hexyl} -amide hydrochloride as a foam. Rf(C1) 0.43; ESI-MS: (M+H)+= 563.

The starting material can be prepared, for example, as follows:

a) N-(2-Chloro-guinazolin-4-yl)-N',N'-diethyl-propane-1 ,3-diamine hydrochloride

A suspension of 2,4-dichloro-quinazoline (30 g) in isopropanol (200 ml) is treated by dropwise addition of a solution of N,N-diethyl-1 ,3-diaminopropane (26.1 ml) in isopropanol (50 mi) in an exothermic reaction. The reaction mixture is concentrated in vacuo and the residue is stirred overnight in isopropylether/isopropanol. The resulting suspension is collected by filtration and dried in vacuo to give N-(2-chloro-quinazoliπ-4-yl)-N',N'-diethyl- propane-1 ,3-diamine hydrochloride as a powder melting at 163-164 °C. Rf(Cl) 0.32.

b) {6-[4-(3-Diethylamino-propylamino)-quinazolin-2-ylamino]-hex ylV-carbamic acid tert-butyl ester

A mixture of N-(2-chloro-quinazolin-4-yl)-N',N'-diethyl-propane-1 ,3-diamine hydrochloride (2.24 g), N-tert.-butoxy-carbonyl-1 ,6-diamino-hexane (1.47 g), diisopropylethylamine (3.5 ml) and phenol (9.6 g) is heated to 150 °C for 3 h to produce a melt. The reaction mixture is taken up in dichloromethane, washed with a 1 N aqueous NaOH solution, brine and dried over sodium sulfate. Concentration in vacuo followed by chromatography (silica gel, C1)

gives {6-[4-(3-dιethylamιno-propylamιno)-quιnazolιn-2-ylammo] -hexyl}-carbamιc acid tert.- butyl ester as an oil Rf(C2) 0.69, ESI-MS: (M+H)+= 473

c) N(2)-(6-Ammo-hexyl)-N(4)-(3-dιethylamιno-propyl)-guιnazol ιne-2,4-dιamιne A solution of {6-[4-(3-dιethylamιno-propylamιno)-quιnazolιn-2-ylamιn o]-hexyl}-carbamιc acid tert.-butyl ester (0.2 g) in dichloromethane (10 ml) is cooled to 0 °C and treated by slow addition of trifluoroacetic acid (10 ml). Upon completion of the reaction, the solution is concentrated in vacuo and the residue is chromatographed (silica gel, C2) to give N(2)-(6- amιno-hexyl)-N(4)-(3-dιethylamιno-propyl)-quιnazolιne-2 ,4-diamιne as an oil Rf(C2) 0.29; ESI-MS: (M+H) ⁺ = 373

Example 9- Naphthalene-1 -sulfonic acid f6-(4-amιno-6-bromo-qumazolιn-2-ylamιπo)-hexyl]- amide hydrochloride

Following the procedure described in Example 2; 6-bromo-2-chloro-quιnazolιn-4-yl-amιne (prepared as described in Khim.-Farm. Zh. 1987, 21, 802) (0.259 g) and naphthalene-1- sulfonic acid (6-amιno-hexyl)-amιde (0.355 g) yields naphthalene-1 -sulfonic acid [6-(4- amιno-6-bromo-quιnazolιn-2-ylammo)-hexyl]-amιde hydrochloride as an amorphous solid: Rf(A5) 0.42; FAB-MS: (M+H)+ = 528.

Example 10: N-(3-{2-f4-(Cvclopropylmethyl-amιno)-guιnazolιn-2-ylamιn ol-ethoxyy-propyl)-4- fluoro-benzenesulfonylamide

A solution of 4-cyclopropylmethylamιno-2-chloroquιnazolιne (0.862 g), N-[3-(2-amιno- ethoxy)-propyl]-4-fluoro-benzenesulfonamιde trifluoroacetic acid salt (1 44 g) and diisopropylethylamine (1.89 ml) in isopentanol (20 ml) is stirred at 120 °C for 19 h The solvent is removed under reduced pressure and the residue is added to 1 N aqueous NaOH and extracted with dichloromethane The combined extracts are dried over sodium sulfate, concentrated in vacuo and chromatographed to give N-(3-{2-[4-(cyclopropylmethyl-amιno)-

quinazolin-2-ylamino]-ethoxy}-propyl)-4-fluoro-benzenesulfon ylamide as amorphous solid: Rf(B2) 0.41 ; ESI-MS: (M+H) ⁺ = 474.

The starting material can be prepared, for example, as follows:

a) Toluene-4-sulfonic acid 2-(2-tert.-butoxycarbonylamino-ethoxy)-ethyl ester

To a stirred solution of [2-(2-hydroxy-ethoxy)-ethyl]-carbamic acid tert-butyl ester (CAS No.139115-91 -6) (93.7 g) and triethylamine (74.21 ml) in dichloromethane (200 ml) is added a solution of p-toluenesulfonyl chloride (88.82 g) in dichloromethane (250 ml) at 5 °C. The mixture is stirred at 0 °C for 6 h. After addition of tert.-butylethylether the triethylamine hydrochloride is removed by filtration. The filtrate is washed with 0.5N aqueous HCl solution, aqueous sodium hydrogen carbonate solution and brine. The organic layer is dried over sodium sulfate and concentrated in vacuo to give toluene-4-sulfonic acid 2-(2- tert-butoxycarbonylamino-ethoxy)-ethyl ester as a colorless oil: Rf (C3) 0.26.

b) [2-(3-Cvano-propoxy)-ethvn-carbamic acid tert-butyl ester

A suspension of toluene-4-sulfonic acid 2-(2-tert-butoxycarbonylamino-ethoxy)-ethyl ester (61.31 g) and sodium cyanide (25.08 g) in N,N-dimethylformamide (200 ml) is stirred at 50 °C for 4h. N,N-dimethylformamide is removed under reduced pressure. To the residue is added water and the mixture is extracted with tert.-butyi methyl ether. The combined extracts are washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography to give [2-(3-cyano-propoxy)-ethyl]-carbamic acid tert-butyl ester as an oil: Rf(C3) 0.19; ESI-MS: (M+H)+=215.

c) [2-(3-Amino-propoxy)-ethyll-carbamic acid tert-butyl ester

A solution of [2-(3-cyano-propoxy)-ethyl]-carbamic acid tert-butyl ester (11.7 g) in ethanol containing 5% ammonia (200 ml) is stirred in the presence of RaNi (3 g) under hydrogen for 3h. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography to give [2-(3-amιno-propoxy)- ethyl]-carbamic acid tert-butyl ester as an oil: Rf (A4) 0.45; ESI-MS: (M+H) ⁺ =219.

d) {2-f3-(4-Fluoro-benzenesulfonylamino)-propoxyl-ethyl}-carbam ic acid tert-butyl ester

A solution of [2-(3-amino-propoxy)-ethyl]-carbamic acid tert-butyl ester (1.68 g), diiso¬ propylethylamine (2.63 ml) and p-fluorobenzensulfonyl chloride (1.65 g) in dichloromethane (35 ml) is stirred at 0 °C for 90 min. To the reaction is added water and the mixture is extracted with dichloromethane. The combined extracts are washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash chromatography to give {2-[3-(4-fluoro-benzenesulfonylamino)- propoxy]-ethyl]-carbamic acid tert-butyl ester as an oil: Rf (A1) 0.45; ESI-MS: (M+H) ⁺ =377.

e) N-f3-(2-Amino-ethoxy)-propyll-4-fluoro-benzenesulfonamide trifluoroacetic acid To a solution of {2-[3-(4-fluoro-benzenesulfonylamino)-propoxy]-ethyl}-carbam ic acid tert- butyl ester (2.45 g) in dichloromethane (20 ml) is added trifluoroacetic acid (5 ml) at 0 °C. After stirring at 0 °C for 3h, the solvent is removed under reduced pressure to obtain N-[3- (2-amino-ethoxy)-propyl]-4-fluoro-benzenesulfonamide trifluoroacetic acid as an amorphous solid: Rf(A1) 0.11.

Example 1 1 : 4-(4-Chloro-phenylamino)-2-[3-(N-pyrrolo)-propyl-1-amino1-8- methoxy- quinazolme hydrochloride

2-Chloro-4-(4-chloro-phenylamino)-8-methoxy-quinazoline hydrochloride (0.64 g) and 3-(N- pyrrolo)-propylamine (prepared as described in J. Heterocycl. Chem. 1976, 13, 711 ) (0.33 g) is heated for 0.5 min to produce a melt which is dissolved in isopropanol. The salt of the product is obtained upon addition of a slight excess of 4 N HCl in dioxane. Recrystallization from an isopropanol acetone mixture yields 4-(4-chloro-phenylamino)-2-[3-(N-pyrrolo)- propyl-1 -amino]-8-methoxy-quinazoline hydrochloride, m.p. 247-249 °C.

The starting material can be prepared, for example, as follows:

a) 2-Chloro-8-methoxy-4-(4-chloro-phenylamino)-guinazolιne hydrochloride

A solution of 2,4-dichloro-8-methoxy-guinazo!ine (2.3 g), diisopropyl-ethylamine (5.0 ml) and

4-chloro-aniiine (1.5 g) in isopropanol (20 ml) is heated to reflux for 1 h. The cold reaction

mixture is concentrated in vacuo and crystallized from diethyl ether to give 2-chloro-8- methoxy-4-(4-chloro-phenylamino)-quinazolιne hydrochloride, m.p. 261-262 °C.

b) 2,4-Dιchloro-8-methoxy-guinazolιne

N,N-Dimethylaniline (0.36 ml) is added slowly to a solution of 8-methoxy-1 H,3H-quιnazolin- 2,4-dιone (prepared as described in J. Chem. Soc. 1921 , 1425) (1.20 g) in phosphorousoxychloride (3.70 ml) while this mixture is heated up to 125 °C. Refluxing is continued for 10 h after the completion of the addition. Evaporation of the solvent in vacuo gives a residue which is added to ice and water Extraction with ethylacetate yields 2,4- dιchloro-8-methoxy-quιnazolιne, Rf(C4) 0.64

Example 12: 4-(4-Chloro-phenylamιno)-2-[3-(N-ιmιdazolo)-propyl-1 -amino1-guiπazoline hydrochloride

2-Chloro-4-(4-chloro-phenylamino)-quinazoline hydrochloride (0.765 g) and 3-(N-ιmidazolo)- propylamme (0.36 ml) is heated for 3 min to produce a melt which is dissolved in isopropanol. The salt of the product is obtained upon addition of a slight excess of 4N HCl in dioxane. Recrystallization from an isopropanol acetone mixture yields 4-(4-chloro- phenylammo)-2-[3-(N-imidazolo)-propyl-1 -ammo]-quιπazolιne hydrochloride, Rf(D1) 0.66.

The starting material can be prepared, for example, as follows'

a) 2-Chloro-4-(4-chloro-phenylamιno)-quιnazolιne

A solution of 2,4-dichloro-quιnazoline (19.9 g), diisopropylethylamine (50 ml) and 4-chloro- anilme (14.0 g) in isopropanol (200 ml) is heated to 80 °C for 1 h. The reaction mixture is concentrated in vacuo. The residue is chromatographed (silica gel, A2) to yield after crystallization from ethanol ether 2-chloro-4-(4-chloro-phenylamιno)-quιnazolιne: m.p. 170- 171 °C, Rf(A1 ) 0.83

b) 2,4-Dιchloro-quιnazolιne

N.N-Dimethylaniline (1 14.0 g) is added slowly to a solution of 1 H,3H-quιnazolιn-2,4-dione (146.0 g) in phosphorousoxychloride (535 4 ml) while this mixture is heated up to 140 °C. Refluxing is continued for 20 h after the completion of the addition. The reaction mixture is filtered and evaporated to give a residue which is added to ice and water The product is

extracted by dichloromethane and crystallized from ether and petrolether to yield 2,4- dichloro-qumazoline, m.p. 115-116 °C.

In an analogous manner as described hereinbefore, for example, following compounds can be prepared:

Example 13: N(4)-(4-Chloro-phenylamιno)-N(2)-(2-cvclohexylamιno-ethyl) -quιnazolin-2.4- diamme dihydrochloride M p 295-297 °C

Example 14: 4-(4-Chloro-phenylamιno)-2-r3-(N-pyrrolιdιno)-propyl-1-am ιno]-guιnazolιne hydrochloride

Rf(D 1) 0.82

Example 15 4-Cyclohexylamιno-2-[3-(N-pyrrolo)-propyl-1 -amιno1-guιnazolιne hydrochloride M.p 132-135 °C

Example 16. [3-(4-Cvclohexylamιno-guιnazolιn-2-yl-amιno)-propyl]-car bamιc acid tert -butyl ester

Rf(E1) 0.18.

Example 17: ,3-(4-Benzylamιno-ouιnazolιn-2-yl-amιno)-propyl]-carbamÎ ¹c acιd tert-butyl ester

Benzyl-(2-chloro-quιnazolιn-4yl)-amιne (0 269 g) and (3-amιno-propyl)-carbamιc acid tert butyl ester(0.382 g) is heated for 5 mm to produce a melt which is dissolved in methanol and chromatographed (silica gel, C4) to give [3-(4-beπzylamιno-quιnazolιn-2-yl-amιno)- propyl]-carbamιc acid tert -butyl ester Rf(A1 ) 0 16

The starting material can be prepared, for example, as follows:

Benzyl-(2-chloro-guinazolin-4yl)-amine

A solution of 2,4-dichloro-quinazoline (3.98 g) and of benzylamine (5.5 ml) in THF (30 ml) is stirred at room temperature for 16 h. The reaction mixture is concentrated in vacuo. The residue is crystallization from hot ethanol to yield benzyl-(2-chloro-quinazolin-4yl)-amine: FAB-MS: (M+H)+ = 270.

Example 18: 4-Benzylamino-2-(3-aminopropyl-amino)-guinazolin

[3-(4-Benzylamino-quinazolin-2-yl-amino)-propyl]-carbamic acid tert.-butyl ester (0.130 g) are treated with 4N HCl in dioxane (15 ml) at ambiente temperature for 2 h. Evaporation of the solvent in vacuo yields amorphous [3-(4-benzylamino-quinazolin-2-yl-amino)-propyl]- carbamic acid tert.-butyl ester: FAB-MS: (M+H)+ = 308.

Example 19: In a manner analogous to that described hereinbefore, following compounds it can be manufactured:

4-(4-Chloro-phenylamino)-2-f3-(N-pyrrolo)-propyl-1-amino1 -quinazoline hydrochloride

4-(4-Chloro-phenylamino)-2-f2-(N-pyrrolo)-ethyl-1-amino]- quinazoline hydrochloride

4-(4-Chloro-phenylamino)-2-[2-(N-imidazolo)-ethyl-1 -amino1-guinazoline hydrochloride

4-(4-Chloro-phenylamino)-2-f2-(N-pyrrolidino)-ethyl-1-ami no]-guinazoline hydrochloride

4-(4-Chloro-phenylamino)-2-[3-(N-imidazolo)-propyl-1 -amino1-8-methoxy-guinazoline hydro¬ chloride

4-(4-Chloro-phenylamino)-2-[4-(N-imidazolo)-butyl-1 -amino1-guinazoline hydrochloride

4-Cvclohexylamino-2-[3-(N-pyrrolo)-propyl-1 -amino1-8-methoxy-quinazoline hydrochloride

4-Cvclohexylamino-2-[3-(N-imidazolo)-propyl-1-amino]-quinazo line hydrochloride

-Cvclohexylamino-2-[3-(N-pyrrolidino)-propyl-1 -amino]-guinazoline hydrochloride

4-Cyclohexylamino-2-r2-(N-pyrrolo)-ethyl-1-amino]-quinazo line hydrochloride

4-Cvclohexylamino-2-[2-(N-imidazolo)-ethyl-1-amιno]-quin azoline hydrochloride

4-Cvclohexylamino-2-[2-(N-pyrrolidino)-ethyl-1 -amino]-guinazoline hydrochloride

4-Cvclohexylamino-2-f3-(N-imidazolo)-propyl-1 -amino]-8-methoxy-quinazoline hydrochloride

4-Cvclohexylamino-2-r4-(N-imidazolo)-butyl-1-amino1-ouina zoline hydrochloride

Example 20: Tablets, each containing 50 mg of active ingredient, for example, naphthalene-1 -sulfonic acid [7-(4-amino-quinazolin-2-ylamino)-heptyl]-amide hydrochloride, can be prepared as follows:

Composition (for 10,000 tablets)

Active ingredient 500.0 g

Lactose 500.0 g

Potato starch 352.0 g Gelatin 8.0 g Talc 60.0 g

Magnesium stearate 10.0 g

Silica (highly disperse) 20.0 g

Ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened using an alcoholic solution of the gelatin and granulated by means of a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of weight

145.0 mg each and active ingredient content 50.0 mg which, if desired, can be provided with breaking notches for finer adjustment of the dose.

Example 21 : Coated tablets, each containing 100 mg of active ingredient, for example, naphthalene-1 -sulfonic acid [7-(4-amino-quinazolin-2-ylamino)-heptyl]-amide hydrochloride, can be prepared as follows:

Composition (for 1000 tablets):

Active ingredient 100.00 g

Lactose 100.00 g

Corn starch 70.00 g Talc 8.50 g

Calcium stearate 1.50 g

Hydroxypropylmethylcellulose 2.36 g

Shellac 0.64 g

Water q.s.

Dichloromethane q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste prepared from 15 g of corn starch and water (with warming). The granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed to give tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the coated tablet: 283 mg).

Example 22: Tablets and coated tablets containing another compound of the formula I or a pharmaceutically acceptable salt of a compound of the formula I, for example as in one of Examples 1 to 19, can also be prepared in an analogous manner to that described in Examples 20 and 21

SEQUENCE LISTING

(1) INFORMATION FOR SEQ ID NO:1 :

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1501 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 61..1432

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1

TTAGTTTTGT TCTGAGAACG TTAGAGTTAT AGTACCGTGC GATCGTTCTT CAAGCTGCTA 60

ATG GAC GTC CTC TTC TTC CAC CAG GAT TCT AGT ATG GAG TTT AAG CTT 108

Met Asp Val Leu Phe Phe His Gin Asp Ser Ser Met Glu Phe Lys Leu

1 5 10 15

GAG GAG CAT TTT AAC AAG ACA TTT GTC ACA GAG AAC AAT ACA GCT GCT 156

Glu Glu His Phe Asn Lys Thr Phe Val Thr Glu Asn Asn Thr Ala Ala

20 25 30

GCT CGG AAT GCA GCC TTC CCT GCC TGG GAG GAC TAC AGA GGC AGC GTA 204

Ala Arg Asn Ala Ala Phe Pro Ala Trp Glu Asp Tyr Arg Gly Ser Val

35 40 45

GAC GAT TTA CAA TAC TTT CTG ATT GGG CTC TAT ACA TTC GTA AGT CTT 252

Asp Asp Leu Gin Tyr Phe Leu lie Gly Leu Tyr Thr Phe Val Ser Leu

50 55 60

CTT GGC TTT ATG GGC AAT CTA CTT ATT TTA ATG GCT GTT ATG AAA AAG 300

Leu Gly Phe Met Gly Asn Leu Leu lie Leu Met Ala Val Met Lys Lys

65 70 75 80

CGC AAT CAG AAG ACT ACA GTG AAC TTT CTC ATA GGC AAC CTG GCC TTC 348

Arg Asn Gin Lys Thr Thr Val Asn Phe Leu lie Gly Asn Leu Ala Phe

85 90 95

TCC GAC ATC TTG GTC GTC CTG TTT TGC TCC CCT TTC ACC CTG ACC TCT 396

Ser Asp lie Leu Val Val Leu Phe Cys Ser Pro Phe Thr Leu Thr Ser

100 105 110

GTC TTG TTG GAT CAG TGG ATG TTT GGC AAA GCC ATG TGC CAT ATC ATG 444

Val Leu Leu Asp Gin Trp Met Phe Gly Lys Ala Met Cys His lie Met

115 120 125

CCG TTC CTT CAA TGT GTG TCA GTT CTG GTT TCA ACT CTG ATT TTA ATA 492

Pro Phe Leu Gin Cys Val Ser Val Leu Val Ser Thr Leu lie Leu lie

130 135 140

TCA ATT GCC ATT GTC AGG TAT CAT ATG ATA AAG CAC CCT ATT TCT AAC 540

Ser He Ala He Val Arg Tyr His Met He Lys His Pro He Ser Asn

145 150 155 160

AAT TTA ACG GCA AAC CAT GGC TAC TTC CTG ATA GCT ACT GTC TGG ACA 588

Asn Leu Thr Ala Asn His Gly Tyr Phe Leu He Ala Thr Val Trp Thr

165 170 175

CTG GGC TTT GCC ATC TGT TCT CCC CTC CCA GTG TTT CAC AGT CTT GTG 636

Leu Gly Phe Ala He Cys Ser Pro Leu Pro Val Phe His Ser Leu Val

180 185 190

GAA CTT AAG GAG ACC TTT GGC TCA GCA CTG CTG AGT AGC AAA TAT CTC 684

Glu Leu Lys Glu Thr Phe Gly Ser Ala Leu Leu Ser Ser Lys Tyr Leu

195 200 205

TGT GTT GAG TCA TGG CCC TCT GAT TCA TAC AGA ATT GCT TTC ACA ATC 732 Cys Val Glu Ser Trp Pro Ser Asp Ser Tyr Arg He Ala Phe Thr He 210 215 220

TCT TTA TTG CTA GTG CAG TAT ATC CTG CCT CTA GTA TGT TTA ACG GTA 780 Ser Leu Leu Leu Val Gin Tyr He Leu Pro Leu Val Cys Leu Thr Val 225 230 235 240

AGT CAT ACC AGC GTC TGC CGA AGC ATA AGC TGT GGA TTG TCC CAC AAA 828 Ser His Thr Ser Val Cys Arg Ser He Ser Cys Gly Leu Ser His Lys 245 250 255

GAA AAC AGA CTC GAA GAA AAT GAG ATG ATC AAC TTA ACC CTA CAG CCA 876 Glu Asn Arg Leu Glu Glu Asn Glu Met He Asn Leu Thr Leu Gin Pro 260 265 270

TCC AAA AAG AGC AGG AAC CAG GCA AAA ACC CCC AGC ACT CAA AAG TGG 924 Ser Lys Lys Ser Arg Asn Gin Ala Lys Thr Pro Ser Thr Gin Lys Trp 275 280 285

AGC TAC TCA TTC ATC AGA AAG CAC AGA AGG AGG TAC AGC AAG AAG ACG 972 Ser Tyr Ser Phe He Arg Lys His Arg Arg Arg Tyr Ser Lys Lys Thr 290 295 300

GCC TGT GTC TTA CCC GCC CCA GCA GGA CCT TCC CAG GGG AAG CAC CTA 1020 Ala Cys Val Leu Pro Ala Pro Ala Gly Pro Ser Gin Gly Lys His Leu 305 310 315 320

GCC GTT CCA GAA AAT CCA GCC TCC GTC CGT AGC CAG CTG TCG CCA TCC 1068 Ala Val Pro Glu Asn Pro Ala Ser Val Arg Ser Gin Leu Ser Pro Ser 325 330 335

AGT AAG GTC ATT CCA GGG GTC CCA ATC TGC TTT GAG GTG AAA CCT GAA 1116 Ser Lys Val He Pro Gly Val Pro He Cys Phe Glu Val Lys Pro Glu 340 345 350

GAA AGC TCA GAT GCT CAT GAG ATG AGA GTC AAG CGT TCC ATC ACT AGA 1164 Glu Ser Ser Asp Ala His Glu Met Arg Val Lys Arg Ser He Thr Arg 355 360 365

ATA AAA AAG AGA TCT CGA AGT GTT TTC TAC AGA CTG ACC ATA CTG ATA 1212 He Lys Lys Arg Ser Arg Ser Val Phe Tyr Arg Leu Thr He Leu He

370 375 380

CTC GTG TTC GCC GTT AGC TGG ATG CCA CTC CAC GTC TTC CAC GTG GTG 1260 Leu Val Phe Ala Val Ser Trp Met Pro Leu His Val Phe His Val Val 385 390 395 400

ACT GAC TTC AAT GAT AAC TTG ATT TCC AAT AGG CAT TTC AAG CTG GTA 1308 Thr Asp Phe Asn Asp Asn Leu He Ser Asn Arg Kis Phe Lys Leu Val 405 410 415

TAC TGC ATC TGT CAC TTG TTA GGC ATG ATG TCC TGT TGT CTA AAT CCG 1356 Tyr Cys He Cys His Leu Leu Gly Met Met Ser Cys Cys Leu Asn Pro 420 425 430

ATC CTA TAT GGT TTC CTT AAT AAT GGT ATC AAA GCA GAC TTG AGA GCC 1404 He Leu Tyr Gly Phe Leu Asn Asn Gly He Lys Ala Asp Leu Arg Ala 435 440 445

CTT ATC CAC TGC CTA CAC ATG TCA TGA TTCTCTCTGTG CACCAAAGAG 1452

Leu He His Cys Leu His Met Ser * 450 455

AGAAGAAACG TGGTAATTGA CACATAATTT ATACAGAAGT ATTCTGGAT 1501

(2) INFORMATION FOR SEQ ID NO:2:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 457 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:

Met Asp Val Leu Phe Phe His Gin Asp Ser Ser Met Glu Phe Lys Leu 1 5 10 15

Glu Glu His Phe Asn Lys Thr Phe Val Thr Glu Asn Asr. Thr Ala Ala

20 25 30

Ala Arg Asn Ala Ala Phe Pro Ala Trp Glu Asp Tyr Arg Gly Ser Val 35 40 45

Asp Asp Leu Gin Tyr Phe Leu He Gly Leu Tyr Thr Phe Val Ser Leu 50 55 60

Leu Gly Phe Met Gly Asn Leu Leu He Leu Met Ala Val Met Lys Lys 65 70 75 80

Arg Asn Gin Lys Thr Thr Val Asn Phe Leu He Gly Asn Leu Ala Phe 85 90 95

Ser Asp He Leu Val Val Leu Phe Cys Ser Pro Phe Thr Leu Thr Ser 100 105 110

Val Leu Leu Asp Gin Trp Met Phe Gly Lys Ala Met Cys His He Met 115 120 125

Pro Phe Leu Gin Cys Val Ser Val Leu Val Ser Thr Leu He Leu He 130 135 140

Ser He Ala He Val Arg Tyr His Met He Lys His Pro He Ser Asn 145 150 155 160

Asn Leu Thr Ala Asn His Gly Tyr Phe Leu He Ala Thr Val Trp Thr 165 170 175

Leu Gly Phe Ala He Cys Ser Pro Leu Pro Val Phe His Ser Leu Val 180 185 190

Glu Leu Lys Glu Thr Phe Gly Ser Ala Leu Leu Ser Ser Lys Tyr Leu 195 200 205

Cys Val Glu Ser Trp Pro Ser Asp Ser Tyr Arg He Ala Phe Thr He 210 215 220

Ser Leu Leu Leu Val Gin Tyr He Leu Pro Leu Val Cys Leu Thr Val 225 230 235 240

Ser His Thr Ser Val Cys Arg Ser He Ser Cys Gly Leu Ser His Lys 245 250 255

Glu Asn Arg Leu Glu Glu Asn Glu Met He Asn Leu Thr Leu Gin Pro 260 265 270

Ser Lys Lys Ser Arg Asn Gin Ala Lys Thr Pro Ser Thr Gin Lys Trp 275 280 285

Ser Tyr Ser Phe He Arg Lys His Arg Arg Arg Tyr Ser Lys Lys Thr 290 295 300

Ala Cys Val Leu Pro Ala Pro Ala Gly Pro Ser Gin Gly Lys His Leu 305 310 315 320

Ala Val Pro Glu Asn Pro Ala Ser Val Arg Ser Gin Leu Ser Pro Ser 325 330 335

Ser Lys Val He Pro Gly Val Pro He Cys Phe Glu Val Lys Pro Glu 340 345 350

Glu Ser Ser Asp Ala His Glu Met Arg Val Lys Arg Ser He Thr Arg 355 360 365

He Lys Lys Arg Ser Arg Ser Val Phe Tyr Arg Leu Thr He Leu He 370 375 380

Leu Val Phe Ala Val Ser Trp Met Pro Leu His Val Phe His Val Val 385 390 395 400

Thr Asp Phe Asn Asp Asn Leu He Ser Asn Arg His Phe Lys Leu Val 405 410 415

Tyr Cys He Cys His Leu Leu Gly Met Met Ser Cys Cys Leu Asn Pro 420 425 430

He Leu Tyr Gly Phe Leu Asn Asn Gly He Lys Ala Asp Leu Arg Ala

435 440 445

Leu He His Cys Leu His Met Ser * 450 455

(3) INFORMATION FOR SEQ ID NO:3:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1457 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: cDNA

(iii) HYPOTHETICAL: NO

(iv) ANTI-SENSE: NO

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 61..1432

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:

GTTTCCCTCT GAATAGATTA ATTTAAAGTA GTCATGTAAT GTTTTTTTGG TTGCTGACAA 60

ATG TCT TTT TAT TCC AAG CAG GAC TAT AAT ATG GAT TTA GAG CTC GAC 108 Met Ser Phe Tyr Ser Lys Gin Asp Tyr Asn Met Asp Leu Glu Leu Asp 1 5 10 15

GAG TAT TAT AAC AAG ACA CTT GCC ACA GAG AAT AAT ACT GCT GCC ACT 156 Glu Tyr Tyr Asn Lys Thr Leu Ala Thr Glu Asn Asn Thr Ala Ala Thr 20 25 30

CGG AAT TCT GAT TTC CCA GTC TGG GAT GAC TAT AAA AGC AGT GTA GAT 204 Arg Asn Ser Asp Phe Pro Val Trp Asp Asp Tyr Lys Ser Ser Val Asp 35 40 45

GAC TTA CAG TAT TTT CTG ATT GGG CTC TAT ACA TTT GTA AGT CTT CTT 252 Asp Leu Gin Tyr Phe Leu He Gly Leu Tyr Thr Phe Val Ser Leu Leu 50 55 60

GGC TTT ATG GGG AAT CTA CTT ATT TTA ATG GCT CTC ATG AAA AAG CGT 300 Gly Phe Met Gly Asn Leu Leu He Leu Met Ala Leu Met Lys Lys Arg 65 70 75 80

AAT CAG AAG ACT ACG GTA AAC TTC CTC ATA GGC AAT CTG GCC TTT TCT 3 8 Asn Gin Lys Thr Thr Val Asn Phe Leu He Gly Asn Leu Ala Phe Ser 85 90 95

GAT ATC TTG GTT GTG CTG TTT TGC TCA CCT TTC ACA CTG ACG TCT GTC 396 Asp He Leu Val Val Leu Phe Cys Ser Pro Phe Thr Leu Thr Ser Val 100 105 110

TTG CTG GAT CAG TGG ATG TTT GGC AAA GTC ATG TGC CAT ATT ATG CCT 444 Leu Leu Asp Gin Trp Met Phe Gly Lys Val Met Cys His He Met Pro 115 120 125

TTT CTT CAA TGT GTG TCA GTT TTG GTT TCA ACT TTA ATT TTA ATA TCA 492 Phe Leu Gin Cys Val Ser Val Leu Val Ser Thr Leu He Leu He Ser 130 135 140

ATT GCC ATT GTC AGG TAT CAT ATG ATA AAA CAT CCC ATA TCT AAT AAT 540 He Ala He Val Arg Tyr His Met He Lys His Pro He Ser Asn Asn 145 150 155 160

TTA ACA GCA AAC CAT GGC TAC TTT CTG ATA GCT ACT GTC TGG ACA CTA 588 Leu Thr Ala Asn His Gly Tyr Phe Leu He Ala Thr Val Trp Thr Leu 165 170 175

GGT TTT GCC ATC TGT TCT CCC CTT CCA GTG TTT CAC AGT CTT GTG GAA 636 Gly Phe Ala He Cys Ser Pro Leu Pro Val Phe His Ser Leu Val Glu 180 185 190

CTT CAA GAA ACA TTT GGT TCA GCA TTG CTG AGC AGC AGG TAT TTA TGT 684 Leu Gin Glu Thr Phe Gly Ser Ala Leu Leu Ser Ser Arg Tyr Leu Cys 195 200 205

GTT GAG TCA TGG CCA TCT GAT TCA TAC AGA ATT GCC TTT ACT ATC TCT 732 Val Glu Ser Trp Pro Ser Asp Ser Tyr Arg He Ala Phe Thr He Ser 210 215 220

TTA TTG CTA GTT CAG TAT ATT CTG CCC TTA GTT TGT CTT ACT GTA AGT 780 Leu Leu Leu Val Gin Tyr He Leu Pro Leu Val Cys Leu Thr Val Ser

225 230 235 240

CAT ACA AGT GTC TGC AGA AGT ATA AGC TGT GGA TTG TCC AAC AAA GAA 828 His Thr Ser Val Cys Arg Ser He Ser Cys Gly Leu Ser Asn Lys Glu 245 250 255

AAC AGA CTT GAA GAA AAT GAG ATG ATC AAC TTA ACT CTT CAT CCA TCC 876 Asn Arg Leu Glu Glu Asn Glu Met He Asn Leu Thr Leu His Pro Ser 260 265 270

AAA AAG AGT GGG CCT CAG GTG AAA CTC TCT GGC AGC CAT AAA TGG AGT 924 Lys Lys Ser Gly Pro Gin Val Lys Leu Ser Gly Ser His Lys Trp Ser 275 280 285

TAT TCA TTC ATC AAA AAA CAC AGA AGA AGA TAT AGC AAG AAG ACA GCA 972 Tyr Ser Phe He Lys Lys His Arg Arg Arg Tyr Ser Lys Lys Thr Ala 290 295 300

TGT GTG TTA CCT GCT CCA GAA AGA CCT TCT CAA GAG AAC CAC TCC AGA 1020 Cys Val Leu Pro Ala Pro Glu Arg Pro Ser Gin Glu Asn His Ser Arg 305 310 315 320

ATA CTT CCA GAA AAC TTT GGC TCT GTA AGA AGT CAG CTC TCT TCA TCC 1068 He Leu Pro Glu Asn Phe Gly Ser Val Arg Ser Gin Leu Ser Ser Ser 325 330 335

AGT AAG TTC ATA CCA GGG GTC CCC ACT TGC TTT GAG ATA AAA CCT GAA 1116 Ser Lys Phe He Pro Gly Val Pro Thr Cys Phe Glu He Lys Pro Glu 340 345 350

GAA AAT TCA GAT GTT CAT GAA TTG AGA GTA AAA CGT TCT GTT ACA AGA 1164 Glu Asn Ser Asp Val His Glu Leu Arg Val Lys Arg Ser Val Thr Arg 355 360 365

ATA AAA AAG AGA TCT CGA AGT GTT TTC TAC AGA CTG ACC ATA CTG ATA 1212 He Lys Lys Arg Ser Arg Ser Val Phe Tyr Arg Leu Thr He Leu He 370 375 380

TTA GTA TTT GCT CTT AGT TGG ATG CCA CTA CAC CTT TTC CAT GTG GTA 1260 Leu Val Phe Ala Val Ser Trp Met Pro Leu His Leu Phe His Val Val 385 390 395 400

ACT GAT TTT AAT GAC AAT CTT ATT TCA AAT AGG CAT TTC AAG TTG GTG 1308

Thr Asp Phe Asn Asp Asn Leu He Ser Asn Arg His Phe Lys Leu Val 405 410 415

TAT TGC ATT TGT CAT TTG TTG GGC ATG ATG TCC TGT TGT CTT AAT CCA 1356 Tyr Cys He Cys His Leu Leu Gly Met Met Ser Cys Cys Leu Asn Pro 420 425 430

ATT CTA TAT GGG TTT CTT AAT AAT GGG ATT AAA GCT GAT TTA GTG TCC 1404 He Leu Tyr Gly Phe Leu Asn Asn Gly He Lys Ala Asp Leu Val Ser 435 440 445

CTT ATA CAC TGT CTT CAT ATG TAA TAA TTCTCACTGT TTACCAAGGA 1452 Leu He His Cys Leu His Met * * 450 455

AAGAAC 1457

(41 ) INFORMATION FOR SEQ ID NO:4:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 457 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:

Met Ser Phe Tyr Ser Lys Gin Asp Tyr Asn Met Asp Leu Glu Leu Asp

1 5 10 15

Glu Tyr Tyr Asn Lys Thr Leu Ala Thr Glu Asn Asn Thr Ala Ala Thr 20 25 30

Arg Asn Ser Asp Phe Pro Val Trp Asp Asp Tyr Lys Ser Ser Val Asp 35 40 45

Asp Leu Gin Tyr Phe Leu He Gly Leu Tyr Thr Phe Val Ser Leu Leu 50 55 60

Gly Phe Met Gly Asn Leu Leu He Leu Met Ala Leu Met Lys Lys Arg 65 70 75 80

Asn Gin Lys Thr Thr Val Asn Phe Leu He Gly Asn Leu Ala Phe Ser 85 90 95

Asp He Leu Val Val Leu Phe Cys Ser Pro Phe Thr Leu Thr Ser Val 100 105 110

Leu Leu Asp Gin Trp Met Phe Gly Lys Val Met Cys His He Met Pro 115 120 125

Phe Leu Gin Cys Val Ser Val Leu Val Ser Thr Leu He Leu He Ser 130 135 140

He Ala He Val Arg Tyr His Met He Lys His Pro He Ser Asn Asn 145 150 155 160

Leu Thr Ala Asn His Gly Tyr Phe Leu He Ala Thr Val Trp Thr Leu 165 170 175

Gly Phe Ala He Cys Ser Pro Leu Pro Val Phe His Ser Leu Val Glu 180 185 190

Leu Gin Glu Thr Phe Gly Ser Ala Leu Leu Ser Ser Arg Tyr Leu Cys 195 200 205

Val Glu Ser Trp Pro Ser Asp Ser Tyr Arg He Ala Phe Thr He Ser 210 215 220

Leu Leu Leu Val Gin Tyr He Leu Pro Leu Val Cys Leu Thr Val Ser 225 230 235 240

His Thr Ser Val Cys Arg Ser He Ser Cys Gly Leu Ser Asn Lys Glu 245 250 255

Asn Arg Leu Glu Glu Asn Glu Met He Asn Leu Thr Leu His Pro Ser 260 265 270

Lys Lys Ser Gly Pro Gin Val Lys Leu Ser Gly Ser His Lys Trp Ser 275 280 285

Tyr Ser Phe He Lys Lys His Arg Arg Arg Tyr Ser Lys Lys Thr Ala

290 295 300

Cys Val Leu Pro Ala Pro Glu Arg Pro Ser Gin Glu Asn His Ser Arg 305 310 315 320

He Leu Pro Glu Asn Phe Gly Ser Val Arg Ser Gin Leu Ser Ser Ser 325 330 335

Ser Lys Phe He Pro Gly Val Pro Thr Cys Phe Glu He Lys Pro Glu 340 345 350

Glu Asn Ser Asp Val His Glu Leu Arg Val Lys Arg Ser Val Thr Arg 355 360 365

He Lys Lys Arg Ser Arg Ser Val Phe Tyr Arg Leu Thr He Leu He 370 375 380

Leu Val Phe Ala Val Ser Trp Met Pro Leu His Leu Phe His Val Val 385 390 395 400

Thr Asp Phe Asn Asp Asn Leu He Ser Asn Arg His Phe Lys Leu Val 405 410 415

Tyr Cys He Cys His Leu Leu Gly Met Met Ser Cys Cys Leu Asn Pro 420 425 430

He Leu Tyr Gly Phe Leu Asn Asn Gly He Lys Ala Asp Leu Val Ser 435 440 445

Leu He His Cys Leu His Met * * 450