WO2010043592A1

WO2010043592A1 - Lipase inhibitors for use for the treatment of obesity

Info

Publication number: WO2010043592A1
Application number: PCT/EP2009/063282
Authority: WO
Inventors: Ewald M. Aydt; Daniel Bock; Bo Heinemann; Remo Kranich
Original assignee: Revotar Biopharmaceuticals Ag
Priority date: 2008-10-15
Filing date: 2009-10-12
Publication date: 2010-04-22

Abstract

Specific aromatic compounds of the general formula (I) can be used for the treatment of obesity wherein R¹ e. g. denotes -H, -CH₃, -F, -Cl, -Br, -I or -OH, -NH₂; -X-Y e.g. denotes a group (1), with n being 1, 2, 3; -Y e. g. denotes a group (2), wherein R⁵ and R⁶are -OH and -A is e. g. a group -CF₃.

Description

Lipase Inhibitors for Use for the Treatment of Obesity

The present invention relates to a new class of small molecule lipase inhibitors which can be used for the treatment and/or prophylaxis of obesity and diseases or conditions related to obesity.

Several drug compounds have been developed in recent years for the treatment of obesity having different modes of action. However many of these compounds have to be applied at a high dose and have significant side effects. Overweight and obesity are recognized to become a global epidemic problem. The World Health Organization (WHO) projects that today globally more than 1.6 billion adults (age 15 and older) are overweight with a body mass index (BMI) of 25 kg/m² and more. More than 400 million adults are classified as obese with a BMI of 30 kg/m² and more. It is also suggested that at least 20 million children under the age of 5 years are overweight globally. The WHO further projects that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese. This increased incidence of obesity is due in part to the ready availability of food and "westernized diets" that have high saturated fat and low content of fibers. The food of many people is very "energy dense". In addition, the lifestyle of populations in many countries of the world changed and a steady reduction of manual labor intensive industries can be observed. This results in an energy imbalance between the energy intake from energy dense food and the reduced energy demand required for a sedentary lifestyle. Some of the excess energy intake is stored as fat in the adipose tissue of which the accumulation over a period of time results in obesity. This can be a significant contributory factor to other diseases and disorders.

Current pharmacological approaches to treat obesity focus either on the development of drugs that increase energy expenditure, drugs that reduce energy intake, or drugs that suppress appetite.

However, the drugs developed so far often suffer from both, only moderate efficacy and unwanted side effects, which make the therapeutic treatment unpleasant for patients. The drug compound Orlistat, as described in EP-A 0 129 748, is one example for a known compound for the treatment of obesity which prevents the absorption of fat from the gastrointestinal tract by inhibiting hydrolytic enzymes, in particular the pancreatic lipases. Drug compounds like Orlistat show only moderate activity and have been observed to have several unwanted side effects, such as fatty stool, intestinal gas with discharge, bowel movement urgency, poor bowel control, incontinence, and headaches. The moderate efficacy and/or the unwanted side effects of current anti-obesity drug substances reduce the patient's compliance for the therapeutic strategy.

In many cases, obesity itself is not treated rather than its secondary complications or sequelae, leaving the BMI of a patient, and therefore also the probability of suffering from secondary complications or sequelae, unchanged. Therefore, the treatment of secondary complications or sequelae caused by obesity does not represent an appropriate strategy for the treatment and prophylaxis of obesity or overweight.

Taking the general need for new and better therapeutic products and the growing number of overweight and obese people worldwide into account, a particularly high demand for effective and safe therapies of obesity can be stated. Thus, there is a need to provide alternative drugs for use in the control and treatment of obesity and obesity-related diseases and conditions as well as in promoting non-medical weight loss. The unmet medical need to develop novel, safe, and effective anti-obesity therapeutics is considered very high.

The present invention provides a new class of highly active lipase inhibitors which are e.g. useful for the treatment and/or prophylaxis of obesity and obesity related diseases and conditions. The compounds described show a high level of activity and have less unwanted side effects than the known drug compounds, e. g. have less unwanted side effects than the drug compound Orlistat.

The aromatic amide compounds of general formula (I) and method of preparation, e. g. by chemical synthesis, are partly known.

(I) In EP-A 1577 289, EP-A 1764 094, EP-A 1764 096, and EP-A 1764 095 the preparation of various aromatic drug compounds according to general formula (I) are described.

The compounds are described to be suitable for the preparation of pharmaceutical and dermato logical compositions for the treatment, diagnosis, and prophylaxis of selectin- mediated inflammatory or micro -inflammatory diseases or condition. Specifically mentioned are diseases such as asthma, psoriasis, chronic obstructive pulmonary disease (COPD), and skin ageing.

Surprisingly, it has now been found that several of these compounds strongly inhibit lipases. Several compounds described in EP-A 1577 289, EP-A 1764 094, EP-A 1764 096 and EP-A 1764 095 have lipase inhibiting properties which are better than or in the range of modern marketed anti-obesity drug compounds.

The compounds of the following formula (I) also have fewer side effects as compared to several marketed anti-obesity drugs, such as e.g. Orlistat, which also acts through the inhibition of lipases. Up to date, the compounds of formula (I) are known neither as lipase inhibitors nor as drugs for the treatment of obesity or obesity related diseases. Some polyphenolic compounds, mostly from natural sources (see e. g. Birari R. B. and Bhutani K. K., Drug Discovery Today, 2007, 12, 879-889) have been described in the literature as lipase inhibitors, but the disclosed compounds are structurally very different as compared to the compounds of formula (I) of the present invention. In addition, these compounds of the literature have only intermediate inhibitory activities and - due to the tendency to chemically react to complex molecular structures - pharmaceutical development of these compounds seems rather difficult.

The selectins are associated with inflammatory or micro -inflammatory diseases and conditions, which may potentially arise also as a consequence of overweight or obesity, but not with obesity or overweight itself. Treating obese patients suffering from inflammatory diseases or conditions with anti-inflammatory drugs in general, such as selectin-antagonists can therefore not prevent or treat obesity or overweight.

The present invention generally relates to the use of compounds of formula (I) and/or a polymorphic form thereof and/or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition or medicament for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions. According to the current definition of the WHO the term "obesity" is herein defined by a state in which the BMI of a person is greater than or equals 30 kg/m².

The term "obesity related diseases" is deemed to be an umbrella term for diseases caused by obesity excepting inflammatory or micro -inflammatory diseases. Obesity related diseases are in particular selected from appetite disorders, hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), and musculoskeletal disorders. Here, the term "obesity related conditions" includes overweight, non medical weight loss, and cosmetic weight loss. Non-medical weight loss and cosmetic weight loss is weight loss associated with overweight (BMI >= 25 kg/m², according to the current definition by the WHO) and with BMI below 25 kg/m², respectively.

The present invention also provides compounds of formula (I) and/or a polymorphic form thereof and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions whereby the compound of formula (I) is defined as

wherein the symbols of the substituents have the following meanings:

-R¹ denotes -H, -CH₃, -F, -Cl, -Br, -I, -OH, -NH₂, preferably -H, -CH₃, or -OH;

(the substitution with R¹ at the phenyl ring can be either in the ortho, meta or para position with respect to the amine-group, preferably it is in ortho and meta position);

-X-Y denotes one of the following groups a)

wherein R² being -H, -OH, -F, -Cl, -Br, -I, -CH₃, -CH₂CH₃, -NO₂, -NR³R⁴, -CF₃, -OCH₃₅-SO₃H, -SO₂NR³R⁴, -CO₂R³, preferably -H, -F, -Cl, -CH₃, -NR³R⁴,-CF₃, - OCH₃, -SO₃H, -SO₂NR³R⁴, -CO₂R³, particularly preferably, -H, -F, -Cl, -CH₃, -NR³R⁴, -OCH₃, -SO₂NR³R⁴, -CO₂R³, and very particularly preferably -H, -F, -Cl, -CH₃, - CO₂R^3'; and R³ and R⁴ being independently from each other -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃

(-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl), preferably -H, -CH₃, - CH₂CH₃, -(CH₂)₂CH₃, (-propyl), -CH(CH₃)₂ (-isopropyl), particularly preferably -H, - CH₃, -CH₂CH₃, -(CH₂)₂CH₃, (-propyl), and very particularly preferably -H, -CH₃, - CH₂CH₃; and -[R³R⁴]- can also be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-;

b)

with n being 1, 2, 3; c)

and the group -Y denotes a)

whereby R⁵ and R⁶ are either R⁵ = -OH and R⁶ = -OH or R⁵ = -H and R⁶ = -OH or -OCH₃, b)

whereby R⁶ and R⁷ are either R⁷ -H and R⁸ = -OH or R⁷ = -OH and R⁸ = -H or R⁷ = -NO₂ and R⁸ = -H c)

d)

e) one of the following two groups

and -A denotes

whereby R⁹ and R¹⁰ being independently from each other are

-H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-IsOPr₀PyI)₅-CH₂(C₆H₅) (- benzyl); and -[R⁹R¹⁰]- can also be a group -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b) a group

with m = 0,1 and with R⁹ is -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂

(-IsOPrOPyI)₅-CH₂(C₆H₅) (-benzyl), preferably -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (- propyl), -CH(CH₃)₂ (-isopropyl);

c) a group

l>^cN

d) a group

in which R⁹ is -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl);

e) a group

in which R⁹ and R¹⁰ independently from each other are -H, -CH₃, -CH₂CH₃,

-(CH₂)₂CH₃ (-propyl), -CH(CH₃), (-isopropyl),-CH₂(C₆H₅) (-benzyl); and -[R⁹R¹⁰]- can also be a group -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-,

f) a group

g) a group

.9 in which R^y is -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl).

The present invention also provides compounds of formula (I) and/or a polymorphic form thereof and/or a parmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity. The present invention also provides compounds of formula (I) and/or a polymorphic form thereof and/or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related diseases. The present invention also provides compounds of formula (I) and/or a polymorphic form thereof and/or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related conditions.

A preferred embodiment of the invention relates compounds of formula (II) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions,

wherein the symbols of the substituents have the following meanings: -R¹ denotes -H, -CH₃, -F, -Cl, -Br, -I, -OH, -NH₂, preferably -H, -CH₃, or -OH; (the substitution with R¹ at the phenyl ring can be either in the ortho, meta or para position with respect to the amine-group, preferably it is in ortho and meta position); -X' -Y denotes a group: a)

whereby R^2' being -H, -OH, -F, -Cl, -CH₃, -CH₂CH₃, -NR³ R^4', -SO₂NR³ R^4', -CO₂R^3'; preferably -H, -F, -Cl, -CH₃, -NR³R⁴,-CF₃, -OCH₃, -SO₃H, -SO₂NR³R⁴, -CO₂R³; more preferably, -H, -F, -Cl, -CH₃, -NR³R⁴, -OCH₃, -SO₂NR³R⁴, -CO₂R³; and particularly preferably -H, -F, -Cl, -CH₃, -CO₂R^3'; and R³ and R⁴ being independently from each other -H, -CH₃, -CH₂CH₃; and -[R³ R^4']- can also be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-;

b)

with n being 1, 2, 3;

c)

and -Y is a)

whereby R⁵ and R⁶ are either R⁵ = -OH and R⁶ = -OH or R⁵ = -H and R⁶ = -OH or -OCH₃; b)

whereby R⁷ and R⁸ being either R⁷ = -H and R⁸ = -OH or R⁷ = -OH and R⁸ = -H or R⁷ = -NO₂ and R⁸ = -H; c)

d)

e) one of the two groups

and -A denotes a) a group

-CO₂R , -CF₃, -S0₂NR 9^yτR> 10 whereby R⁹ and R¹⁰ being independently from each other -H, -CH₃, -CH₂CH₃, (CH₂)₂CH₃

(-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl) and -[R⁹R¹⁰]- also can be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-, b)

withm = 0,1

C)

d)

e)

f)

wherein the groups R 9 and J r R_>10 are defined as above Another preferred embodiment of the invention relates to compounds of formula (II) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity. A preferred embodiment of the invention relates to compounds of formula (II) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related diseases. A preferred embodiment of the invention relates to compounds of formula (II) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related conditions.

The invention also relates to preferred compounds of formula (III) and/or a polymorphic form thereof and/or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions:

wherein the symbols of the substituents have the following meanings:

-R¹ denotes -H, -CH₃, -OH; (the substitution with -R¹ at the phenyl ring can be either in the ortho, meta or para position with respect to the amine-group; preferably it is in ortho and meta position; very often -R ,r is in the ortho-position to the amine-group);

and -X' '-Y denotes one of the following ; groups a)

and R³ being -H, -CH₃, -CH₂CH₃; b)

with n being 1, 2, 3; c)

O

V H

and -Y denotes a)

whereby R⁵ and R⁶ being either R⁵ = -OH and R⁶ = -OH, or R⁵ = -H and R⁶ = -OH, -OCH₃;

b)

whereby R⁷ and R⁸ being either R⁷ = -H and R⁸ = -OH, or R⁷ = -OH and R⁸ = -H, or R⁷ = -NO₂ and R⁸ = -H; c)

d)

e) one of the two groups

and -A' denotes a group a) -CO₂R^9', -CF₃, -SO₂NR⁹ R^10' whereby R⁹ and R¹⁰ being independently from each other -H, -CH₃, -CH₂CH₃; and -[R⁹ R^10']- also can be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b)

with m = 0,1;

C)

d)

e)

f)

whereby R⁹ and R¹⁰ are defined as above.

The invention also relates to preferred compounds of formula (III) and/or a polymorphic form thereof and/or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity. The invention also relates to preferred compounds of formula (III) and/or a polymorphic form thereof and/or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related diseases. The invention also relates to preferred compounds of formula (III) and/or a polymorphic form thereof and/or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related conditions. The invention also relates to preferred compounds of formula (IV), formula (V), and formula (VI) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions

wherein the symbols of the substituents have the following meanings

-R¹ denotes -H, -CH₃, -OH; (the substitution with -R¹ at the phenyl ring can be either in the ortho, meta or para position with respect to the amine-group; preferably it is in ortho and meta position; very often -R¹ is in the ortho-position to the amine-group);

and -Z-Y is a group: a)

b)

with n being 1, 2, 3; c)

and -Y denotes a group a)

whereby R⁵ and R⁶ are either R⁵ = -OH and R⁶ = -OH or R⁵ = -H and R⁶ = -OH, -OCH₃; b)

whereby R⁷ and R⁸ are either R⁷ = -H and R⁸ = -OH, or R⁷ = -OH and R⁸ = -H, or R⁷ = -NO₂ and R⁸ = -H; c)

d)

e) one of the two groups

and -B denotes a group: a) -CO₂R^9', -CF₃, -SO₂NR⁹ R^10' whereby R⁹ and R¹⁰ being independently from each other -H, -CH₃, -CH₂CH₃ and [R⁹ R^10'] being also -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b)

and -B² denotes a group: a) -CO₂R^9', -CF₃, -SO₂NR⁹ R^10'; b)

and -B³ denotes a group a)

9'

with m = 0,1

b)

c)

d)

The invention also relates to preferred compounds of formula (IV), formula (V), and formula (VI) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity. The invention also relates to preferred compounds of formula (IV), formula (V), and formula (VI) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related diseases. The invention also relates to preferred compounds of formula (IV), formula (V), and formula (VI) and/or a polymorphic form and/or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related conditions.

In a further embodiment, the invention relates to preferred compounds of the following formulas (1) to (24) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions.

In another embodiment, the invention relates to preferred compounds of the following formulas (1) to (24) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity. In a further embodiment, the invention relates to preferred compounds of the following formulas (1) to (24) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related diseases. In a further embodiment, the invention relates to preferred compounds of the following formulas (1) to (24) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity related conditions. A further aspect of the invention is a physiologically-hydrolysable and pharmaceutically acceptable ester of alcohols and/or acids of formula (I). By hydro lysable and acceptable ester as used herein is meant an ester in which the hydroxyl group is esterified and which is hydrolysable under physiological conditions to yield an acid which by itself is physiologically tolerable at dosages to be administered. The term is thus to be understood as defining a regular prodrug form of compounds of formulae (I), (II), (III), (IV), (V) and (VI). Examples of such esters include for example acetates and benzoates, of the compounds of formulae (I), (II), (III), (IV), (V) and (VI) and of compounds (1) to (24).

The compounds according to the invention are preferably used either alone or in combination with another drug compound (e.g. a further anti-obesity drug) for the treatment and/or prophylaxis of obesity. Obesity normally is defined as a BMI of at least 30 kg/m².The compounds according to the invention can also be used for the treatment and/or prophylaxis of overweight (BMI >= 25 kg/m²), for cosmetic and/or non-medical weight loss, which also includes improving bodily appearance in general.

The compounds according to the invention can also be used for the treatment and/or prophylaxis of overweight (BMI >= 25 kg/m²). Another aspect of the invention is the use of the compounds according to the invention for the promotion and/or prophylaxis of cosmetic and/or non medical weight loss. The use of the compounds according to the invention for improving the bodily appearance in general is also subject of the invention.

The compounds according to the invention can also be used for the treatment and/or prophylaxis of obesity related diseases. The compounds according to the invention can also be used for the treatment and/or prophylaxis of obesity related diseases or conditions such as appetite disorders, hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), and musculoskeletal disorders.The compounds of the invention show improved biological in vitro and in vivo efficacy as compared to prior art compounds, such as the marketed drug compound Orlistat. For example, the IC50 value from a lipase based molecular enzymatic assay for compound (17) is 20OnM, representing a improved IC50 value as compared to Orlistat 's IC50. In addition the compound (17) shows improved in vivo results in an animal model where the inhibitory effect of lipase inhibitors is measured as compared to Orlistat. Furthermore, the side effects as observed with Orlistat are in general not observed with the compounds of the invention.

According to their inhibitory effects, the compounds of the invention can be used for the treatment and/or prophylaxis of diseases and/or conditions mediated by hydro lytic enzymes. The compounds according to the invention can particularly be used for the treatment and/or prophylaxis of lipase-mediated diseases and/or conditions and more particularly for the treatment and/or prophylaxis of diseases and/or conditions mediated by pancreatic lipases.

The compounds according to this invention can be used for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions in humans and animals. In veterinary application the compounds of the invention are particularly useful in relation to medical and non-medical weight loss in companion animals such as pet cats, dogs, and horses as well as in animals which provide meat for human consumption. In the case of the latter, the application of the present invention is to reduce fat content in order to provide a leaner meat product. The compounds according to this invention can be used for the treatment and/or prophylaxis of obesity in humans and animals. The compounds according to this invention can be used for the treatment and/or prophylaxis of obesity related diseases in humans and animals. The compounds according to this invention can be used for the treatment and/or prophylaxis of obesity related conditions in humans and animals.

Since it is believed that increasing the amount of undigested fat passing through the body enhances diffusion of toxins from fat stored in the body into fats in the blood, and hence in the intestine, the compounds of the invention can also be used to reduce levels of toxins stored in body fat.

The compounds of this invention can also be used for test and diagnostic methods and the control and inhibition of unwanted enzymes, preferably lipases, in any process or in any product. The processes or products, which preferably involve a lipase include: processing of agricultural commodities (e.g. oilseeds), recovery and isolation of enzymes from biotechno logical processes (e.g. involving lysis of microorganisms), the manufacture and extraction of crude oil (especially oil and plastics), the industrial manufacture of triglycerides or other fats, manufacture of healthcare goods which comprise surfactants, soap, or detergent (e.g. bath oil, creams), the manufacturing and processing of liposomes (e.g. healthcare products, diagnostics, gene therapy), the treatment of industrial waste (e.g. paper effluent treatment) and preventing the degradation of foodstuff which comprises a fat (e.g. chocolate processing). Thus, the compounds of the invention can also be used e.g. as additive to foodstuff, in particular in foodstuff which have a high fat content such as cakes, biscuits, pastry-products and the like and chocolate products.

A further aspect of the invention provides pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof according and at least one further pharmaceutically tolerable additive for the use of the treatment and/or prophylaxis of obesity and obesity related diseases or conditions. The pharmaceutical composition can also comprise a pharmaceutically effective amount of compound of formula (II) to (IV).

Another aspect of the invention provides pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof according and at least one further pharmaceutically tolerable additive for the use of the treatment and/or prophylaxis of obesity. The pharmaceutical composition can also comprise a pharmaceutically effective amount of compound of formula (II) to (IV).

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof according and at least one further pharmaceutically tolerable additive for the use of the treatment and/or prophylaxis of obesity related diseases. The pharmaceutical composition can also comprise a pharmaceutically effective amount of compound of formula (II) to (IV).

The present invention also relates to a pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof according and at least one further pharmaceutically tolerable additive for the use of the treatment and/or prophylaxis of obesity related conditions. The pharmaceutical composition can also comprise a pharmaceutically effective amount of compound of formula (II) to (IV).

Suitable additives are well known in the art and include wetting agents, silica, gum arabic, pharmaceutical grade starch, mannitol, lactose magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose (or other sugars), magnesium carbonate, gelatin, oil, alcohol, glycerol, detergents, nanoparticles, emulsifϊers, or water (preferable sterile water). The composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate, or sequential use including administration. According to the invention, the pharmaceutical composition preferably comprises 0.1 mg to 4000 mg of the compound of formula (I) and at least one further pharmaceutically tolerable additive. The pharmaceutical composition for use according to the invention often comprises 1 mg to 2000 mg of the compound of formula (I). In a further embodiment, the pharmaceutical composition comprises 5 mg to 1000 mg of a compound of formula (I), and more preferred of formulae (II) or (III), and several further pharmaceutically tolerable additives.

The compounds according to the invention for the use in the aforementioned indications can be administered by any convenient method including topical (e.g. inhalation), enteral (e.g. oral and rectal), or parenteral (e.g. intravenous, intra-arterial, intramuscular, subcutaneous, transmucosal including buccal, sublingual, and nasal, or transdermal) to humans and animals in appropriate dosage units. Preferred routes of administration of the compound according to the invention include oral, nasal, intravenous, intramuscular routes.

The appropriate dosage forms for administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administration, aerosols, implants, forms for subcutaneous, intramuscular, intravenous, intranasal, or intraocular administration and forms for rectal administration.

When preparing a solid composition in the form of tablets, a wetting agent such as sodium laurylsulfate can be added to the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof optionally micronized, which is then mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, with various polymers or other appropriate substances or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof continuously.

A preparation in the form of gelatin capsules is obtained by mixing the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof with a diluent such as a glycol or a glycerol ester and pouring the mixture obtained into soft or hard gelatin capsules. A preparation in the form of a syrup or elixir can contain the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof together with a sweetener, which is preferably calorie-free, methyl-paraben and propylparaben as an antiseptic, a flavoring and an appropriate color. The water-dispersible powders or granules can contain the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof mixed with dispersants or wetting agents, or suspending agents such as polyvinyl-pyrrolidone, and also with sweeteners or taste correctors. Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example cacao butter or polyethylene glycols.

Parenteral or intranasal administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol, butylene glycol, or polyethylene glycol. Thus a cosolvent, for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween® 80, can be used to prepare an aqueous solution injectable by intravenous route. The compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof can be solubilized by a triglyceride or a glycerol ester to prepare an oily solution injectable by intramuscular route.

Transdermal administration is effected using multilaminated patches or reservoirs into which the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof is in the form of an alcoholic solution. Administration by inhalation is effected using an aerosol containing for example sorbitan trioleate or oleic acid together with trichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas.

The compounds of formula (I) or a polymorphic form or a pharmaceutically acceptable salt thereof can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives.

Among the prolonged-release forms which are useful in the case of chronic treatments, implants or stants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium. The compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof can also be presented in the form of a complex with a cyclodextrin, for example alpha-, (beta- or gamma-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin or methyl-beta-cyclodextrin.

The invention also relates to the use of compounds of formulae (I) to (VI) for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of obesity and of obesity related diseases or conditions. The invention also relates to the use of compounds of formulae (I) to (VI) for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of obesity. The invention also relates to the use of compounds of formulae (I) to (VI) for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of obesity related diseases. The invention also relates to the use of compounds of formulae (I) to (VI) for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of obesity related conditions.

A further embodiment of the invention is a pharmaceutical composition comprising at least one compound of formula (I) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof and at least one further pharmaceutically tolerable additive for the use of the treatment and/or prophylaxis of obesity and of obesity related diseases or conditions, in particular selected from hypertension, hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), and musculoskeletal disorders. The pharmaceutical composition can also comprise a compound of the more specific formulae (II) to (VI).

When in the following description a compound of formula (I) is mentioned, this also relates to the more precise formulae (II) to (VI) and to the specific compounds (1) to (24).

In the pharmaceutical compositions of the present invention the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof is generally formulated as dosage units containing from 0.1 to 4000 mg, preferably 1 to 2000 mg, and more preferably between 5 to 1000 mg of said compounds of formula (I) or a polymorphic form thereof or pharmaceutically acceptable salt thereof per dosage unit for daily administration.

For all aspects of the invention, particularly medical ones, the administration of a compound or composition has a dosage regime which will ultimately be determined by the attending physician and will take into consideration such factors such as the compound being used, animal type, gender, age, weight, severity of symptoms, method of administration, adverse reactions and/or other contraindications. Specific defined dosage ranges can be determined by standard design clinical trials with patient progress and recovery being fully monitored. Such trials may use an escalating dose design using a low percentage of the maximum tolerated dose in animals as the starting dose in man.

The physiologically acceptable compounds according to the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 0.01 mg/kg (mg per kilogram of body weight of the mammal to be treated) and 100 mg/kg, preferably between 0.1 mg/kg and 75 mg/kg, and more preferably between 1 mg/kg and 50 mg/kg. A daily intravenous, subcutaneous, or intramuscular dose will normally be between 0.01 mg/kg and 50 mg/kg, preferably between 0.1 mg/kg and 40 mg/kg, and more preferably between 1 mg/kg and 30 mg/kg of the compound according to the invention. The compound according to the invention is administered 1 to 6 times per day, preferably 1 to 5 times daily, and more preferably between 1 and 4 times daily. Suitably the compounds according to the invention will be administered for a period of continuous therapy, for example for a week or more.

The pharmaceutical composition can also comprise one or several of the compounds of the more specific formulae (II) to (VI).

The invention also relates to a pharmaceutical combination product comprising at least one compound of formula (I) - or of the more specific formulae (II) to (VI) -, at least one further anti-obesity drug compound and at least one further pharmaceutically tolerable additive. Typical examples of appropriate "further anti-obesity drug compounds" are inhibitors of lipases, serotonine and noradrenaline reuptake inhibitors. Further examples are CBl receptor antagonists, 5HT2C agonists, beta 3-adrenergic receptor agonists, leptins, leptin receptor, CCK-A agonists, appetite suppressants, appetite suppressing hormones, neuropeptide Y2 and Y4 agonists, compounds to delay gastric emptying, grehlin-targeted vaccines, incretin mimetics, human growth hormones, and compounds to induce adipose tissue wasting.

In particular, the "further anti-obesity drug compound" is a compound selected from the following known and/or commercialized drug compounds or development candidates: Orlistat, Sibutramine, Rimonabant, ATL-962 (Cetilistat), GT389-255, APD356, PYY(3-36), TM30338, Symlin, CYT-009-GhrQb, AOD9604 (hGH177-191), SLV319, CP945 598, SR58611A, L796568, modified leptin (e.g. Metreleptin), Leptin, GI181771, Oleoyl estrone, 1426, P57, Oxyntomodulin, Qnexa, Contrave, Lorcaserin, Pramlintide, Pramlintide/Leptin combination, Liraglutide GLP-I (glucagon- like peptide- 1), Empatic, Metformin, and Exenatide.

Some of these "further anti-obesity drug compounds" are described e. g. by Birari R. B. and Bhutani K. K. in Drug Discovery Today, 2007, 12, 879-889 and by Melnikova I. and Wages D., Nature Reviews Drug Discovery, 2006, 5, 369-370.

Due to unwanted side effects of treatments with current anti-obesity drug substances the dosage unit of the additional pharmaceutically active anti-obesity-drug substance is by a factor of at least two lower as compared to the dosage unit of the standalone therapy with the corresponding anti-obesity drug. This decreases the probabilities of unwanted side effects of standard anti-obesity therapies, while increasing unexpected synergistic effects related to efficacy of a combination product comprising at least one compound according to the invention and at least one further anti-obesity drug compound.

Surprisingly, the compounds according to the invention also showed to be effective inhibitors of catechol-O-methyltransferase (COMT). The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of COMT-mediated diseases or conditions. In particular, the present invention relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of Morbus Parkinson, whereby at least one of the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof is used as co-drug in order to prolong the half life of drug substances used for the treatment and/or prophylaxis and/or diagnosis of Morbus Parkinson. The compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof can also be used for the enhancement of drug action for drug substances that are metabolized by COMT, selected from, but not limited to, adrenaline, benserazide, carbidopa, dobutamine, dopamine, dopexamine, entacapone, isoprenaline, L-dopa, α- methyldopa and rimiterol. Surprisingly, the compounds according to the invention also showed to be effective inhibitors of endothelial nitric oxide synthase (eNOS). The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of eNOS-mediated diseases or conditions. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of stable or unstable angina pectoris, coronary heart disease, coronary artery disease, Prinzmetal angina, acute coronary syndrome, cardiac insufficiency, endothelial dysfunction, restenosis, endothel damage after PTCA, hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes, diabetes complications, nephropathy, retinopathy, angiogenesis, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance or a restricted ability to learn, or for lowering cardiovascular risk of postmenopausal women or after intake of contraceptives in a patient in need thereof.

Unexpectedly, the compounds according to the invention also showed to be effective inhibitors of phosphodiestease 4 (PDE4). The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of PDE4-mediated diseases or conditions. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of age-associated memory impairment, delirium, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, mental retardation, cerebrovascular disease, an affective disorder, psychotic disorders, neurotic disorders, attention deficit disorder, subdural hematoma, normal- pressure hydrocephalus, brain tumor, or head or brain trauma, schizophrenia, Pick's disease, Creutzfeld- Jakob disease, depression, aging, CNS hypoxia, cerebral senility, HIV, age-related cognitive decline.

Unexpectedly, the compounds according to the invention also showed to be effective inhibitors of phosphodiestease 5 (PDE5). The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of PDE5-mediated diseases or conditions. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of erectile dysfunction, albinism, vitiligo, piebaldism, Pityariasis alba, Hypomelanoses, Leukodermas, hypopigmentation, Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, the Angelman and Prader-Willi syndrome, cardiac hypertrophy, reduced systolic function, reduced diastolic function, maladaptive hypertrophy, heart failure with preserved systolic function, diastolic heart failure, hypertensive heart disease, aortic stenosis, and hypertrophic cardiomyopathy.

Surprisingly, the compounds according to the invention also showed to be effective inhibitors of spleen protein tyrosine kinase (Syk). The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of Syk-mediated diseases or conditions. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of mantle cell lymphoma, tumor associated angiogenesis, and systemic lupus erythematosus.

Surprisingly, the compounds according to the invention also showed to be effective inhibitors of xanthine oxidase. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of xanthine oxidase-mediated diseases or conditions. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of gout and renal insufficiency, hypertension and coronary disease, tumor lysis syndrome, circulatory shock, chronic heart failure, hypertension, hypercholesterolemia, diabetes, and toxic organ injury.

Surprisingly, the compounds according to the invention also showed to be effective inhibitors of prostaglandine E receptor 4. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of prostaglandine E receptor 4-mediated diseases or conditions.

The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of preventing preterm labor, dysmenorrhea, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, sexual dysfunction, osteporosis bone fracture, metastatic bone disease, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia, ulcerative colitis, stomatitis, gastritis, ocular hypertension, glaucoma, neuropathic pain, bone pain, and Reflex Sympathetic Dystrophy syndrome (RSD). Unexpectedly, the compounds according to the invention also showed to be effective inhibitors of purinergic P2y. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of purinergic P2y-mediated diseases or conditions. The present invention also relates to compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of sodium homeostasis, aldosteronism; heightened sensitivity to aldosterone and/or essential hypertension Parkinson's disease peripheral artery disease, cerebrovascular disease, embolisms and CNS disorders, emphysema, primary ciliary dyskinesia, and alpha 1 antitrypsin deficiency.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments, which are given for illustration of the invention and are not intended to be limiting thereof.

Examples

Example 1 :

The compounds of formula (I) and some pharmaceutically acceptable salts thereof were investigated for their inhibitory capacity employing a lipase-based molecular binding in vitro assay. The assay can be established using standard technologies, known to the person skilled in the art, according to Nakai, M., et al, J. Agric. Food Chem. 2005, 53, 4593-4598. The compounds of formula (I) according to the invention were tested for their ability to inhibit pancreatic lipase.

The pancreatic lipase activity was measured through hydrolysis of the fatty acid substrate 4-methylumbelliferyl oleate (4-MUO, Sigma, Schnelldorf, Germany) in a Tris(hydroxymethyl)-aminomethan (tris)-buffered, sodium chloride and calcium containing solution. The pancreas lipase mediates hydrolysis of 4-MUO, with release of the fluorophore 4-methylumbelliferyl (4-MU) from oleic acid, and the fluorescence was used as measure for lipase activity. The compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof were dissolved in DMSO, and diluted in a tris- buffered, sodium chloride and calcium containing solution to reach the desired concentration. Porcine lipase was acquired from Sigma as crude powder (15-35units/mg). In order to improve specific activity of lipase, the acquired lipase was purified by standard gel-filtration chromatography. The porcine lipase was eluted in a tris-buffer containing sodium chloride and ethylenediaminetetraacetic acid (EDTA).

The assay was performed in a 96-well OptiPlate (PerkinElmer, Rodgau-Jϋgesheim, Germany), placed on a Precision2000 pipetting-device (Biotek, Bad Friedrichshall, Germany). 25μl compound-containing solution was mixed at room temperature with 50μl 4-MUO solution, 25 μl lipase containing solution was added to initiate hydrolysis, and the reaction solution was mixed thoroughly. The hydrolysis reaction was allowed to proceed for 18 minutes, and was then stopped by adding lOOμl quench-buffer consisting of sodium citrate. The resulting fluorescence was measured in a Fusion α-FP (PerkinElmer, Rodgau- Jϋgesheim, Germany) with excitation at 365nm and emission at 460nm.

Some results obtained by testing the compounds of formula (I) as to their anti-obesity activity are listed in the following Table 1 :

Table 1: (Biological in vitro results from pancreatic lipase assay)

Compound (17), for example, shows an improved ICso-values as compared to the commercial compound Orlistat. Other compounds of formula (I) have ICso-values in the range of Orlistat.

Example 2

The in vivo efficacy of the compounds of formula (I) and some pharmaceutically acceptable salt thereof is assessed by employing a standard obesity model using standard methodologies known to the person skilled in the art. The compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof are tested in vivo for their inhibitory effect on absorption of fat from the intestine, taken in with the food. Inhibition of absorption can be induced by inhibiting the pancreatic lipase, and can be demonstrated in a double-labelling experiment in mice. The mice are fed a meal consisting of ¹⁴C-oleic acid and ³H triolein. Oleic acid is not absorbed by the mouse and will be excreted, whereas triolein is hydro lysed by the pancreas lipase and will be mostly absorbed. By inhibiting the pancreatic lipase, the ratio between triolein and oleic acid in feces will change. The in vivo inhibition of absorption of fat from the intestine by the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof is improved as compared to the reference drug Orlistat. In addition, as compared to Orlistat fewer side effects of the compounds of formula (I) or a polymorphic or pharmaceutically acceptable salt thereof are observed in this study.

Example 3 :

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a catechol-O-methyltransferase (COMT)-based molecular enzymatic in vitro assay. The assay was established using COMT from pig and standard technologies, known to the person skilled in the art, according to Zurcher G. et al. J. Neurochem., 1982, 38:191. The IC50 value of compound (23) is 3.0 μM. Compound (22) inhibits COMT 86% at inhibitor concentration of 10 μM. Example 4:

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a endothelial nitric oxid synthase (eNOS)-based molecular enzymatic in vitro assay. The assay was established using bovine eNOS and standard technologies, known to the person skilled in the art, according to Alderton W.K. et al. Biochem. J., 2001, 357: 593 and Southan GJ. et al. Br. J. Pharmacol, 1995, 114(2): 510. The IC₅₀ value of compound (23) is 0.5 μM. Compound (22) inhibits eNOS 52% at inhibitor concentration of 10 μM.

Example 5 :

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a phosphodiesterase 4 (PDE4)-based molecular enzymatic in vitro assay. The assay was established using human PDE4 and standard technologies, known to the person skilled in the art, according to Nicholson CD. et al., Trends Pharmacol. Sci., 1991, 12:19 and Cortijo J. et al., Br. J. Pharmacol, 1993, 108:562. The IC₅₀ value of compound (23) is 2.3 μM. Compound (24) inhibits PDE4 82% at inhibitor concentration of 10 μM.

Example 6:

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a phosphodiesterase 5 (PDE5)-based molecular enzymatic in vitro assay. The assay was established using human PDE5 and standard technologies, known to the person skilled in the art, according to Nicholsen CD. et al, Trends Pharmacol. Sci., 1991, 12:19 and Hidaka H. and Asano T. Biochim. Biophys. Acta., 1976, 429:485. Compound (24) inhibits PDE5 67% at inhibitor concentration of 10 μM.

Example 7:

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a spleen protein tyrosine kinase (Syk)- based molecular enzymatic in vitro assay. The assay was established using human Syk and standard technologies, known to the person skilled in the art, according to Shichijo M. et al. Biol. Pharm. Bull, 2003, 26, 1685 and Zhang J. et al, MoI. Cell Biol, 2002, 22, 8144. The IC50 value of compound (23) is 1.1 μM.

Example 8:

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a xanthine oxidase-based molecular enzymatic in vitro assay. The assay was established using bovine xanthine oxidase and standard technologies, known to the person skilled in the art, according to Hatano T. et al., Chem. Pharm. Bull, 1990, 38, 1224. The IC₅₀ value of compound (23) is 3.0 μM. Compound (24) inhibits xanthine oxidase 63% at inhibitor concentration of 10 μM.

Example 9:

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a prostaglandin E receptor 4-based molecular binding in vitro assay. The assay was established using human prostaglandin E receptor 4 and standard technologies, known to the person skilled in the art, according to Bastepe M. and Ashby B. MoI. Pharmacol, 1997, 51, 343 and Boie Y. et al., Eur. J. Pharmacol, 1997, 340, 227. The IC₅₀ value of compound (20) is 2.6 μM.

Example 10:

The compounds of formula (I) and some pharmaceutically acceptable salt thereof were investigated for their inhibitory capacity employing a purinergic P2y-based molecular binding in vitro assay. The assay was established using purinergic P2y from rat and standard technologies, known to the person skilled in the art, according to Ziganshin A.U. et al; Br. J. Pharmacol, 1993, 110, 1491 and Bo X. and Burnstock G., Br. J. Pharmacol, 1990, 101, 291. Compound (21), compound (22), and compound (24) inhibit purinergic P2y 86%, 74%, and 73% at inhibitor concentration of 10 μM, respectively.

Example 11 :

Soft gelatine capsules of the following composition are manufactured using standard methods known to the skilled person in the art. The gelantine capsules comprise 100 mg of compound (17) and 400 μL of NEOBEE M5. The solution of the compound (17) (or an acceptable salt thereof) in NEOBEE M-5 is filled into soft gelantine capsules of suitable size.

Example 12: Soft gelatine capsules of the following composition are manufactured using standard methods known to the skilled person in the art. The gelantine capsules comprise 60 mg of compound (17) (or a pharmaceutical acceptable salt thereof), 30 mg of Orlistat and 400 μL of NEOBEE M5. The solution of the compound (17) or a polymorphic form or a pharmaceutical acceptable salt thereof and Orlistat in NEOBEE M-5 is filled into soft gelantine capsules of suitable size.

Example 13:

Gastric resistant hard gelatine capsules of the following composition are manufactured using standard methods known to the skilled person in the art. 100 mg of compound (17) is mixed with extender comprising 0.5% (w/w) Aerosil® and 99.5% (w/w) Lactose DlO to fill the capsules. The capsules are sealed with gelantine solution and coated with Eudragit® L 12.

Example 14: Gastric resistant hard gelatine capsules of the following composition are manufactured using standard methods known to the skilled person in the art. 50 mg of compound (17) and 20 mg of Orlistat are mixed with extender comprising 0.5% (w/w) Aerosil® and 99.5% (w/w) Lactose DlO to fill the capsules. The capsules are sealed with gelantine solution and coated with Eudragit® L 12.

Claims

1. Compound of formula (I) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof for the treatment and/or prophylaxis of obesity and obesity related diseases or conditions whereby the compound of formula (I) is defined as

wherein the symbols of the substituents have the following meanings:

-R¹ denotes -H, -CH₃, -F, -Cl, -Br, -I, -OH, -NH₂; and -X-Y denotes one of the following groups a)

wherein R² being -H, -OH, -F, -Cl, -Br, -I, -CH₃, -CH₂CH₃, -NO₂, -NR³R⁴, -CF₃,

-OCH₃,

-SO₃H, -SO₂NR³R⁴, -CO₂R³, and R³ and R⁴ being independently from each other -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃

(-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl), and -[R³R⁴]- can also be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-, b)

with n being 1, 2, 3; c)

O

V H

and the group -Y denotes a)

whereby R⁵ and R⁶ are either R⁵ = -OH and R⁶ = -OH or R⁵ = -H and R⁶ = -OH or -OCH₃,

b)

whereby R⁶ and R⁷ are either R⁷ -H and R⁸ = -OH or R⁷ = -OH and R⁸ = -H or R⁷ = -NO₂ and R⁸ = -H; c)

d)

e) one of the following two groups

and -A denotes a) -CO₂R⁹, -CF₃, -SO₂NR⁹R¹ whereby R⁹ and R¹⁰ being independently from each other are

-H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-IsOPr₀PyI)₅-CH₂(C₆H₅) (- benzyl) and -[R⁹R¹⁰]- can also be a group -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b) a group

with m = 0,1 and with R⁹ is -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-isopropyl),-CH₂(C₆H₅) (-benzyl);

c) a group

d) a group

in which R⁹ is -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl); e) a group

in which R⁹ and R¹⁰ independently from each other are -H, -CH₃, -CH₂CH₃, (CH₂)₂CH₃

(-propyl), -CH(CH₃)₂ (-isopropyl),-CH₂(C₆H₅) (-benzyl) and -[R⁹R¹⁰]- can also be a group -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-,

f) a group

g) a group

in which R⁹ is -H, -CH₃, -CH₂CH₃, -(CH₂)₂CH₃ (-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl).

2. Compound of formula (I) for the use according to claim 1, whereby the compound is further defined by formula (II) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof

wherein the symbols of the substituents have the following meanings: -R¹ denotes -H, -CH₃, -F, -Cl, -Br, -I, -OH, -NH₂; and -X'-Y denotes a group a)

whereby R^2' being -H, -OH, -F, -Cl, -CH₃, -CH₂CH₃, -NR³ R^4', -SO₂NR³ R^4', -CO₂R^3' and R³ and R⁴ being independently from each other -H, -CH₃, -CH₂CH₃ and -[R³ R^4']- can also be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-;

b)

with n being 1, 2, 3;

c)

O

V H

and -Y denotes a)

whereby R and R are either R⁵ = -OH and R⁶ = -OH or R⁵ = -H and R⁶ = -OH, -OCH₃;

b)

whereby R⁷ and R⁸ being either R⁷ = -H and R⁸ -OH or R⁷ = -OH and R⁸ = -H or R⁷ = -NO₂ and R⁸ = -H; c)

d)

e) one of the two groups

and -A denotes a) a group

-CO₂R⁹, -CF₃, -SO₂NR⁹R¹⁰; whereby R⁹ and R¹⁰ being independently from each other -H, -CH₃, -CH₂CH₃, (CH₂)₂CH₃

(-propyl), -CH(CH₃)₂ (-isopropyl), -CH₂(C₆H₅) (-benzyl) and -[R⁹R¹⁰]- also can be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b)

with m = 0,1;

c)

d)

e)

f)

wherein R⁹ and R¹⁰ are defined as above.

3. Compound of formula (I) for use according to claim 1 or 2, whereby the compound is further defined by formula (III) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof

wherein the symbols of the substituents have the following meanings:

-R^{1 '} denotes -H, -CH₃, -OH; and -X" -Y denotes one of the following groups a)

whereby R^2" being -H, -F, -Cl, -CH₃, -CO₂R^3', and R^3' being -H, -CH₃, -CH₂CH₃;

b)

with n being 1, 2, 3; C)

and -Y denotes a)

whereby R and R being either R⁵ = -OH and R⁶ = -OH, or R⁵ = -H and R⁶ = -OH, -OCH₃,

b)

whereby R⁷ and R⁸ being either R⁷ = -H and R⁸ = -OH, or R⁷ = -OH and R⁸ = -H, or R⁷ = -NO₂ and R⁸ = -H, c)

d)

e) one of the two groups

and -A' denotes a group a) -CO₂R^9', -CF₃, -SO₂NR⁹ R^10'; whereby R⁹ and R¹⁰ being independently from each other -H, -CH₃, -CH₂CH₃ and -[R⁹ R^10']- also can be -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b)

9'

with m = 0,1;

c)

d)

e)

f>

whereby R > 9' and . r R, 10' are defined as above.

4. Compound of formula (I) for the use according to one of the claims 1 to 3, whereby the compound is further defined by one of the formulas (IV) or (V) or (VI) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof:

wherein the symbols of the substituents have the following meanings: -R^{1 '} denotes -H, -CH₃, -OH; and -Z-Y is a group: a)

b)

with n being 1, 2, 3; C)

and -Y denotes a group a)

b)

whereby R⁷ and R⁸ are either R⁷ = -H and R⁸ -OH, or R⁷ = -OH and R⁸ = -H, or R⁷ = -NO₂ and R⁸ = -H, c)

d)

e) one of the two groups

and -B denotes a group: a) -CO₂R^9', -CF₃, -SO₂NR⁹ R^10'; whereby R⁹ and R¹⁰ being independently from each other -H, -CH₃, -CH₂CH₃ and [R⁹ R^10'] being also -(CH₂)₄-, -(CH₂)₅-, -CH₂-CH₂-O-CH₂-CH₂-; b)

and -B denotes a group: a) -CO₂R^9', -CF₃, -SO₂NR⁹ R¹ b)

and -B denotes a group: a)

with m = 0,1 b)

c)

d)

whereby R⁹ and R¹⁰ are defined as above.

5. Compound of formula (I) for the use according to claim 1, whereby the compound is further defined by the following formulas (1) to (24) or a polymorphic form thereof or a pharmaceutically acceptable salt thereof

6. Pharmaceutical composition comprising a pharmaceutically effective amount of compound of formula (I) according to one of the claims 1 to 5 or a polymorphic form thereof or a pharmaceutically acceptable salt thereof, and at least one further pharmaceutically tolerable additive, for the use of the treatment and/or prophylaxis of obesity and obesity related diseases or conditions.

7. Pharmaceutical composition for use according to claim 6 which is used for the treatment and/or prophylaxis of obesity and obesity related diseases selected from hypertension, hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), and musculoskeletal disorders.

8. Pharmaceutical composition for use according to claim 6 or 7 wherein the pharmaceutical composition comprises 0,1 mg to 4000 mg of the compound of formula (I) and at least one further pharmaceutically tolerable additive.

9. Pharmaceutical composition for use according to one of the claims 6 to 8 wherein the composition comprises 1 mg to 2000 mg of the compound of formula (I).

10. Pharmaceutical composition for use according to one of the claims 6 to 9 wherein the composition comprises 5 mg to 1000 mg of a compound of formulae (II) or (III) and several further pharmaceutically tolerable additives.

11. Pharmaceutical combination product comprising a compound of formula (I) as defined in claims 1 to 5, a further anti-obesity drug compound and at least one further pharmaceutically tolerable additive.