OA16708A

OA16708A - Novel piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma.

Info

Publication number: OA16708A
Application number: OA1201400045
Authority: OA
Inventors: Pascale A. J. POUZET; Peter Nickolaus; Ulrike Werthmann; Rogelio P. Frutos; Bing-Shiou Yang; Soojin Kim; Jason Alan Mulder; Nitinchandra Patel; Chris H. Senanayake; Thomas G. Tampone; Xudong Wei
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2011-08-24
Filing date: 2012-07-18
Publication date: 2015-12-07

Abstract

The invention relates to novel piperidinodihydrothienopyrimidine sulfoxides of formula I, wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is CI and wherein R may be located either in the para-, meta- or ortho-position of Ring A, wherein S* is a sulphur atom that represents a chiral center, and all pharmaceutically acceptable salts, enantiomers and racemates, hydrates and solvates thereof and the use of these compounds for the treatment of inflammatory or allergic diseases of the respiratory tract such as COPD or asthma.

Description

NOVEL PIPERIDINO-DIHYDROTHIENOPYRIMIDINE SULFOXIDES AND

THEIR USE FOR TREATING COPD AND ASTHMA

The invention relates to novel piperidino-dihydrothienopyrimidine sulfoxides of formula I,

wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is Cl and wherein R may be located either in the para-, meta- or ortho-position of Ring A, wherein S* is a sulphur atom that represents a chiral center, and ail pharmaceutically acceptable salts, enantiomers and racemates, hydrates and solvatés thereof and the use of these compounds for the treatment of inflammatory or allergie diseases of the respiratory tract such as COPD or asthma.

PRIOR ART

WO 2006/111549 and WO 2007/118793 each disclose dihydrothienopyrimidinesulfoxides which are substituted by piperazine instead of piperidine. WO 2009/050248 discloses piperidino-dihydrothienopyrimidines which differ from the compounds of the invention in their substitution pattern. Due to their particular substitution pattern the compounds of the invention are at the same time more potent

PDE4 inhibitors than the compounds disclosed in WO 2009/050248 and show a minimized potential for the development of unwanted gastrointestinal side effects.

DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the compounds of the invention are due to their particular substitution pattern particularly suitable for the treatment of inflammatory disease. The compounds of the invention are further superior to the corresponding piperazino-dihydrothienopyrimidine sulfoxides of the prior art document WO 2009/050248.

The présent invention therefore relates to compounds of formula I

wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and wherein R is Cl and wherein R may be located either in the para-, meta- or ortho-position of Ring A, wherein S* représente a sulphur atom that is a chiral center, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvatés and polymorphs thereof. yy

The invention further relates to the above-mentioned compounds of formula I, wherein R is Cl and wherein R is preferably located in the para-position of Ring A, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvatés and polymorphs thereof.

The invention further relates to the above-mentioned compounds of formula I, wherein Ring A is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvatés and polymorphs thereof. The invention preferably relates to the above-mentioned compounds of formula I, wherein Ring A is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl and wherein R is a C)-substituent in the para-position, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvatés and polymorphs thereof.

U, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvatés and polymorphs thereof.

In particular the invention concems the compound of formula III, —

and ali pharmaceutically acceptable salts thereof, enantiomers and racemates thereof, hydrates, solvatés and polymorphs thereof.

The invention further relates to the above-mentioned compounds according of one of formula I, II or IH, wherein S* represents a sulphur atom which represents a chiral center being in the R-configuration.

The invention further relates to the above-mentioned compounds according of one of formula I, II or III, wherein S* respresents a sulphur atom which represents a chiral center being in the S-configuration.

For the compound of formula ΙΠ three different polymorphs, two different anhydrous forms and one dihydrate form hâve been identified and characterized by X-ray powder diffraction (XRPD), by thermogravimetric analysis (TGA) and by differential scanning calorimetry (DSC).

Fig. 3a shows the X-ray powder diffraction diagram of the anhydrous form A of formula III (see Example 2).In this XRPD diagram of the anhydrous form A of formula III the followingthe 20-values and d-values could be observed (Table l). —

Table 1 : Ali observable neaks for the anhydrate Form A:

2-Theta	d(Âj	l/lo
4.48	19.70	27
8.76	10.09	46
9.54	9.26	11
12.98	6.82	69
13.44	6.58	9
15.50	5.71	2
16.56	5.35	8
17.94	4.94	35
18.54	4.78	20
19.18	4.62	100
20.36	4.36	15
20.64	4.30	10
21.48	4.13	23
22.62	3.93	38
22.98	3.87	15
23.65	3.76	4
24.46	3.64	15
24.76	3.59	21
26.61	3.35	5
27.34	3.26	13
27.92	3.19	28
29.14	3.06	15
30.68	2.91	11
31.05	2.88	17
32.34	2.77	8
32.65	2.74	3

33.28	2.69	20
33.54	2.67	17

The major peaks of the XRPD diagram of anhydrous Form A of the compound of formula III are listed in Table 2.

Table 2: Major peaks for the anhydrate Form A:

2-Theta	“d(Âj	l/lo
4.48	19.70	27
8.76	10.09	46
12.98	6.82	69
17.94	4.94	35
19.18	4.62	100
21.48	4.13	23
22.62	3.93	38
24.76	3.59	21
27.92	3.19	28

The most prominent peaks of the XRPD diagram of anhydrous Form A of the compound of formula III are listed in Table 3.

Table 3: Prominent peaks for the anhydrate Form A:

2-Theta	“d(Âj	l/lo
8.76	10.09	46
12.98	6.82	69
19.18	4.62	100

Fig. 3b shows the X-ray powder diffraction diagram of the anhydrous form B of formula III (see Example 2). In this XRPD diagram of the anhydrous form B of formula III the following 20-vaIues and d-values could be observed (Table 4).

Table 4: ΑΠ observable peaks for the anhydrate Form B:

2-Theta	d(A)	l/lo
4.78	18.47	46
9.78	9.04	25
14.56	6.08	5
15.14	5.85	17
16.96	5.22	43
17.48	5.07	14
19.18	4.62	100
19.74	4.49	41
20.80	4.27	38
21.30	4.17	71
21.72	4.09	28
23.82	3.73	50
24.28	3.66	55
24.58	3.62	35
25.53	3.49	4
26.64	3.34	21
27.12	3.29	2
27.61	3.23	13
27.90	3.20	31
28.48	3.13	8
28.78	3.10	18
29.74	3.00	8
30.92	2.89	18

31.75	2.82	6
32.04	2.79	10
32.78	2.73	2
34.55	2.59	8

The major peaks of the XRPD diagram of anhydrous Form B of the compound of formula

III are listed in Table 5.

Table 5: Major peaks for the anhydrate Form B:

2-Theta	d(A)	l/lo
4.78	18.47	46
9.78	9.04	25
15.14	5.85	17
16.96	5.22	43
19.18	4.62	100
19.74	4.49	41
20.80	4.27	38
21.30	4.17	71
21.72	4.09	28
23.82	3.73	50
24.28	3.66	55
27.90	3.20	31

The most prominent peaks of the XRPD diagram of anhydrous Form B of the compound of formula III are listed in Table 6.

Table 6: Prominent peaks for the anhydrate Form B

2-Theta	d(A)	l/lo
4.78	18.47	46
16.96	5.22	43
19.18	4.62	100
21.30	4.17	71
24.28	3.66	55
23.82	3.73	50

Consequently the invention concems a crystalline anhydrous compound of formula III which shows a reflex peak in the X-ray powder diffraction diagram with a d-value of 4.62 Â.

Further the invention concems a crystalline anhydrous compound of formula III which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Â, 6.82 Â and 10.09 Â.

Further the invention concems a crystalline anhydrous compound of formula III. which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 A, 4.17 Â and 3.66 Â.

Additionally the invention relates to a crystalline anhydrous compound of formula III, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Â, 6.82 Â, 10.09 Â, 3.93 Â and 4.94 Â.

Additionally the invention relates to a crystalline anhydrous compound of formula III, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 A, 4.17 Â, 3.66 Â, 3.73 Â and 18.47 Â. —

Fig. 3c shows the X-ray powder diffraction diagram of the dihydrate form C of formula III (see Example 2).In this XRPD diagram of the dihydrate form C of formula III the following 20-values and d-values could be observed (Table 7).

Table 7: Ail observable peaks for the dihydrate Form C:

2-Theta	d(A)	l/lo
8.60	10.27	4
9.78	9.04	15
10.28	8.60	28
11.10	7.97	6
12.96	6.83	8
13.72	6.45	16
14.72	6.01	5
15.46	5.73	9
17.20	5.15	70
18.72	4.74	21
19.10	4.64	29
19.70	4.50	33
20.04	4.43	26
20.70	4.29	75
21.54	4.12	100
22.48	3.95	61
23.00	3.86	5
23.78	3.74	5
24.26	3.67	7
24.62	3.61	15
24.98	3.56	19

26.50	3.36	41
27.92	3.19	8
28.62	3.12	20
29.21	3.05	9
29.64	3.01	15
30.18	2.96	19
30.66	2.91	16
31.88	2.80	4
33.00	2.71	12
33.94	2.64	9

The major peaks of the XRPD diagram of dihydrate Form C of the compound of formula III are listed in Table 8.

Table 8: Major peaks for the dihydrate Form C:

2-Theta	d(A)	l/lo
10.28	8.60	28
17.20	5.15	70
18.72	4.74	21
19.10	4.64	29
19.70	4.50	33
20.04	4,43	26
20.70	4.29	75
21.54	4.12	100
22.48	3.95	61
26.50	3.36	41
28.62	3.12	20

The most prominent peaks of the XRPD diagram of dihydrate Form C of the compound of formula III are listed in Table 9.

Table 9: Prominent peaks for the dihydrate Form C:

2-Theta	d(A)	l/lo
17.20	5.15	70
20.70	4.29	75
21.54	4.12	100
22.48	3.95	61
26.50	3.36	41

Consequently, the invention relates to a crystalline dihydrate compound of formula III, which shows a reflex peak in the X-ray powder diffraction diagram with a d-value of 4.12 Â.

The invention also relates to a crystalline dihydrate compound of formula III. which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.12 Â, 4.29 Â and 5.15 Â.

The invention further relates to a crystalline dihydrate compound of formula HI, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.12 Â, 4.29 Â, 5.15 Â, 3.95 Â and 3.36 Â.

In another aspect the invention relates to the above-mentioned compounds for use as a médicament.

Another aspect of the invention concems a method of treating a disease which can be treated by the inhibition of the PDE4-enzyme comprising the step of administering one of the aforementioned compounds according to at least one of formulas I, II or III to a patient in need thereof.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, Il or III for preparing a médicament for the treatment and/or prévention of a disease which can be treated by the inhibition of the PDE4-enzyme.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I, II or III for the treatment_and/or prévention of a disease which can be treated by the inhibition of the PDE4-enzyme.

The invention further relates to the above-mentioned method of treating a disease which can be treated by the inhibition of the PDE4-enzyme comprising the step of administering one of the aforementioned compounds according to at least one of formulas 1. Il or III to a patient in need thereof, characterised in that the disease to be treated is selected from the group consisting of a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, the skin or the eyes, cancer and a disease of the peripheral or central nervous system.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, II or III for preparing a médicament for the treatment and/or prévention of a disease which can be treated by the inhibition of the PDE4-enzyme, wherein the disease to be treated is selected from the group consisting of a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, the skin or the eyes, cancer and a disease of the peripheral or central nervous system.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I, II or III for the treatment_and/or prévention of a disease which can be treated by the inhibition of the PDE4-enzyme, wherein the disease to be treated is selected from the group consisting of a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, the skin or the eyes, cancer and a disease of the peripheral or central nervous system. —

The invention further relates to the above-mentioned method of treating a disease which is selected from the group consisting of a respiratory or pulmonary disease which is accompanied by increased mucus production, inflammations and/or obstructive diseases of the respiratory tract, comprising the step of administering one of the aforementioned compounds according to at least one of formulas I, II or III to a patient in need thereof.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, Il or III for preparing a médicament for the treatment and/or prévention of a disease selected from the group consisting of a respiratory or pulmonary disease which is accompanied by increased mucus production, inflammations and/or obstructive diseases of the respiratory tract, comprising the step of administering one of the aforementioned compounds according to at least one of formulas I. H or 111 to a patient in need thereof.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I,11 or III for the treatment and/or prévention of a disease selected from the group consisting of a respiratory or pulmonary disease which is accompanied by increased mucus production, inflammations and/or obstructive diseases ofthe respiratory tract, comprising the step of administering one of the aforementioned compounds according to at least one of formulas I. II or II.

The invention further relates to the above-mentioned method of treating a disease which is selected from the group consisting of COPD, chronic sinusitis, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, asthma and chronic bronchitis, comprising the step of administering one of the aforementioned compounds according to at least one of formulas I, Il or III to a patient in need thereof.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, II or III for preparing a médicament for the treatment and/or prévention of a disease selected from the group consisting of COPD, chronic sinusitis, __ idiopathic pulmonary fibrosis, alpha l antitrypsin deficîency, asthma and chronic bronchitis.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I, II or HI for the treatment and/or prévention of a disease selected from the group consisting of COPD, chronic sinusîtis, idiopathic pulmonary fibrosis, alpha l antitrypsin deficiency, asthma and chronic bronchitis.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, Il or III for preparing a médicament for the treatment and/or prévention of a disease selected from the group consisting of rheumatoid arthritis, sarcoidosis, glaucoma and the dry eyes syndrome.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I, II or III for the treatment and/or prévention of a disease selected from the group consisting of rheumatoid arthritis, sarcoidosis, glaucoma and the dry eyes syndrome.

The invention further relates to the above-mentioned method of treating a disease which is selected from the group consisting of Crohn’s disease and ulcerative colitis, comprising the step of administering one of the aforementioned compounds according to at least one of formulas I, Il or III to a patient in need thereof.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, II or III for preparing a médicament for the treatment and/or prévention of a disease selected from the group consisting of Crohn’s disease and ulcerative colitis.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I, II or III for the treatment and/or prévention of a disease selected from the group consisting of Crohn’s disease and ulcerative colitis.

The invention further relates to the above-mentioned method of treating a disease which is selected from the group consisting of dépréssion, bipolar or manie dépréssion, acute and chronic anxiety states, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute and hypoxia or cranio-cerebral trauma, comprising the step of administering one of the aforementioned compounds according to at least one of formulas I, Π or III to a patient in need thereof.

Further the invention concems the use of one of the aforementioned compounds according to at least one of formulas I, Π or III for preparing a médicament for the treatment and/or prévention of a disease selected from the group consisting of dépréssion, bipolar or manie dépréssion, acute and chronic anxiety states, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia or cranio-cerebral trauma.

Further the invention concems one of the aforementioned compounds according to at least one of formulas I, II or III for the treatment and/or prévention of a disease selected from the group consisting of dépréssion, bipolar or manie dépréssion, acute and chronic anxiety states, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia or cranio15 cérébral trauma.

In another aspect the invention concems a pharmaceutical composition comprising at least one of the aforementioned compounds according to at least one of formulas I, II or IH.

In a further aspect the invention relates to a pharmaceutical composition characterised in that it contains at least one of the aforementioned compounds of at least one of formulas I, Il or III in combination with one or more active substances selected from the group consisting of betamimetics, corticosteroids, anticholinergics, other PDE4 inhibitors, NS AIDS, COX2 inhibitors, EP4 receptor antagonists, EGFR-inhibitors, LTD4- antagonists, CCR3-inhibitors, iNOS-inhibitors, MRP4-inhibitors and SYK inhibitors.

In another aspect the invention relates to a method of manufacturing the compound A _v__ hxV°^H

A wherein HX is a pharmaceutically acceptable acid, comprising the steps a) and b), wherein in step a) compound B

wherein HY is a pharmaceutically acceptable acid, îs reduced by borane and wherein in step b) a pharmaceutically acceptable acid HX is added in order to obtain compound A.

In one embodiment of the above-mentioned method of manufacturing compound A the borane for the réduction in step a) is added directly.

In another embodiment of the above-mentioned method of manufacturing compound A the borane for the réduction in step a) is generated in-situ.

In a preferred embodiment of the above-mentioned method of manufacturing compound A the borane for the réduction in step a) is generated in situ either from the combination of NaBH4 and h or from the combination of NaBFL and BF3-OEt₂.

In another preferred embodiment of the above-mentioned method of one of manufacturing compound A the acid HX is selected from tosylic acid or hydrochloric acid,

In a further embodiment of the above-mentioned method of one of manufacturing compound A the pharmaceutically acceptable acid HY in compound B is HCl.

In another aspect the invention relates to a method of manufacturing compound C

C wherein HX is tosylic acid, hydrochloric acid or sulphuric acid, comprising the steps i), ii) and iii), wherein in step i) 4-cyano-piperidine is contacted first with an acid and is then reacted with ammonia in order to obtain intermediate E

and wherein in step ii) intermediate E is reacted with compound D in the presence of a base

I ^Cl U

D and wherein in step iii) the acid HX is added. vj'

In a preferred embodiment of the above-mentioned method of manufacturing compound C 4-cyano-piperidine is contacted with hydrochloric acid and is then reacted with ammonia in order to obtain intermediate E in step i).

In a preferred embodiment of the above-mentioned method of manufacturing compound C the intermediate E is reacted with compound D in the presence of sodium methanolate in step ii).

In a further aspect the invention relates to intermediates of formula VIII

N. /Cl

ΌΗ

VIII and their salts.

In a further aspect the invention relates to intermediates of formula IX

N^/CI

and their salts, wherein S* stands for a sulphur atom that represents a chiral center.

IX

Compounds of the general formulas I, II und III contain basic groups. Therefore compounds of the general formulas I, II und III may form salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or with organic acids (such as for instance maleic acid, fumaric acid, citric acid, tartane acid or acetic acid).

As described above the compounds of formulas I, II and III may be transfonned into their pharmacologically acceptable salts for their use as pharmaceutics. For instance these compounds may form physiologically and pharmacologically acceptable acid addition salts with inorganic or with organic acids. In order to produce these acid addition salts of the compounds of formulas I, II and III for instance hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methyl sulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid may be used. Further it is possible to use mixtures of the aforementioned acids.

The compounds of formulas I, II and III may also be présent in the form of their individual optic isomers or enantiomers, in mixtures of the individual enantiomers or in the form of their racemates, and in the form of their free bases or in the form of their acid addition salts with pharmacologically acceptable acids (for instance acid addition salts with hydrohalogenic acids such as hydrochloric acid or hydrobromic acid or with organic acids such as oxalic acid, fumaric acid, diglycolic acid or methyl sulfonic acid.

The compounds of the invention may also be présent in their racemic forms, but may also be présent in the form of one pure enantiomers, that means in their (R)- or in their (S)forms.

As mentioned before the pharmacologically acceptable salts of the compounds of formula I, H and III are also a preferred aspect of the instant invention. These pharmaceutically acceptable salts of the compounds of formulas I, II and III may also be présent in the form of their hydrates (for instance mono- or dihydrates) and/or in the form of their solvatés.

A solvaté of a compound of formula I, II or III is defined herein as a crystalline sait of the respective compound of formula I, II or III which contains solvent molécules (for instance éthanol, methanol etc.) within its crystal lattice. —

A hydrate of a compound of formula I, II or III is defined herein as a crystalline sait of a compound of formula I, II or III which contains crystalline water in its crystal lattice.

METHODS OF SYNTHESIS

Génération of Examples 1 and 2:

Scheme I:

chiral Example 1

I · J R = 4-chlorophenyl;

X or Example 2

R = 5-chloropyrlmldlne~2-yl

X-= CI-or Ts-or HSO,·

C: R ³ 4-Chkxophenyl

G: R » 5-ChloropyrlmkHoe-2-yl

3.1. Génération of Compound VII:

Scheme 2

^°Y^SH ₊	Piperidine	t—C0,Me CO ₂ Me	Ti(O‘Pr)CI₃EtjN	fi	Η,Ν^ΝΗ,
0	O *			^g-^COjMe	U
				L J	MeOH
1	II	111		IV	HCl

Cl

Vil

Dlethylanlline S

HjO

OH

VI

NaOH

V

3.1.1 Synthesis of Dimethyl-3-thiaadipate (Compound 111)

Piperidine (0.02 equiv)

CO₂Me

III

Methyl thioglycolate (292 g, 2.61 mol) and piperidine (4.43 g, 0.052 mol) were charged to an inerted jacketed reactor equipped with an addition funnel, mechanical stirrer, N2 line and thermocouple thermometer. Methyl acrylate (250 g, 2.87 mol) was then added slowly over a period of 30 min keeping the température at approximately 45 °C. Upon complété addition, the mixture was stirred at 45 °C for 30 min. Piperidine (17.9 g, 210 mmol) was added and stirring at 45 °C continued for 30 min (in order to scavenge of excess acrylate). Tert-butylmethylether (MTBE) (251 ml) was charged, the mixture was cooled to 15 °C and 1 M HCl (251 ml) was added. The mixture was stirred for 5 min and the organic layer was collected and washed with water (251 ml). The mixture was concentrated to a minimum volume by distillation under reduced pressure at 50 °C. Dichloromethane (251 ml) was charged and the mixture was again concentrated under reduced pressure by distillation at 40-45 °C. Crude product III (480 g) was used in the next step without further purification.

3.1.2 Synthesis of Μο(Ην1-3-οχο-ίείΓ3Ηνί1ι·οίΙΐΐορ1ΐοιΐ6-2-£«Γί)οχν13ίο (Compound IV) t—CO₂Me \g/^CO₂Me τί(0'ΡΓ)α₃

Et₃N

CO₂Me

III

IV

T1CI4 (1.0 M CH2CI2, 1.16 L; 1.16 mol) was charged to an inerted and dried jacketed reactor equipped with température probe, mechanical stirrer and a dropping funnel. The reactor contents were cooled to -10 °C and isopropanol (89.6 ml, 1.16 mol) was charged at or below -ΙΟ “C. The mixture was stirred at -ÎO °C for 30 min and dimethyl 3-thiaadipate (200 g, l.Ol mol) was charged slowly over I h keeping the internai température at or below -10 °C. The réaction was stirred for an additional 30 min at -10 °C and Et₃N (489 mL, 3.49 mol) was slowly charged over 1.5 hours keeping the internai température at or below - ÎO °C. The mixture was stirred at or below - ÎO °C for 1.5 hours. 3 N HCl (l.Ol L; 3.03 mol) was slowly charged keeping the internai température below 10 °C. The température was increased to 30 °C and the mixture was stirred for l hour. The mixture was allowed to settle, the organic layer was collected and the aqueous layer was extracted with dichloromethane twice (1.5 l per extraction). The combined organic portions were washed twice with water (1.5 l per wash) and dried with MgSÛ4 (40 g). The resulting solution was concentrated to a minimum volume under reduced pressure at 25-35 °C to afford crude IV (148.6 g). The spectral data of IV is consistent with literature values (Liu, H.-J.; Teng, K. N. Can. J. Chem. 1982, 60, 437).

3.1.3 Synthesis of 3“Urcido-4,5-dihvdro-thiophene-2-carboxylic acid methyl ester (Compound V)

Urea,

CO,Me --------MeOH/HCI

IV

Urea (2.16 kg, 35.9 mol) was charged into a dry, jacketed reactor equipped with a stirrer, N₂ line and thermocouple thermometer. 3-oxo-tetrahydro-thiophene-2-carboxylic acid methyl ester (Compound IV, 3.0 kg) was charged followed by methanol (4.5 1). Conc. HCl (297 ml, 3.59 mol) was charged at 20-25 °C and the mixture stirred at reflux for 4-6 hours. The reaction mixture was cooled to 0 °C and the resulting solid was collected by filtration. The cake was washed with water twice (2 1 water per wash) and dried in a vacuum oven at 50 °C to afford 4.17 kg (83 % ^w/w) of compound V (95% yield), 'H NMR (500 MHz, (CD3)2SO) δ 3.10 (dd, 2 H, J= 8.5, 8.5 Hz), 3.50 (dd, 2 H, J = 8.5, 8.5 Hz), 3.73 (s, 3 H), 6.50-7.20 (bs, 2 H), 9.47 (s, I H); ^l3C NMR (125 MHz, (CD3)₂SO) δ 28.7, 37.8, 52.4, 100.0, 151.6, 154.7, 165.7; LCMS (El) for C₇HnN₂O₃S, (M+H)+ calcd. 203.0, measd. 203.0.

3.1.4 Synthesis of 6.7-Dihydro-thienoI3,2-<Z|pyrimidine-2_t4-diol (Compound VI)

V

NaOH

H₂O

OH

VI

Compound V (2.0 kg, 9.47 mol) was added to a solution of water (6.0 1) and NaOH (379 g, 9.47 mol) at normal room température. The above mixture was stirred at 85 °C for 3 hours. After cooling to 0 °C, conc. HCl (861 ml, 10.4 mol) was added slowly until the pH of the solution was 0-1. The mixture was cooled to 0 °C, stirred for 5-10 min and the resulting solid was collected by filtration. The cake was washed thoroughly with water twice (1 1 per rinse), air-dried for 2-3 hours (suction) and then dried further in a vacuum oven at 50 °C for 12-16 hours to afford 1.67 kg of compound VI. ^!H NMR (500 MHz, (CD3)2SO) Ô 3.11 (dd, 2 H, J= 8.5, 8.5 Hz), 3.31 (dd, 2 H, J = 8.5, 8.5 Hz), 11.14 (s, 1 H), 11.38 (s, 1 H); ¹³C NMR (125 MHz, (CD3)₂SO) δ 29.3, 35.4, 108.5, 150.5, 152.4, 160.4; LCMS (El) for C₆H₇N₂O₂S, (M+H)⁺ calcd. 171.0, measd. 171.0.

3.1.5 Synthesis of Z.d-dichloro-thienolS.Z-dlpvrimidine (Compound VII):

POCI₃

800 g of solid Compound VI (4.66 mol) was charged into to an inert and dry jacketed reactor (reactor 1 ) equipped with a température probe, mechanical stirrer and a dropping funnel. 1.5 litre (9.31 mol) Diethylaniline was charged over 30 min to l h keeping the température at or below 25 °C. The internai température was brought up to 105-110 °C and 0.68 equiv. (868 ml,34% of the total) of phosphorus oxychloride was added into the reactor (reactor l) over 5-10 min. When the inside température began to decrease, the internai température was maintained at 110 °C and addition of the remaining POCh (1.32 equiv. or 66% of the total) resumed over a period of 30-40 min. The internai température was adjusted to 105-110 °C and the mixture was stirred for 18-24 h or until complété (HPLC analysis). The mixture was cooled to 45 °C and THF (400 mL) was charged at 45 °C. The above crude mixture was placed into a secondary dry vessel or reactor (vessel or reactor 2). 4.8 1 of water was charged into the reactor 1 and cooled to 5 °C. The crude reaction mixture (in reactor or vessel 2) is then slowly charged into reactor 1 containing water keeping the température at 5-10 °C. The mixture was stirred at 5 °C for 30 min to 1 h and the resulting solid was collected by filtration. The cake was rinsed with water twice (1.6 1 per rinse) and the cake was air dried in the funnel for 6-8 h to afford 964 g (92%w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) is charged into a

L reactor. Crude Compound VII and activated carbon (46.2 g) were charged into the reactor, the mixture is heated to 40°C and stirred for 20 min. The resulting solution was collected by filtration through a filter media to remove charcoal. The cake was rinsed with dichloromethane twice (175 ml per rinse). The solution was concentrated under reduced pressure to a minimum stirrable volume and the remaining dichloromethane was chased away by distillation with a minimum amount of petroleum ether. Additional petroleum ether (1.3 1) was charged into the reactor, the mixture was cooled to 10°C and stirred for I hr. The resulting solid was collected by filtration and the cake was rinsed with petroleum ether twice (150 ml per rinse), The cake was air dried in the funnel (suction) until it appeared dry, The resulting solid Compound VII was transferred to a suitable tared container and dried in an oven at 50 °C for 6 hr to get final product: 'H NMR (400 MHz, DMSO-d6) δ 3.45-3.56 (m, 4H); ^l3C NMR (400 MHz, DMSO-d6) δ 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.

3.2 Génération of Example 1:

Scheme 3:

HClOH

C

X- = CI- or Ts- or HSO₄A (66%)

3.2.1 Synthesis of Compound A

1. Ij/NaBH^

2. p-TsOH

NaBH4 (28.6 g, 757 mmol, 2.87 eq) and THF (500 ml) were charged to a 2 L reactor under nitrogen and the mixture was cooled to -5 °C. A solution of h (63.6 g, 251 mmol, 0.95 eq) in 125 mL THF was prepared and added to the reactor slowly over 45 min maintaining an internai temp of -5 to 5 °C. The addition funnel was then rinsed with 42 mL THF. Compound B (50 g, 264 mmol, 1 eq) was then charged at -6 °C, then the température rose to approx. 5 °C. The reaction mixture was then heated to 65 °C for 23 h (Note: Reaction conversion was analyzed by GC/FID by quenching 0.1 mL reaction mixture with MeOH, then derivatizing with 0.5 mL of a 5/2/2 mixture of THF/acetic anhydride/TEA). 83 mL MeOH were then charged to the reaction mixture slowly over 20 min maintaining the température between 20-27 °C. The reaction mixture was concentrated to a minimum stirrable volume and 500 mL 2-methyltetrahydrofurane (MeTHF) were added. 485 g of 25 wt% aq. NaOH (11.5 eq) were then added, solids were dissolved. The layers were separated and the aqueous phase was extracted twice with 500 ml 2 methyltetrahydrofurane (MeTHF). The organics were then filtered through a pad of celite and MgSO4 and rinsed with 50 mL 2-methyltetrahydrofurane (MeTHF). A solution of ptoluenesulfonic acid monohydrate (51 g, 264 mmol, l eq) in MeTHF (100 ml) was prepared and added to the organics (altematively HCl may be used to obtain the HCl-salt of compound A). A homogeneous light yellow solution resulted. The solution was concentrated to -275-300 mL and the water content was checked. Addltional MeTHF was added and concentrated to the original volume until the water content was <0.l %. The resulting solid was filtered and rinsed with 50 ml MeTHF, left to dry in the funnel overnight and then dried further in the vacuum oven at 50 °C. 6l.7l g of compound A were collected:

‘H NMR (DMSO-d6, 400 MHz) δ 1.70-1.92 (m, 2H), 1.94-2.03 (m, 2H), 2.04-2.18 (m, 2H), 2.29 (s, 3H), 3.55 (s, 3H), 5.47 (brs, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.95 (br s, 3H); ^l3C NMR (DMSO-d6, 100 MHz) δ 13.3, 20.8, 56.4, 63.5, 125.5, 128.1, 137.8, 145.4

3.2.2 Synthesis of Compound VIII

Et₃N ch₃cn

Intermediates VII (180 g, 852 mmol) and A (129 g, 937 mol) were sequentially charged into a multi-neck vessel equipped with a condenser, thermocouple thermometer and nitrogen line. Acetonitrile (900 ml) and triethylamine (594 ml, 4.26 mol) were then added at 22 °C and the mixture was stirred at 75-77 °C for 12 h. Water (1.2 1) was charged slowly over 20 min, the mixture was seeded with Compound VIII crystals (0.3 g) at 40 °C and then cooled to 25 °C over 2 h. The mixture was stirred for an addltional 12h at normal room température and the resulting solid was collected by filtration. The filter cake was rinsed with 2:l mixture of water/MeCN (400 mL) followed by water (200 ml). The resulting solid was dried under vacuum at 50 °C for 12 h to afford 132 g (57% yield) of compound VIII: 'H NMR (400 MHz, CDCl₃) δ 1.85-2.05 (m, 2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J= 8.0, 8.4 Hz, 2H), 3.43 (dd, J= 8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, IH); ^l3C NMR (CDCl₃, 100 MHz) δ 14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1,156.2, 168.0.

3.2.3 Svnthcsis of Compound IX:

S-(-)-Binaphthol

Ti(OIPr)₄OH H₂O t-BuOOH

CH₂CI₂, 22 °C * chiral

Compound VIII (122 g, 429 mmol), S-(-)-l,l’-Bi-2-naphthol (S-(-)-BlNOL) (12.4 g, 42.9 mmol), dichlorométhane (608 mL), Ti(OiPr)4 (6.54 mL, 21.4 mmol), and water (7.72 ml, 429 mmol) were charged to a 2 1 multi-neck flask at 20 °C under nitrogen and stirred for 1 h. ierf-Butyl hydroperoxide (70% in water, 62.3 ml, 472 mmol) was added at once at 21 °C; the mixture became completely homogeneous and the température rose to approx. 40 °C. The mixture was ailowed to reach normal room température, was stirred for 1.5 h and filtered. The cake was twice rinsed with îsopropyl acetate (243 ml per rinse) and the cake was air-dried in the filter for > 6 h to afford 114.4 g of compound IX.

*H NMR (400 MHz, DMSO-d6) δ 1.70-1.85 (m, 2H), 2.14-2.34 (m, 4H), 2.98-3.08 (m, IH), 3.09-3.19 (m, IH), 3.30-3.40 (obscured m, IH), 3.50-3.62 (m, IH), 3.65-3.77 (m, 2H), 4.91 (t, J= 6 Hz, IH), 8.63 (s, IH); ^BC NMR (100 MHz, DMSO-d6) δ 14.5, 29.6, 29.8, 32.6, 48.6, 59.2, 62.8, 119.0, 157.8, 161.4, 175.3.

The other enantiomer of compound IX may be produced when S-(-)-l,l’-Bi-2-naphthol is replaced by R-(+)-l,r-Bi-2-naphthol. A racemate of compound IX may be produced methods known by those skilled in the art that exclude chiral agents and conditions. An example for such a procedure to produce racemic sulfoxides is given in WO 06/l 11549.

3.2.4 Synthesis of Examplc 1

Sulfoxide IX (6.48 g; 22.5 mmol), 4-(4-Chlorophenyl)-piperidine hydrochloride C (5.75 g;

24.8 mmol) (altematively the p-TsOH-salt or the HaSOj-salt of compound C) and N,N- diisopropylethylamine ( 12.4 ml; 72.1 mmol) were mixed in 47 ml of dioxane. The resulting mixture was charged to three 20 ml vials which were heated to 120 °C for 25 min. in a microwave oven. After cooling to room température, the reaction mixtures were poured on ice water. The resulting precipitate was filtered off, taken up in 500 ml ethyl acetate and heated to reflux. After refluxing, the mixture was cooled in an ice bath and the resulting precipitate was filtered off and dried in a dry box at 50 °C at reduced pressure yielding7.57 g of Example l.

’H NMR (400 MHz, DMSO-d6) δ 1.43-1.57 (m, 2H), 1.67-1.85 (m, 4H), 2.11-2.21 (m, 2H), 2.26-2.43 (m, 2H), 2.80-3.01 (m, 5H), 3.17-3.47 (m, intégration compromised by water peak), 3.67-3.76 (m, 2H), 4.74-4.86 (m, 3H), 7.25-7.36 (m, 5H). — ^I3C NMR (100 MHz, DMSO-d6) Ô 14.3, 29.4, 29.6, 32.3, 32.5, 41.4, 44.2, 48.5, 58.4,

63.6,

109.2, 128.2, 128.6, 130.5, 144.7, 157.6, 161.5, 174.7

3.3 Génération of Example 2:

Scheme 4:

* chiral

3.3.1 Génération of Compound G:

Scheme 5:
t 1	1	hn_<_nh₂	1. NaOMe MeOH
r	k I.MeOH, HCl	Ί -ne	2. HX
	2. NHJMeOH	0 H	I ?' I
H
10	F	E	D

3.3.1.1_______Synthesis of Compound E:

N II

2. NH₃/MeOH

F

1. MeOH, HCl/ Dioxane

4M HCl in dioxane (225 ml, 3 eq, 900 mmol) was charged to a 500 ml 3-neck jacketed reactor equipped with a mechanical stiner, température probe and argon line. The solution was cooled to 0 °C and 4-cyanopiperidine (33.04 g, 300 mmol) was charged followed by methanol (36.4 ml, 900 mmol, 3 equiv) over -30 min while keeping the température below 10 °C (température rose). The above mixture was stirred for 6-8 h at normal room température until complété conversion was observed by 'H NMR analysis of an aliquot in D2O (the clear solution tumed into a white slurry after 30 min). The mixture was cooled to 5 °C and 25 wt% NaOMe in methanol (129.6g, 600 mmol, 2 eq) was charged while maintaining the température below 15 °C. The mixture was then stirred for 1 h. 7.0 N ammonia in methanol (64.2 ml, 1.5 eq, 450 mmol) was charged to the above mixture and stirred for 2 h at normal room température. The mixture was concentrated under reduced pressure at 60 °C to a volume of ~250 ml to afford a solution of crude compound E that was used without isolation:

*H NMR (400 MHz, D₂O) δ 1.80-1.95 (m, 2H), 2.15 (br d, J = 4.4 Hz, 2H), 2.79-2.90 (m,

1H), 3.02 (ddd, J= 13.2, 13.2, 3.0 Hz, 2H), 3.48 (m, 2H).

3.3.1.2______Synthesis of Compound G:

The above solution of intermediate compound

E was cooled to -20 °C and 25 wt%

NaOMe in methanol (162 g, 2.5eq, 750 mmol) was charged. The mixture was then stirred for 30 min. Compound D (= (Z)-N-(2-chloro-3-(dimethylamîno)allylidene)-Nmethylmethan-aminium hexafluorophosphate (V)), (82.3g of 95 wt % purity, 0.85 eq, 255 mmol) was charged to the above mixture in two portions at normal room température over

-30 min and stirred for 3 h at room température. The mixture was concentrated under reduced pressure at 60 °C to a volume of -200 ml. 2-Methyltetrahydrofuran (400 ml) was charged and the mixture was concentrated further to a volume of-150 ml under reduced pressure at 60 °C. 2-methyl tetrahydrofuran (250 ml) was charged, the mixture was cooled to ~20 °C, water (150 ml) was added and the mixture was stirred for 5 min. The layers were separated and the organic layer was collected. The organic layer was washed with 30 % aqueous NaOH (120 ml) and the layers were separated. The organics were concentrated to a minimum stirrable volume (-150 mL) and n-propanol (350 ml) was charged. A solution of p-toluenesulfonic acid monohydrate in n-propanol (0.85 equiv., 255 mmol, 48.4 g in 100 ml n-propanol) was charged to the above clear solution over 10 min at -65 °C. The above mixture was concentrated at -65 °C under reduced pressure to maintain

-350 ml and <1.0 % water (it is recommended to hâve a water content below 1.0 % to avoid product losses to the mother Iiquor). The batch was cooled to 20 °C with stirring over 3 h. The solids were filtered, rinsed with the filtrate and then with n-propanol (120 mL) to afford 111g (68 % w/w by assay, 75.48 g) of compound G after vacuum drying at °C in a vacuum oven for 12 h.

'H NMR (DMSO-d6, 400 MHz) δ 1.83-1.99 (m, 2H), 2.13 (d, J = 12 Hz, 2H), 2.97 (s, 3H), 3.0-3.11 (m, 2H), 3.13-3.23 (m, 1H), 3.30-3.42 (m, 2H), 7.14 (d, J= 8.0 Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H), 8.47 (br, 2H), 8.91 (s, 2H); ^,3C NMR (DMSO-d6, 100 MHz) δ 20.7, 27.0, 40.8, 42.8, 125.5, 128.1, 128.8, 137.9, 145.2, 155.8, 169.0.^,—

3.3.2 Svnthesis of Example 2:

G with HX being HCl, TsOH or H₂SO₄

Compound IX (86.5 g, 291 mmol, l eq), compound G (160 g, 305 mmol, l .05 eq), tetrahydrofuran (THF) (484 ml), water (I2l ml) and DIPEA (N,N-diisopropylethylamine, 127 ml, 727 mmol, 2.5 eq) were ali charged to a 3 l round bottom flask under nitrogen and heated to 65 °C for 3 h. Water (l 125 ml, 13 ml/g compound IX) was then charged at the température 65 °C and stirred for 2 h while cooling to 20 °C. The mixture was filtered and the cake was washed twice with 173 ml acetone. The cake was then left to dry on the funnel overnight to afford 116,7 g of Example 2:

‘H NMR (400 MHz, CDCl₃) δ 1.75-1.95 (m, 4H), 2.02-2.11 (m, 2H), 2.12-2.26 (m, 2H), 2.38 (q, J= 9.6 Hz, 2H), 2.93-3.12 (m, 4H), 3.12-3.22 (m, IH), 3.28-3.39 (m, IH), 3.533.65 (m, IH), 3.80 (d, J= 5.6 Hz, 2H), 4.42 (t, J= 5.2 Hz, IH), 4.82 (br d, J= 11.2 Hz, 2H), 6.47 (s, IH), 8.62 (s, 2H); ^l3C NMR (100 MHz, CDClj) δ 14.8, 30.0, 30.1,30.6, 32.7, 44.3,49.4, 59.1,68.2, 107.5, 129.1, 155.5, 159.0, 162.3, 170.5, 174.6.

3.3.2.1 Crystallization to anhydrous Form A of Example 2

Préparation of seed crystals (anhydrous Form A)

Small amounts of crude Example 2(1-2 mg) were suspended in approximately 0.1 ml of the following solvents: éthanol, acetone, 2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran, l-propanol, 2-butanol, and acetonitrile. After a heating/cooling cycle, the samples resulted in suspensions of crystalline anhydrous Form A as analysed by X-ray powder diffraction.

a. Crystallization from acetic acid, dimethyl sulfoxide, or N-methvl-2-Dvrrolidone:

Approximately l g of crude Example 2 is dissolved in 10 ml of a polar organic solvent such as acetic acid, dimethyl sulfoxide, or N-methyl-2-pyrrolidone at a température of>60°C. The solution is cooled to 30-40°C and an antisolvent (approximately 5-10 ml) such as isopropyl alcohol, ethyl alcohol, or acetone is added. The solution is seeded with anhydrous Form A crystals of Example 2 and cooled to 20°C. An additional amount of antisolvent (5-10 ml) is added to increase the yield. The resulting slurry is filtered within 1 hr of cooling and the wet cake is dried at 60 °C under vacuum. Anhydrous Form A is obtained as a white solid as confirmed by X-ray powder diffraction (XRPD) of the anhydrous Form A standard on file.

b. Crystallization from tetrahvdrofuran/water:

Approximately 1 g of crude Example 2 is dissolved in 10 ml of tetrahydrofuran/water mixture (8:2, v/v) at a température of >60°C. The solution is cooled to 40-50°C, seeded with anhydrous Form A crystals of Example 2, and further cooled to 20°C in less than 1 hr. Approximately 5-10 ml of antisolvent (an organic solvent such as isopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is filtered within 1 hr after the antisolvent addition and the wet cake is dried at 60 °C under vacuum. Anhydrous Form A is obtained as a white solid as confirmed by X-ray powder diffraction (XRPD) of the anhydrous Form A standard on file.

c. Drving from Dihydrate:

Approximately 1 g of the Dihydrate form of Example 2 is washed with approximately 5 ml of an anhydrous solvent such as éthanol, methanol, isopropanol, or acetone on a buchner funnel. The wet cake is then dried at 60 °C under vacuum. Anhydrous Form A is obtained as a white solid as confirmed by X-ray powder diffraction (XR.PD) of the anhydrous Form A standard on file.

3.3.2.2 Crystallization to anhydrous Form B of Examplc 2

Préparation of seed crystals of anhydrous Form B

Small amounts of crude Example 2 (l-2 mg) were suspended in approximately 0.1 ml of 2-propanol and water mixtures (one with 3.3% of water and another with 6.6% water). After a heating/cooling cycle, the samples resulted in suspensions of crystalline anhydrous Form B by X-ray powder diffraction analysis. The samples in anhydrous 2-propanol subjected to the same conditions resulted in the mixture of Form A and Form B as analysed by X-ray powder diffraction. The mixture of Form A and Form B, slurried at 20°C for 4 days in mixtures of water and the following solvents: methanol, éthanol, 2propanol, 1-propanol, and acetone (ail with approximately 9% water), resulted in Form B as analysed by X-ray powder diffraction.

a. Crystallization from n-propanol/water:

g of crude Example 2 is dissolved in 160 ml of n-propanol/water mixture (9:1, v/v) at a température of>65°C. The solution is cooled to 60°C, seeded with anhydrous Form B crystals of Example 2, and aged for 0.5 hr. The slurry is cooled to 30°C over at least 5 hrs. Optionally the slurry is distilled at 30°C under reduced pressure to reduce the volume to approximately 80-100 ml in order to maximize the yield. The slurry is further cooled to 0° C and the slurry is aged for at least 8 hrs or until anhydrous Form A is no longer detected. The slurry is filtered and the wet cake is dried at 60 °C under vacuum. Anhydrous Form B of Example 2 is obtained as a white solid in a 90% yield. X-ray powder diffraction (XRPD) conforms to the anhydrous Form B standard on file, —

b. Crystallization from tetrahydrofuran/water:

Approximately l g of crude Example 2 is dissolved in 10 ml of tetrahydrofuran/water mixture (8:2, v/v) at a température of >60°C. The solution is cooled to 40-50°C, seeded with anhydrous Form B crystals of Example 2, and is further cooled to 20°C over 2 hrs. Approximately 10 ml of antisolvent (an organic solvent such as îsopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry. The resulting slurry is aged for at least 8 hrs or until anhydrous Form A is no longer detected. The slurry is then filtered and the wet cake is dried at 60 °C under vacuum. Anhydrous Form B of Example 2 is obtained as a white solid. X-ray powder diffraction (XRPD) conforms to the anhydrous Form B standard on file.

c. Conversion from Dihydrate:

Approximately 1 g of Dihydrate of Example 2 is suspended in 5-10 ml of an anhydrous solvent such as éthanol, methanol, isopropanoi, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with anhydrous Form B crystals of Example 2 and stirred at 20-40 °C for at least 4 hrs or until the conversion to anhydrous Form B is complété as checked by X-ray powder diffraction (XRPD) analysis.

d. Conversion from anhydrous Form A:

Approximately 1 g of anhydrous Form A of Example 2 is suspended in 5-10 ml of an anhydrous solvent such as éthanol, methanol, isopropanoi, acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. The suspension is seeded with anhydrous Form B crystals of Example 2 and stirred at 20-40 °C for at least 4 hrs or until the conversion to anhydrous Form B is complété as checked by X-ray powder diffraction (XRPD) analysis. —

3.3.2.3 Crystallization to Dihydrate Form of Example 2

Préparation of seed crystals of the Dihydrate Form

The mixture of anhydrous Form A and anhydrous Form B crystals of Example 2, siurried at 20°C for 4 days in 2-butanone/water (with 9% water), resulted in the Dihydrate crystals as confirmed by X-ray powder diffraction analysis.

a. Crystallization from n-propanol/water:

g of crude Example 2 is dissolved in 120 ml of n-propanol/water mixture (8:2, v/v) at a température of >65°C. The solution is cooled to 50°C, seeded with Dihydrate crystals of Example 2, and aged for 0.5 hr. Water (approximately 60-100 ml) is added to the slurry. The slurry is cooled to 20°C over at least 5 hrs and then aged for at least 8 hrs. The slurry is filtered, and the wet cake is washed with water and then air-dried.

b. Crystallization in THF/water:

Approximately l g of crude Example 2 is dissolved in 10 ml of tetrahydrofuran/water mixture (8:2, v/v) at a température of >60°C. The solution is cooled to 3O-5O°C, seeded with Dihydrate crystals of Example 2, and further cooled to 20°C over 2 hrs.

Approximately 10 ml of water is added to the slurry. The resulting slurry is aged for at least 8 hrs. The slurry is filtered, and the wet cake is washed with water and then air-dried. X-ray powder diffraction (XRPD) of the product shows the Dihydrate pattern.

c. Conversion from anhydrous Form A or from anhydrous Form B:

Approximately l g of anhydrous Form A or of anhydrous Form B of Example 2 is suspended in approximately 5-10 ml of a mixture of at least 30% water and an organic solvent such as éthanol, methanol, isopropanol, acetone, or tetrahydrofuran. The suspension is seeded with Dihydrate crystals of Example 2 and stirred at 20°C for at least 4 hrs or until the conversion to the Dihydrate Form is complété as checked by X-ray powder diffraction (XRPD) analysis. The slurry is filtered, and the wet cake is washed with water and then air-dried.

The polymorphe of Example 2 were characterized by X-ray powder diffraction (XRPD) as shown in Figures 3a, 3b and 3c showing the X-ray powder diffraction diagrams and the tables with ail observable reflex peaks. For the performance of the X-ray powder diffraction analysis a Rigaku Miniflex II instrument was used with an X-ray generator of the type Power 450 W (30 kV-l 5 mA) (Optics: variable divergence slit). The Goniometer range was 3.0 - 35.0 ⁰ 2 Θ and the scan speed was 0.02° 2 Θ/min with an accuracy of more than 0.01 °. As a monochromator a foil filter/graphite was used and as a detector the scintillation counter Nal 23.0 mm diameter was used. The sample was analysed on a low background Si (510) sample holder.

The polymorphs of Example 2 were further characterized by differential scanning calorimetry (DSC) with a TA Instruments DSC QI000 as shown in Figures 4a, 5a and 6a. The samples were analyzed in an unsealed Aluminium pan under an N₂ flow. The ramp that was used for the measurements was 10°C/min from 20°C to 300°C.

The polymorphs of Example 2 were further characterized by thermogravimetric analysis (TGA) with a TA Instruments TGA Q500 as shown in Figures 4b, 5b and 6b. The samples were analyzed in an open platinum sample pan under N₂ flow. The ramp that was used for the measurements was l0°C/min from 20°C to 300°C.

FIGURES:

Fig. la:

Fig. lb:

gastric emptying for rats that had received Example l intestinal transit for rats that had received Example l

Fig. 2a:

gastric emptying for rats that had received Example 2

Fig. 2b:	intestinal transit for rats that had received Example 2
Fig. 3a:	X-ray powder diffraction diagram of anhydrous form A of Example 2
Fig. 3b:	X-ray powder diffraction diagram of anhydrous form B of Example 2
Fig. 3c:	X-ray powder diffraction diagram of dihydrate form C of Example 2
Fig. 4a:	Differential Scanning Calorimetrie (DSC) of the anhydrous Form A of Example 2 (DSC indicates a melt endotherm at about 235°C, followed by a décomposition when heating continued above melting)
Fig. 4b:	Thermogravimetric Analysis (TGA) of the anhydrous Form A of Example 2 (TGA indicates non-solvated form as shown by negligible volatile content (minimal weight loss of (0.145 %) up to the melting température)
Fig. 5a:	Differential Scanning Calorimetrie (DSC) of the anhydrous Form B of Example 2 (DSC indicates either a solid-solid transition or a simultaneous melt/recrystallization occuring at about 2l8°C. The resulting form is most likely anhydrous form A as indicated by the melt exotherm at 235°C, corresponding to the melting point of form A. After the melting of form A the compound is decomposed when heated above 240°C)
Fig. 5b:	Thermogravimetric Analysis (TGA) of the anhydrous form B of Example 2 (TGA shows negligible volatile content for form B (indicated non-solvated form) as shown by the minimal weight loss (0.057 %) up to the melting température)
Fig. 6a:	Differential Scanning Calorimetrie (DSC) of the dihydrate Form C of Example 2 (DSC indicates low température déhydration as indicated by the broad endotherm at <1OO°C. The dehydrated solid is most likely form A as indicated by the melt endotherm occuring at about 236°C characteristic of form A. Form A is then decomposed when heated above melting température),
Fig. 6b:	Thermogravimetric Analysis (TGA) of the dihydrate form C of Example 2 (TGA shows a large weight loss for form C indicating the déhydration by heating at <100°C. The dehydrated material (likely form A) shows almost

no weight loss up to melting (from 1OO°C to 236°C) consistent with the previous observations for form A)

Examples:

The following Examples were prepared analogously to the methods of synthesis described hereinbefore.

Table A: Chemical structures of the example compounds of the instant invention

Example No.	Chemical Structure
I	rr^cl

	< ] T
	/f
	° HN. 7\
	wherein S* stands for a sulphur atom which represents a chiral
	center
2

	s*-^y^N
	⁰ HN. ÿ
	wherein S* stands for a sulphur atom which represents a chiral
	center

The following Prior Art compounds A to D are the structurally ciosest compounds disclosed in WO 2009/050248 which is the ciosest piece of prior art.

Table B: Chemical structures ofthe structurally ciosest compounds disclosed in WO

2009/050248.

Prior art compound	Chemical Structure
Prior art compound	rr^cl
A
(=Examplc 2 of

WO 2009/050248)	ο I
	^hnK^0H
	wherein S* stands for a sulphur atom which represents a chiral
	center
Prior art compound B	H N fl \
(=Example 27 of
WO 2009/050248)

	ο I

	wherein S* stands for a sulphur atom which represents a chiral
	center

Prior art compound C
(=Example 34 of			Μ
WO 2009/050248)	.S·^4,
	0	^hnX^0H
	wherein S* stands for a sulphur atom which represents a chiral
	center
Prior art compound			Cl 1
D			A
(=Example 39 of		o
WO 2009/050248)	s··^
	// 0	^ΗΝχ^οΗ
	wherein S* stands for a	sulphur atom which represents a chiral
	center

BIOLOGICAL EXPERIMENTS

5.1 Détermination of the PDE4B ICsn-valucs (in vitro):

The ICso-values of the compounds of the invention (Example Compounds 1 and 2) and of the above-mentioned prior art compounds A to D with respect to their PDE4B-inhibiting ability hâve been determined with a Scintillation Proximity (SPA) Assay (GE Healthcare, No. TRKQ7090).

The Scintillation Proximity (SPA) Assay is based on the détection of the different affinities of the cyclic 3'-5'-adenosine monophosphate (cAMP, low affinity) and the linear 10 5'-adenosine monophosphate (AMP, high affinity) to yttrium-silicate-scintilator beads.

The cAMP-specific phosphodiesterase (PDE) PDE4B cleaves the 3’-phosphodiester bond of the tritium-labelled-[³H]cAMP to the [³H]5'-AMP. This [³H]5'-AMP associâtes with the scintillator beads because of their higher affinity and causes scintillations (light flashes) which can be measured in a Wallac Microbeta Scintillation Counter.

ΙΟ μΐ of a [³H]cAMP-solution (0.05 pCi in H2O, ÎO - 30 Ci/mmol) are added to 89 μΐ of a PDE4B-enzyme-solution (active site fragment comprising the amino acids 152 — 484; 0.15 -O.l8 ng) in assay buffer (50 mM Tris HCl pH 7.5; 8.3 mM MgCh; l,7 mM ethylene glyclol tetraacetic acid (EGTA); 0.25 mg / ml bovine sérum albumin (BSA)) and this mixture is incubated at 30 °C for one hour

a) without the compound to be tested (in the presence of l μΐ dimethylsulfoxide (DMSO), corresponding to l% DMSO) and

b) in the presence of the compound to be tested in a concentration of 125 μΜ, 25 μΜ, 5μΜ, l μΜ, 200 ηΜ, 40 ηΜ, 8 ηΜ, 1.6 ηΜ, 0.32 ηΜ, 0,064 ηΜ, 0.0128 ηΜ (dilution sériés in 5er-steps beginning from 125 μΜ until 0.0128 nM, in the presence of l% DMSO).

After this incubation the reaction is stopped by the addition of 50 μΐ of bead-solution (500 mg beads / 35 ml H2O, 18 mM zinc sulfate). In the following 45 minutes the beads have the opportunity to form a sédiment. After that the scintillations are measured in the scintillation counter. If the tested compound is able to inhibit the enzymatic activity of the PDE4B-enzyme, less [³H]AMP depending on the concentration of the tested compound is produced and less scintillations are measurable. These results are expressed as ICso-values. The ICso-value stands for the compound concentration at which the PDE4B enzyme activity is inhibited to a half maximal value. Therefore the lower the ICso-value is the better is the PDE4B inhibition.

Table C: Experimentally determined ICso-values with respect to PDE4B inhibition for the compounds of the invention and for the Prior art compounds as disclosed in WO 2009/050248

Compound	Experimentally determined ICso-value for PDE4B inhibition [nM]
Example l	43
Example 2	7.2
Prior art compound A	3.3
Prior art compound B	66
Prior art compound C	44
Prior art compound D	7.3

Only prior art compounds A and D hâve IC50 values in the same potency range as Examples l and 2. Consequently ail further experiments hâve been performed just with Examples l and 2 and with prior art compounds A and D.

5.2 Détermination of the dose response relationship and calculation of the halfmaximal effective dose in regard to the inhibition of LPS-induced ncutrophil influx into bronchoalveolar lavage fluid of male Wistar rats

The anti-inflammatory activity of Examples l and 2 and of Prior art compounds A and D was assessed in an in vivo LPS-induced lung inflammation model in rats.

As a measure of the pharmacological potency of the above mentioned compounds the halfmaximal effective dose (ED50) in regard to the inhibition of lipopolysaccharide-induced (LPS-induced) neutrophil influx into the bronchoalveolar lavage fluid (BALF) was determined by assessing the dose response relationship. Bacterial endotoxins (lipopolysaccharides [LPS]) are components of the outer bacterial cell membrane which play an important rôle in the pathogenesis of infections with gram-negative bacteria. It is known that inhalation of such aerosolized LPS induces a dose-dependent increase in neutrophils to lung tissues and airspaces in rats which may be detected by analyzing the amount of neutrophils in the bronchoalveolar lavage fluid (BALF). However, this dose dépendent increase of neutrophils in the BALF should be diminished in a dose-dependent way in the presence of an effective PDE4-inhibitor.

Male Wistar rats (HanWistar) from an approved local distributor were used for the experiments. The ordered weight of the animais was in the range of 200-250 g. Animais were fasted overnight before the experiment. A total number of 32 animais were used for each experiment. Eight animais (n=8) per dose were used for the treatment groups, two animais were used for the LPS-control (positive control) and two animais for the négative control.

The animais of the LPS-control and of the négative control groups receivedvehicle only” (“vehicle only“ corresponds to 10 ml/kg body weight 0,5 % Natrosol solution). The other groups were treated with the different doses of either Example compound l, Example compound 2, Prior art compound A or Prior art compound D respectively (see Table D).

The amount of compound for the highest concentration tested for each compound was suspended in 10 ml 0.5% Natrosol (Hydroxyethylcellulose) solution and then diluted to the respective concentrations as shown in Table D. The respective compound suspension or “vehicle only” (10 ml/kg body weight 0.5 % Natrosol solution) was administered orally by gavage. The resulting doses of the individual compounds corresponded to Table D:

Table D: Tested compounds and their respective doses

ÿ'·'' ι, -j^Compound-^ '•v •.‘IP	?· -# ** Dose (mg/kg)	Concentration of the Stock Solution (mg/ml)
Example 1	0.3	1.0	3.0	0.3
Example 2	0.01	0.10	1.00	0.1
Prior art compound A	0.3	1.0	3.0	0.3
Prio art	0.3	1.0	3.0	0.3

compound D

The above doses were determined due to previous tests in the LPS TNF Ex vivo mouse model.

One hour (0.5 hour for Prior art compound A and for Prior art compound D) after compound application (time set to allow for sufficient exposure as guided by prior pharmacokinetic experiments) the animais were exposed to nebulised/aerosolized LPS. The whole body exposure of 12 animais each was performed in a plexi glas chamber. Animais were separated/individualized with perforated métal plates. The aérosol was generated with a commercially available nebuliser (PARI Master + PARI LL nebuliser (Pari GmbH). The concentration of the nebulized LPS-solution was l mg/ml air. The duration of the LPS exposure was 30 minutes.

hours after the end of LPS exposure animais were anesthetised with Isoflorane and euthanised thereafler by cervical dislocation. The trachea was cannulated and BALF was performed using 2x 5mL lavage buffer (phosphate buffered saline (PBS) + 2% BSA).

Détermination of neutrophil content of the BALF was performed using an ADVIA 120 blood hemacytometer (Bayer Diagnostics). Neutrophil data were normalised (Positive Control (=LPS treatment alone) = 100%, Négative Control (no LPS treatment, administration of “vehicle only”)= 0%) and expressed as percent of LPS control. The ED50 was calculated using a nonlinear fit (with the Graph Pad Prism software and a sîgmoidal dose response fit),

The EDjo-value is the half-maximal effective dosis of the compound in question with respect to its inhibition of an LPS-induced neutrophil influx into BALF. Consequently a very small EDso-value stands for a good capability of the respective compound to prevent neutrophil influx into the lung tissue after LPS exposure and therefore for a good capacity of the respective compound to prevent inflammation of the lung tissue. Since the ED50value is unlike the IC50 value not the resuit of an in vitro assay, but the resuit of an in vivo assay performed in rats and since here not only the direct inhibition of the PDE4B enzyme, but the neutrophil influx into the lung tissue after LPS-exposure is measured, the ED50 value is already a very sensitive parameter for a compound’s suitability to serve as a therapeutic agent in inflammatory airway diseases like COPD and asthma (which are both inflammatory diseases).

Exposure of rats with LPS led to a distinct neutrophil influx into the BALF.

Pretreatment of rats with compounds Example l, Example 2, Prior art compound A and Prior art compound D led to an inhibition of the LPS-induced neutrophil influx into the BALF. The calculated ED50 values for the various compounds are given in Table E.

Table E: EDy values ofthe tested compounds which were calculated from the experimental data:

	EDço(mg/kg body weight)
Example 1	0.31
Example 2	0.1
Prior art compound A	1.13
Prior art compound D	6.66

The experimentally determined EDso-values for the compounds of the invention - that means for Example 1 (ED50 = 0.31 mg/kg body weight) and for Example 2 (ED₅q = 0.1 mg/kg body weight) - demonstrate that these compounds of the invention, Example 1 and Example 2, are between 3 to 66 times more potent in this assay than prior art compounds A and D.

Therefore the compounds of the invention show a better potency to prevent the influx of neutrophils into the lung tissue and are therefore a lot more suitable to be used as a therapeutic to treat inflammatory respiratory diseases such as asthma and COPD. —

5.3 Gastric emptying and gastrointcstinal transit in consciotis rats

In order to identify an active agent which is suitable to serve as a therapeutic PDE4 inhibitor it is necessary to détermine whether the compound in question is effective at a dose that does not cause significant gastrointestinal side effects.

Gastrointestinal side effects are known to be prominent within the field of PDE4 inhibitors (see Diamant, Z., Spina, D.; “PDE4-inhibitors: a novel targeted therapy for obstructive airways disease”, Pulm. Pharmacol. Ther. 2011, 24 (4), pp. 353-360 and Press, N.J.;

Banner, K.H.; “PDE4 Inhibitors - A Review of the Current Field”; Progress in Médicinal Chemistry 2009,47; pp. 37-74).

The experiments l. I and l .2 above hâve shown that the compounds of the invention are clearly more potent with respect to PDE4B enzyme inhibition and/or more potent with respect to preventing neutrophil influx into the lung tissue and are therefore advantageous over the structurally related compounds disclosed in WO 2009/050248, in partîcular in comparison to Compounds A, B, C and D.

In order to evaluate whether the compounds of the présent invention lead to gastrointestinal side effects the compounds of the invention hâve been administered to rats 30 minutes before the rats were fed with a test meal comprising barium sulfate. After that it was tested whether gastric emptying and/or gastrointestinal transit in these rats was affected by the presence of these compounds.

The effects of the compounds Example l and Example 2 on gastric emptying and gastrointestinal transit in concious rats has been investigated as described below.

Wistar rats of both sexes weighing 130-160 g (âges: male 7 wk, female 8 wk) were used. The animais are obtained from an approved local distributor, a minimum of four days quarantine is required before use, during which time the animais are maintained under routine animal care procedures. Groups of up to 5 animais are housed in cages in a room with controlled température and humidity and a light/dark cycle with the lights on from 6 a.m. to 6 p.m.. The animais hâve access to normal rodent chow and water ad libitum. The animais are transported to the laboratory on the day of expérimentation,

Gastric emptying as well as small intestinal propulsion are determined using a barium sulfate test meal.

Five rats CrkWI(Han) of each sex (n=10) were used. The animais were deprived of food 17 h prior to the experiment but allowed free access to water.

The drug under investigation (drug was suspended to the concentration of 10 ml/ kg body weight in 0.5 % Natrosol solution) or the négative control (vehicle alone was given 10 ml/kg body weight ) was administered 30 min. (p.o.) before the test meal at doses calculated to be 3-fold, ΊΟ-fold or 30fold the EDjo found in efficacy studies in the rat.

Compound	Dose 3-fold ED50 [mg/kg body weight p.o.]	Dose 10-fold ED₅₀[mg/kg body weight p.o.]	Dose 30-fold ED_J0[mg/kg body weight p.o.]
Example 1 (ED_ÎO = 0,31 mg/kg BW)	1.0	3.0	10.0
Example 2 (EDj₀ = 0,l mg/kg BW)	0.3	1.0	3.0

The test meal (suspension of 7.5 g barium sulfate in 10 ml salt-free water) is given orally by gavage at a dose of 2 ml/100 g body weight. Thirty minutes after the administration of the test meal the animais were kilied in deep isoflurane anaesthesia by cervical dislocation. The stomach and the intestine were then exposed by laparatomy and removed.

The removed stomach was weighed, then incised, the contents removed and the empty stomach is weighed again.

The length of gut traversed with barium sulfate in relation to the whole length of the gut is determined by direct measurements using a ruler.

Evaluation of gastric emptying

The gastric content was calculated from the weight différence between the filled and empty stomach and normalized to 100 g body weight. Thus, an increase in weight différence indicated an impaired gastric emptying, whereas a decrease in weight différence indicated an enhanced gastric emptying. j^/16708

Evaluation of intestinal transit

The length of gut traversed with barium sulphate (as judged by visual inspection) in relation to the whole length of the gut (from the pylores to the rectum) is determined by direct measurements using a reler.

Intestinal transit is calculated as the percentage movement of barium sulphate in the intestine in relation to the whole length of the gut. Consequently an increased intestinal transit length indicated an accelerated intestinal transit whereas a decreased intestinal transit length indicated decelerated intestinal transît.

Statistics

Data are expressed as mean ± standard déviation (SD). For each dose, comparisons were performed using an analysis of variance (ANOVA) and a post hoc Dunnett test to compare the various groups to the contrôle when the ANOVA was significant. p < 0.05 was considered significant.

Consequently the compounds of the invention show no statistically relevant gastrointestinal side effects, even at doses which are up to the 30-fold ED₅o-dosis, because as shown in Fig. la and b and 2a and b rats which had received either example l or 2 neither showed a substantially enhanced or impaired gastric emptying nor a substantially accelerated or decelerated intestinal transit even at doses up to 30-fold EDso-dose.

For Example l the gastric emptying shows no relevant différences at a 3-fold ED50 dose and at a l O-fold ED50 dose, and only a very moderate enhancement of the weight différence per body weight at a 30-fold ED50 dose. However, the intestinal transits for the corresponding animais which received Example compound l showed no significant différences compared to those intestinal transits of the négative controls even up to the 30fold ED50 dose.

For Example 2 both the gastric emptying and the intestinal transit showed no relevant différences compared to the négative control during ail tested doses of Example compound 2, not even at the 30-fold ED50 dose.

Consequently the compounds of the invention are not only more potent with respect to

PDE4B inhibition than the compounds disclosed in WO 2009/050248 (as shown in

Experiments l.l and 1.2), but also show no relevant gastrointestinal side effects.

6. INDICATIONS

The compounds of formula I have a broad potential in different therapeutic fields. Particular mention should be made of those applications tbr which the compounds according to the invention of formula I_are preferably suited on account of their pharmaceutical efficacy as PDE4 inhibitors. Examples include respiratory or gastrointestinal diseases or complaints, inflammatory diseases of the joints, skin or eyes, cancers, and also diseases of the peripheral or central nervous System.

Particular mention should be made of the prévention and treatment of diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations and/or obstructive diseases of the airways. Examples include acute, allergie or chronic bronchitis, chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema, allergie or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways, infectious bronchitis or pneumonitis, paediatric asthma, bronchiectases, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial oedema, pulmonary oedema, bronchitis, pneumonia or interstitial pneumonie triggered by various causes, such as aspiration, inhalation of toxic gases, or bronchitis, pneumonia or interstitial pneumonia as a resuit of heart failure, irradiation, chemotherapy, cystic fibrosis or mucoviscidosis, or alphalantitrypsin deficiency.

Also deserving spécial mention is the treatment of inflammatory diseases of the gastrointestinal tract. Examples include acute or chronic inflammatory changes in gail biadder inflammation, Crohn's disease, ulcerative colitis, inflammatory pseudopolyps, juvénile polyps, colitis cystica profunda, pneumatosis cystoides intestinales, diseases of the bile duct and gall biadder, e.g. gallstones and conglomérâtes, inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and eyes.

Preferential mention should also be made to the treatment of sarcoidosis.

Preferential mention should also be made of the treatment of cancers. Examples include ail forms of acute and chronic leukaemias such as acute lymphatic and acute myeloid leukaemia, chronic lymphatic and chronic myeloid leukaemia as well as bone tumours such as e.g. osteosarcoma and ail kinds of gliomas such as e.g. oligodendroglioma and glioblastoma.

Preferential mention should also be made of the prévention and treatment of diseases of the peripherai or central nervous system. Examples of these include dépréssion, bipolar or manie dépréssion, acute and chronic anxiety states, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis or acute and chronic pain as well as injuries to the brain caused by stroke, hypoxia or craniocerebral trauma.

Particularly preferably the présent invention relates to the use of compounds of formula I for preparing a pharmaceutical composition for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory tract including the lungs, such as for example allergie rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis. idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, alpha-l-antitrypsin deficiency, particularly COPD, chronic bronchitis and asthma.

It is most préférable to use the compounds of formula I for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, particularly COPD, chronic bronchitis and asthma.

It is also préférable to use the compounds of formula 1 for the treatment of diseases of the peripherai or central nervous system such as dépréssion, bipolar or manie dépréssion, acute and chronic anxiety states, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis or acute and chronic pain as well as injuries to the brain caused by stroke, hypoxia or craniocerebral trauma.

It is also préférable to use the compounds of formula I for the treatment of inflammatory diseases of the eyes, in particular for the treatment of the “dry eyes” syndrome and for the treatment of glaucoma. Individuals with the “dry eyes” syndrome suffer fforn ocular discomfort (dry, gritty feeling; itching; stinging/buming; pain/soreness) and blurred vision. The phosphodiesterase 4 (PDE4) enzymes regulate the biological processes of a host by degrading the second messenger cAMP. PDE4 inhibitors hâve been intensiveiy investigated as antiinflammatory thérapies because increases in cAMP levels are known to attentuate inflammatoy responses in multiple cell types (see Govek et al, Bioorganic & Med. Chem. Lett 20, (2010), pp. 2928-2932).

Furthermore it is also préférable to use the compounds of formula I for the treatment of diseases of the eyes, in particular for the treatment of glaucoma, since it has been shown that an increase in cAMP protects retinal ganglion cells from high intracellular pressure (IOP) induced cell death (see Seki T. et al, J Mol Neurosci. 2011 Jan;43( 1):30-4.), and an increase in cAMP is involved in the réduction of IOP (see Naveh N. et al., Br J Ophthalmol. 2000 Dec;84(12):1411-4), the main reason for the development of glaucoma.

7. Combinations

The compounds of formula I may be used on their own or in conjunction with other active substances of formula I according to the invention. If desired the compounds of formula I may also be used in combination with other pharmacologically active substances. It is préférable to use for this purpose active substances selected for example from among betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists, H1-antihistamines, PAFantagonists and PI3-kinase inhibitors, NSAIDS, COX 2 inhibitors, EP 4-receptor antagonists, DPP4-inhibitors or double or triple combinations thereof, such as for exampie combinations of compounds of formula I with one or two compounds selected from among • EP 4-receptor antagonists, DPP4 inhibitors, NSAIDS, COX 2 inhibitors and corticosteroids, • betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4antagonists, • anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists, • PDE4-inhibitors, corticosteroids, EGFR-inhibitors and LTD4-antagonists • EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists • EGFR-inhibitors and LTD4-antagonists • CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide synthase-inhibitors), (6R)-Lerythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as BH4) and the dérivatives thereof as mentioned in WO 2006/120176 and SYK-inhibitors (spleen tyrosine kinase inhibitors) • anticholinergîcs, betamimetics, corticosteroids, PDE4-inhibitors and MRP4-inhibitors. The invention also relates to combinations of three active substances, each chosen from one of the above-mentioned categories of compounds.

Suitable betamimetics used are preferably compounds selected from among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharine, isoprénaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol, tiaramide, terbutalîne, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide, 5-[2-(5.6diethyl-indan-2-ylamino)-1 -hydroxy-ethyl]-8-hydroxy-1 H-quinolin-2-one, 4-hydroxy-7[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl)ethyl]-amino}ethyl]-2(3H)benzothiazolone, 1 -(2-fluoro-4-hydroxyphenyl)-2-[4-( 1 -benzimidazolyl)-2-methyl-2butylamino]ethanoi, 1 -[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-( 1 benzimidazolyl)-2-methyl-2-butylamino]ethanol, l-[2H-5-hydroxy-3-oxo-4H-l,4benzoxazin-8-yI]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1[2H-5-hydroxy-3-oxo-4H-l,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-nbutyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4benzoxazin-8-yl]-2- (4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2butylamino} éthanol, 5-hydroxy-8-( 1 -hydroxy-2-isopropylaminobutyl)-2H-1,4benzoxazin-3-(4H)-one, l-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.butylamino)ethanol, 6-hydroxy-8- {1 -hydroxy-2-[2-(4-methoxy-phenyl)-1,1 -dimethylethylamino]-ethyl)-4H-benzo[l,4]oxazin-3-one, 6-hydroxy-8-{l-hydroxy-2-[2-( ethyl 4phenoxy-acetate)-l, 1 -dimethyl-ethylamino]-ethyl} -4H-benzo[ 1,4]oxazin-3-one, 6hydroxy-8-(l-hydroxy-2-[2-(4-phenoxy-acetic acid)-l,l-dimethyl-ethylamino]-ethyl}-4H benzo[ l ,4]oxazin-3-one, 8- (2-[ l, l -dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1hydroxy-ethyl}-6-hydroxy-4H-benzo[ l ,4]oxazin-3-one, 6-hydroxy-8-{ l -hydroxy-2-[2-(4hydroxy-phenyl)-1,1 -dimethyl-ethylamino]-ethyl}-4H-benzo[ 1,4]oxazin-3-one, 6hydroxy-8-{l-hydroxy-2-[2-(4-isopropyl-phenyl)-l,l-dimethyl-ethylamino]-ethyl)-4Hbenzo[ 1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-l,l-dimethyl-ethylamino]-l-hydroxyethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1 -dimethylethylam ino]-1 -h ydroxy- ethyl} -6-hyd roxy-4H-benzo [ 1,4]oxazin-3-one, 4-(4- {2- [2hydroxy-2-(6-hydroxy-3-oxo-3.4-dihydro-2H-benzo[l,4]oxazin-8-yl)-ethylamino]-2methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3.4-difluoro-phenyl)-l, 1 -dimethylethylamino]-l -hydroxy-ethyl}-6-hydroxy-4H-benzo[ 1,4]oxazin-3-one and 1 -(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés or hydrates thereof.

According to the invention the acid addition salts of the betamimetics are preferably selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. Of the above-mentioned acid addition salts the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from among the tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospîum salts, tropenoi 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenoi 2-fluoro-

2,2-diphenylacetate methobromide, tropenoi 3,3',4,4'-tetrafluorobenzilate methobromide, scopine 3,3',4,4’-tetrafluorobenzilate methobromide, tropenoi 4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate methobromide, tropenoi 3,3'difluorobenzilate methobromide, scopine 3,3'-difluorobenzilate methobromide, tropenoi 9- — hydroxy-fluorene-9-carboxylate -methobromide, tropenol 9-fluoro-fluorene-9-carboxylate -methobromide, scopine 9-hydroxy-fluoren-9-carboxylate methobromide, scopine 9fluoro-fluorene-9-carboxylate methobromide, tropenol 9-methyl-fluorene-9-carboxylate methobromide, scopine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine benzilate methobromide, cyclopropyltropine 2,2-diphenylpropionate methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxyIate methobromide, cyclopropyltropine 9methyl-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-hydroxy-fluorene-9carboxylate methobromide, methyl cyclopropyltropine 4,4'-difluorobenzilate methobromide, tropenol 9-hydroxy-xanthene-9-carboxylate -methobromide, scopine 9hydroxy-xanthene-9-carboxylate methobromide, tropenol 9-methyl-xanthene-9carboxylate methobromide, scopine 9-methyl-xanthene-9-carboxylate methobromide, tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tropenol 9-difluoromethylxanthene-9-carboxylate methobromide, scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in the form of the solvatés or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active ingrédients. As anions, the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maieate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of ail the salts, the chlorides, bromides, iodides and methanesulphonate are particularly preferred.

Of particular importance is tiotropium bromide. In the case of tiotropium bromide the pharmaceutical combinations according to the invention preferably contain it in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is préférable to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265.

Corticosteroids used here are preferably compounds selected from among prednisolone, prednisone, butixocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS-126, (S)-fluoromethyl 6,9-difluoro-l7-[(2fùranylcarbonyl)oxy]-11 -hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-l l-hydroxy-l6-methyl-3-oxo-l7propionyloxy-androsta-l,4-diene-l 7-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and dérivatives, solvatés and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl 6,9-difluoro-l 7-[(2-furanylcarbonyl)oxy]-l lhydroxy-16-methyl-3-oxo-androsta-l ,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydrofuran-3S-yl) 6,9-difluoro-11 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and dérivatives, solvatés and/or hydrates thereof.

Any reference to steroids includes a reference to any salts or dérivatives, hydrates or solvatés thereof which may exist. Examples of possible salts and dérivatives of the steroids may be: alkali métal salts, such as for example sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acétates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates thereof.

Other PDE4 inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4396 (Sch-351591 ), AWD-12-281 (GW-842470), NCS-613, CDP- _Λ

840, D-4418, PD-168787, Τ-440, Τ-2585, V-l 1294Α, CI-1018, CDC-801, CDC-3052, D22888, ΥΜ-58997, Ζ-l 5370,N-(3,5-dichloro-l-oxo-pyridin-4-yl)-4-difluoromethoxy-3cycl opropylmethoxybenzam ide, (-)ρ- [ (4aR *. 10b S * ) -9-ethoxy-1,2,3,4,4a, l Ob-hexahydro8-methoxy-2-methylbenzo[s][l.6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)l -(4-bromobenzyl)-4- [(3 -cyclopentyloxy)-4-m ethoxyphenyl ] -2-pyrro l i done, 3 (cyclopentyloxy-4-methoxyphenyl)-l-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-

2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-lcarboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4difluoromethoxyphenyl)cyclohexane-1 -one, cis[4-cyano-4-(3-cyclopropylmethoxy-4dîfluoromethoxyphenyl)cyclohexan-l-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(-)-ethyl[4-(3-cyclopentyloxy-4methoxyphenyl)pyrrolidin-2-ylidene]acetate, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2thienyl)-9H-pyrazolo[3,4-c]-l,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro7-ethyl-3-(tert-butyi)-9H-pyrazolo[3,4-c]-l,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvatés and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which the abovementioned PDE4-inhibitors might be in a position to form are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

EP 4 receptor antagonists which may be used are preferably compounds selected from among [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g] quinoline-7yl)-3methylbenzyl]sulfonyl} -2-(2-methoxyphenyl)acetamide] ;

5-butyl-2,4-dihydro-4-[[2^,-[N-(3-methyl-2-thiophene-carbonyl)sulfamoyl]biphenyl-4yl]methyl]-2-[(2-trifluoromethyl)phenyl]-l, 2, 4-triazole-3-on;

(4-{(lS)-l-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic acid;

N-[({2-[4-(2-ethyl-4,6-dimethyl-lH-imidazo [4,5-c]pyridin-l-yl)phenyl]ethyl}amino) carbonyl ]-4-methylbenzol sulfonamide;

4-[[4-(5-methoxy-2-pyridinyl)phenoxy]methyl]-5-methyl-N-[(2-methylphenyl)sulfonyl]-

2-furane carboxamide;

alpha, l5alpha-dihydroxy-l6-(3-methoxymethylphenyl)-9-oxo-l 7,18,19, 20-tetranor-5thia-13(E) prostanoic acid methyl ester;

4-cyano-2-[[2-(4-fluoro-l-naphthalenyl)-l-oxopropyl]amino]-benzene butyric acid and

N-{2-[4-(4,9-diethoxy-l-oxo-1,3-dihydro-2H-benzo[f] isoindol-2yl)phenyl]acetyl}benzene sulphonamide.

NSAIDS which may be used are preferably compounds selected from among Aceclofenac, Acemetacïn, Acetylsaiicylsâure, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenin, Azapropazon, Benorilat, Bermoprofen, Bindarit, Bromfenac, Bucloxinsaure, Bucolom, Bufexamac, Bumadizon, Butibufen, Butixirat, Carbasalatcalcium, Carprofen, Cholin Magnésium Trisalicylat, Celecoxib, Cinmetacin, Cinnoxicam, Clidanac, Clobuzarit, Deboxamet, Dexibuprofen, Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Eltenac, Enfenaminsâure, Etersaiat, Etodolac, Etofenamat, Etoricoxib, Feclobuzon, Felbinac, Fenbufen, Fenclofenac, Fenoprofen, Fentiazac, Fepradinol, Feprazon, Flobufen, Floctafenin, Flufenaminsâure, Flufenisal, Flunoxaprofen, Flurbiprofen, Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, Ibufenac, Ibuprofen, Indobufen, Indometacin, Indometacinfamesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac, Lomoxicam, Loxoprofen, Lumiracoxib, Meclofenaminsâure, Meclofen, Mefenaminsâure, Meloxicam, Mesalazin, Miroprofen, Mofezolac, Nabumeton, Naproxen, Nifluminsâure, Olsalazin, Oxaprozin, Oxipinac, Oxyphenbutazon, Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen, Pirazolac, Priroxicam, Pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsâure, Rofecoxib, Romazarit, Salicylamid, Salicylsâure, Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofensàure, Taramid, Tilnoprofenarbamel, Timegadin, —

Tinoridin, Tiopinac, Tolfenaminsâure, Tolmetin, Ufenamat, Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen.

COX2-inhibitors (Coxibe) which may be used are preferably compounds selected from among Celecoxib,Meloxicam, Etoricoxib, Lumiracoxib, Parecoxib, Rofecoxib and Valdecoxib.

LTD4-antagonists which may be used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM1507), VUF-5078, VUF-K-8707, L-733321, 1 -(((R)-(3-(2-(6,7-difluoro-2quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)methylcyclopropaneacetic acid, 1 -((( 1 (R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-

3-(2-(1-hydroxy-l-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid and [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and dérivatives, solvatés and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which the LTD4antagonists may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. By salts or dérivatives which the LTD4-antagonists may be capable of forming are meant, for example: alkali métal salts, such as, for example, sodium or potassium salts, alkaline earth métal salts, sulphobenzoates, phosphates, isonicotinates, acétates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. —16708

The EGFR-inhibitors used are preferably compounds selected from among 4-[(3-chloro-4fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-l-oxo-2-buten-l-yljamino}-7cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6- {[4-(N,Ndiethylamino)-l-oxo-2-buten-l-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dÎmethylamino)-l-oxo-2-buten-l-yl]amino}-7cyclopropylmethoxy-quinazoline, 4-[ (R)-( l -phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-

1- oxo-2-buten-l-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7-[(S)-(tetrahydrofuran-3yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino)-7-cyclopropylmethoxy-quinazoline, 4[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-Nmethyl-amino]-l-oxo-2-buten-l-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3chloro-4-fluorophenyl)amino]-6-([4-(N,N-dimethylamino)-l-oxo-2-buten-l-yl]amino}-7cyclopentyloxy-quinazoline, 4-[(R)-(l-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxyethyl)-amino)-1 -oxo-2-buten-1 -yljamino} -7-cyclopropylmethoxy-quinazoline, 4-[(R)-( I phenyl-ethyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1 -oxo-2-buten-1 yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(l-phenyl-ethyl)amino]-6-((4-[N(2-methoxy-ethyi)-N-methyl-aminoJ-1 -oxo-2-buten-1 -yl} amino)-7-cycIopropylmethoxyquinazoline, 4-[(R)-( l -phenyl-ethyl)amino]-6-( (4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1 -oxo-2-buten-1 -yl }amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-l-oxo-2-buten-l-yl]amino}-7-((R)tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,Ndimethylamino)-l-oxo-2-buten-l-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,

4-[(3-chloro-4-fluorophenyl)amino]-6-( {4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1 -oxo-

2- buten-l-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-

6- {[4-(N-cyclopropyl-N-methyl-amino)-1 -oxo-2-buten-1 -yljamino} -7-cyclopentyloxyquinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-l-oxo-2buten-l-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4fluorophenyl)amino]-6- {[4-(N,N-dimethylamino)-1 -oxo-2-buten-1 -yl]amino}-7-[(S)(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2 methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-( l -phenyl-ethyl)amino]-6-(4hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-l-oxo-2-buten-l-yl]amino}-7-ethoxyquinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyI]amino}-6-(5-{[(2methanesulphonyl-ethyi)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(l-phenylethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-l-oxo-2-buten-l-yl]amino}-7methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-l-oxo-

2-buten-l-yI]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4fluorophenyl)amino]-6-( {4-[N,N-bis-(2-methoxy-ethyl)-amino]-1 -oxo-2-buten-l yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-

6- {(4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1 -oxo-2-buten-1 -yljamino}-quinazoline, 4[(3-ch!oro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-cthoxy]-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-

4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {2[4-(2-oxo-morpholin-4-yl)-piperidin-l-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-

4-fluoro-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-l-yloxy)-

7- methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4methanesulphonylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-

4-fluoro-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3chloro-4-fluoro-phenyl)amino]-6-{l-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{ l[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-[l-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetraliydropyran-4-yloxy)-7-ethoxyquinazoiine, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4 [(dimethylamino)sulphonylamino]-cyclohexan-l-yloxy}-7-methoxy-quinazoiine, 4-[(3chloro-4-fluoro-pheny l )ami no] - 6- {trans-4-[(morpholi n-4-yl)carbonyl ami no]-cyclohexanl -yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4[(morpholin-4-yl)sulphonylamîno]-cyclohexan-l-yloxy}-7-methoxy'quinazoline, 4-[(3chloro-4-fluoro-phenyl)amîno]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)quinazoline, 4-[(3-chioro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l[(piperidin-l-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-(l-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4yl)carbonyl]-N-methyl-amino}-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3chloro-4-f!uoro-phenyl)amino]-6-(cis-4-{N-[(morphoIin-4-yl)carbonyl]-N-methylamino}-cycIohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin’4-yl)sulphonyl]-N-methyl-amino)-cyclohexan-lyloxy)-7-methoxy- quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4ethansulphonylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amîno]-6-(l-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3chloro-4-fluoro-phenyl)amino]-6-( 1 -methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxyethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[l-(2’methoxy-acetyl)piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3ethynyl-phenyl)amino]-6-[l-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxyquinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4- {N-[(piperidin-1 -yl)carbonyl]N-methyl-amino}-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-l-yl)carbonyl]-N-methyl-amino}cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {cis-

4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3 chlorO“4-fluoro-phenyl)amino]-6-{l-[2-(2-oxopyrrolidin-l-yl)ethyl]-piperidin-4-yloxy}-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(morpholin-4yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynylphenyl)amino]-6-( 1 -acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynylphenyl)amino]-6-( 1 -methyl-piperidin-4-yIoxy)-7-methoxy-quinazoiine, 4-[(3-ethynyl- gz phenyl)amino]-6-( l -methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3chloro-4-fluoro-phenyl)amino]-6-(l-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( l -isopropyloxycarbonyl-piperidin-4yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4methylamino-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7methoxy-quinazoline, 4-[(3-ethynyI-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline, 4-[(3-ethynyl-phcnyl)amino]-6-[ 1 -(2-methoxy-acetyl)-piperidin-4-yÎoxy]-7methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{ 1 -[(morpholin-4-yl)carbonyl]piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l[(cis-2,6-dimethyl-morpholin-4-yl)carbonyI]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chIoro-4-fluoro-phenyl)amino]-6- {1 -[(2-methyl-morpholin-4-yl)carbonyl]-piperidin4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{l-[(S,S)-(2oxa-5-aza-bicycio[2,2,l]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {1 -[(N-methyl-N-2-methoxyethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-(l-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyI)amino]-6- {1 -[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxyquïnazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {1 -[(3-methoxypropyl-amino)carbonyl]-piperidin-4-yIoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methylamino)-cyclohexan-1 -yloxy]-7-methoxy-quinazolîne, 4-[(3-chloro-4-fluorophenyi)amino]-6-(trans-4-methylamino-cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)cyclohexan-1 -yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6(trans-4-dimethylamino-cyclohexan-1 -yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}cyclohexan-l-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2(2,2-dimethyl-6-oxo-morpholin-4-yI)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( 1 -methanesulphonyl-piperidin-4yloxy)-7-methoxy-quinazo!ine, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( 1 -cyanopiperidin-4-yloxy)-7-methoxy-quinazoline, cetuximab, trastuzumab, ABX-EGF and Mab yv—'

ICR-62, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvatés and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which the EGFR-inhibitors may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofiimarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofiimarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably include compounds selected from among bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and viozan. Any reference to the above-mentioned dopamine agonists within the scope of the présent invention includes a reference to any pharmacologically acceptable acid addition salts and optionally hydrates thereof which may exist. By the physiologically acceptable acid addition salts which may be formed by the above-mentioned dopamine agonists are meant, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

Examples of H l-antihistamines preferably include compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. Any reference to the abovementioned H l-antihistamines within the scope of the présent invention includes a reference to any pharmacologically acceptable acid addition salts which may exist. _va/16708

Examples of PAF-antagonists preferably include compounds selected from among 4-(2chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-l-yl]-6H-thieno-[3,2-f|[l,2,4]triazolo[4,3-a][l,4]diazepines, 6-(2-chlorophenyl)-8,9-dihydro-l-methyl-8-[(4morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][l,2,4]triazolo[4,3-

a][l,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from among jV-acetyldinitrophenyl-cysteine, cGMP, cholate, diclofenac, déhydroépiandrostérone 3glucuronide, déhydroépiandrostérone 3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide, estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol

3-sulphate, estrone 3-sulphate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulphate, methotrexate, MK571 ((£)-3-[[[3-[2-(7-chloro-2quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurine riboside, probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, taurolithocholic acid sulphate, topotecan, trequinsin and zaprinast, dipyridamole, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.

By acid addition salts with pharmacologically acceptable acids are meant, for example, salts selected from among the hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-ptoluenesulphonates, preferably the hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and hydromethanesulphonates.

Compounds which may be used as iNOS inhibitors are compounds selected from among:

S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT, Lcanavanine, 2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, Sethylîsothiourea, S-methyltiocitrullin, S-ethylthiocitrulline, L-NA (N‘-nitro-L-arginine),

L-NAME (NT-nitro-L-argininemcthylester), L-NMMA (N^G-monomethyl-L-arginine), LNIO (N’-iminoethyl-L-omithine), L-NIL (N'^-iminoethyl-lysine), (S)-6acetimidoylamino-2-amino-hexanoic acid ( l//-tetrazol-5-yl)-amide (SC-51 ) (J. Med. Chem. 2002,45, 1686-1689), 1400W, (S)-4-(2-acetimidoylamino-ethylsulphanyl)-2amino-butyric acid (GW274150) (Bioorg. Med. Chem. Lett. 2000,10, 597-600), 2-(2-(410 methoxy-pyridin-2-yl)-ethyl]-3//-imidazo[4,5-i>]pyridine (BYK191023) (Mol. Pharmacol. 2006, 69, 328-337), 2-((R)-3-amino-l-phenyl-propoxy)-4-chloro-5fluorobenzonitrile (WO 01/62704), 2-((lR,3S)-3-amino-4-hydroxy-l-thiazol-5-ylbutylsulphanyl)-6-trifluoromethyl-nicotinonitrile (WO 2004/041794), 2-((1 R.3S)-3amino-4-hydroxy-1 -thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile ( WO

2004/041794), 2-((1 R.3S)-3-amino-4-hydroxy-l-thiazol-5-yl-butylsulphanyl)-5-chlorobenzonitrile (WO 2004/041794), (2S.4R)-2-amino-4-(2-chloro-5-trifluoromethylphenylsulphanyl)-4-thiazol-5-yl-butan-l-ol (WO 2004/041794), 2-((1 R.3S)-3-amino-4hydroxy-l-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile (WO 2004/041794), 4((S)-3-amino-4-hydroxy-l -phenyl -butylsulphanyl)-6-methoxy-nicotinonitrile (WO

02/090332), substituted 3-phenyl-3,4-dihydro-l-isoquinolinamine such as e.g, ARC102222 (J. Med. Chem. 2003, 46, 913-916), (lS.5S.6R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-ylamine (ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem. 2004,12,4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine (Bioorg.

Med. Chem. Lett. 2005, 75, 1361), 4-aminotetrahydrobiopterine (Curr. Drug Metabol. 2002, 3,119-121), (E)-3-(4-chloro-phenyl)-7V-(l-{2-oxo-2-[4-(6-trifluoromethylpyrimidin-4-yloxy)-piperidin-1 -yl]-ethylcarbamoyl }-2-pyridin-2-yl-ethyl)-acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3-(2,4-difluoro-phenyl)-6-[2-(4imidazol-l-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine (PPA250) (J. Pharmacol. Exp.

Ther. 2002,303, 52-57), methyl 3-{[(benzo[l,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-

4-(2-imidazol-l-yl-pyrimidin-4-yl)-piperazine-l-carboxylate (BBS-1) (Drugs Future 2004, 29, 45-52), (R)-l-(2-imidazol-l-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2- dV' carboxylic acid (2-benzo[l,3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvatés thereof.

Examples of iNOS-înhibitors within the scope of the présent invention may also include antisense oligonucleotides, particularly those antisense oligonucleotides which bind iNOScoding nucleic acids. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense oligonucleotides, which bind iNOS coding nucleic acids, for modulating the expression of iNOS. iNOS-antisense oligonucleotides as described particularly in WO 01/52902 may therefore also be combined with the PDE4-inhibitors of the présent invention on account of their similar effect to the iNOS-inhibitors.

Compounds which may be used as SYK-inhibitors are preferably compounds selected from among:

- [(2-ami noethyl ) amino] -4- [(3 -bromo phenyl )amino] -5-pyrîm id inecarboxamide;

2-[[7-(3,4-dimethoxyphenyl)imidazo[l,2-c]pyrimidin-5-yl]amino]-3pyridinecarboxamide;

6- [[5-fIuoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2Hpyrido[3,2-b]-1,4-oxazin-3(4H)-one;

N-[3-bromo-7-(4-methoxyphenyl)-l ,6-naphthyridin-5-yl]-1,3-propanediamine

7- (4-methoxyphenyl)-N-methyl-l,6-naphthyridin-5-amine;

N-[7-(4-methoxyphenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-(2-thienyl)-l,6-naphthyridin-5-yl-l,3-propanediamîne;

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-l,2-ethanediamine;

N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-l ,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(4-methoxyphenyl)-3-phenyl-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-(7-phenyl-l,6-naphthyridin-5-yl)-l,3-propanediamine;

N-[7-(3-fluorophenyl)-l ,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(3-chlorophenyl)-1,6-naphthyridin-5-yl]-l ,3-propanediamine;

N-[7-[3-(trifluoromethoxy)phenyl]-l,6-naphthyridin-5yl]-l,3-propanediamine;

N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-l ,3-propanediamine;

N-[7-(4-fluorophenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-(4-chlorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(4'-methyl[ l,l'-biphenyl]-4-yi)-l ,6-naphthyridin-l ,3-propanediamine;

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-l,6-naphthyridin-5-yl]-l,3propanediamine;

N-[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(4-methylphenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-(methylthio)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-[4-( l -methylethyl)phenyl]-l ,6-naphthyridin-5-yl]-1,3-propanediamine;

7-[4-(dimethylamino)phenyl]-N-methyl-l,6-naphthyridin-5-amine;

7-[4-(dimethylamino)phenyl]-N,N-dimethyl-l,6-naphthyridin-5-amine;

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-l,4-butanediamine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,5-pentanediamine;

3- [[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]oxy]-l-propanol;

4- [5-(4-aminobutoxy)-l,6-naphthyridin-7-yl]-N,N-dimethyl-benzenamine;

4-[[7-[4-(dimethylamino)phenyl]-l ,6-naphthyridin-5-yl]amino]-1 -butanol;

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-N-methyl-l,3-propanediamine;

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-y]]-N’-methyl-l,3-propanediamine;

N-[7-[4-(dimethyiamino)phenyl]-l,6-naphthyridin-5-yl]-N,N'-dimethyl-l,3propanediamine;

l-amino-3-[[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]amino]-2-propanol;

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-2,2-dimethyl-l,3propanediamine;

7-[4-(dimethyIamino)phenyl]-N-(3-pyridinylmethyl)-l,6-naphthyridin-5-amine;

N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-amine;

N-[7-[6-(dimethylamino)[l J'-biphenyl]-3-yl]-l,6-naphthyridin-5-yl]-l,3-propanediamine,

N-[7-[3-chloro-4-(diethylamino)phenyl]-l_}6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-(dimethylamino)-3-methoxyphenyl]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-(diethylamino)phenyl]-3-methyl-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-(3'-fluoro[ 1,1 '-biphenyl]-3-yl)-1,6-naphthyridin-5-yl]-1,2-ethanediamine,

N-[7-(4-methoxyphenyl)-l ,6-naphthyridin-5-yl]-1,6-naphthyridine-l ,3-propanediamine;

N,N'-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine;

N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-l,6-naphthyridin-5-yl]-l,6-naphthyridine-

1,3-propanediamine;

N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine;

N-[7-(2-naphthalenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-(2'-fluoro[ 1,1 ’-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(3,4,5-trimethoxyphenyl)-l ,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(3,4-dimethylphenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

l-amino-3-[[7-(2-naphthalenyl)-l,6-naphthyridin-5-yl]amino]-2-propanol;

l -amino-3-[[7-(2'-fluoro[ l, l ’-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol;

l“aminO“3-[[7-(4'-methoxy[l,r-biphenyl]-4-yl)-l,6-naphthyridin-5-yl]amino]-2-propanol;

l-amino-3-[[7-(3,4,5-trimethoxyphenyl)-l,6-naphthyridin-5-yl]amino]-2-propanol;

l-amino-3-[[7-(4-bromophenyl)-l,6-naphthyridin-5-yl]amino]-2-propanol;

N-[7-(4'-methoxy[l,l'-biphenyl]-4-yl)-l,6-naphthyridin-5-yl]-2,2-dimethyl-l,3propanediamine;

1- [(7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]amino]-2-propanol;

2- [[2-[[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]amino]ethyl]thio]-ethanol;

7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-l,6-naphthyridin-5-amine;

7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-l,6-naphthyridin-5-amine;

N-[7-[4-(dimethylamino)phenyi]-1,6-naphthyridin-5-yl]-1,3-cyclohexanediamine;

N,N-dimethyl-4-[5-( l -piperazinyl)-1,6“naphthyridin-7-yl]-benzenamine;

4-[5-(2-methoxyethoxy)-l,6-naphthyridin-7-yl]-N,N-dirnethyl-benzenamine;

l-[7-[4-(dimethylamino)phenyl]-l ,6“naphthyridin-5-yl]-4-piperidinol;

l-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-3-pyrrolidinol;

7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-l,6-naphthyridin-5-amine;

7-[4-(dimethylamino)phenyl]-N-[3-(lH-imidazol-l-yl)propyl]-l,6-naphthyridin-5-amine;

l-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]4“piperidinecarboxamide;

l-[3-[[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yi]amino]propyl]-2-pyrrolidinone;

N-^'-^-ttS-aminopropyOaminoJ-l.ô-naphthyridin^-ylJfU'-biphenylJ-S-yll-acetarnide;

N-[7-(4'-fluoro[l ,r-biphenyl]-4-yl)-l ,6-naphthyridin-5-yl]-l ,3-propanediamine;

N-[4'-[5“[(3-aminopropyl)amino]-l,6-naphthyridin-7-yl][l,r-biphenyl]-3-yl]-acetamide;

N-[7-[4-(l,3-benzodioxol-5-yl)phenyI]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-(2-thienyl)phenyl]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-(3-pyridinyl)phenyl]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-(l,3-benzodioxol-5-yl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-(6-methoxy-2-naphthalenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

7-[4-(dimethylamino)phenyl]-N-(4-pyridÎnylmethyl)-l,6-naphthyridin-5-amine;

3- [[7-[4-(dimethylamino)phenyl]“l,6-naphthyridin-5-yl]methylamino]-propanenitrile;

7-[4-(dimethylamino)phenyl]-N-[ l -(phenylmethyl)-4-piperidinyl]-1,6-naphthyridin-5amine;

(lR.2S)-N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-l,2-cyclohexanediamine,

N-[7-[4-(dimethylamino)phenyl]-l,6-naphthyridin-5-yl]-l,2-benzenedimethanamine;

N-[7-[4-(diethylamino)phenyl]-l,6-naphthyridin-5-yl]-l,4-butanediamine;

N-[7-[3^,.5'-bis(trifluoromethyl)[l,l'-biphenyl]-4-yl]-l,6-naphthyridin-5-yl].3propancdi amine;

N-[7-(3'-methoxy[ l, l '-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(3'-fluoro[ l, l '-biphenyl]-4-yl)-l ,6-naphthyridin-5-yl]-1,3-propanediamine;

4- [[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]oxy]-1 -butanol;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yi]- l ,4-cyclohexanediamine;

7-[4-(dimethylamino)phenyl]-N-(2.2.6.6-tetramethyl-4-piperidinyl)-l,6-naphthyridin-5amine;

N-[7-[3-bromo-4-(dimethylamïno)phenyl]-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-( 1 -methyl-1 H-indol-5-yl)-1,6-naphthyridin-5-yl]-l ,3-propanediamine; _v___

N-[7-[3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-[4-(trifluoromethyI)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N-[7-(3-bromo-4-methoxyphenyl)-l,6-naphthyridin-5-yl]-l,3-propanediamine;

N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4cyclohexanediamine;

N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-l,6-naphthyridin-5-yl]-l,4cycl ohexanedi amine;

N-[7-[4-(dimethylamino)-3-methoxyphenyl]-l,6-naphthyridin-5-yl]-l,4cyclohexanedi ami ne;

N-[7-[4-(4-morpholinyl)phenyiJ-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;

N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-l,6-naphthyridin-5-yI]-l,4-cyclohexanediamine;

4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-l,6-naphthyridin-5-yl]oxy]cyclohexanol;

N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;

N,N-dimethyl-4-[5-(4-methyl-l-piperazinyl)-l,6-naphthyridin-7-yl]-benzenamine;

4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-l,6-naphthyridin-5-yl]oxy]cyclohexanol;

N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-l,6-naphthyridin-5-yl]-l,4butanediamine;

1,1 -dimethylethyl [3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridin-

2-yl]amîno]propyl]-carbamate.

The invention further relates to pharmaceutical préparations which contain a triple combination comprising a compound of formula I, Il or III and two further active agents, both independently from one another selected from the above-mentioned groups of active agents such as another PDE4B-inhibitor, an anticholinergic, a betamimetic, a corticosteroid, an EGFR-inhibitor, a MRP4-inhibitor, an LTD4-antagonist, an iNOSinhibitor, a PAF-antagonist, a H 1-antihistamine, dopamin agonist, SYK. inhibitor. The invention turther refers to the préparation of such a double or triple combination and the use thereof for treating respiratory complaints.

8. Formulations

Suitable forms for administration are for example tablets, capsules, solutions, syrups, émulsions or inhalable powders or aérosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.

The préparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gélatine capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised b y the content of one or more compounds of formula I according to the preferred embodiments above.

It is particularly préférable if the compounds of formula I are administered orally, and it is also particularly préférable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gélatine, lubricants such as magnésium stéarate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers. (VL/'''

Coated tablets may be prepared accordîngly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gélatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the dérivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. éthanol or glycerol), carriers such as e.g. natural minerai powders (e.g. kaolins, clays, talc, chalk), synthetic minerai powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. Magnésium stéarate, talc, stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gélatine and the like. Moreover, lubricants such as magnésium stéarate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

It is also preferred if the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula I hâve to be made available in forms suitable for inhalation. Inhalable préparations include inhalable powders, propellant-containing metered-dose aérosols or propellant-free inhalable solutions, which are optionally présent in admixture with conventional physioiogically acceptable excipients.

Within the scope of the présent invention, the term propellant-free inhalable solutions also includes concentrâtes or stérile ready-to-use inhalable solutions. The préparations which may be used according to the invention are described in more detail in the next part of the spécification.

Inhalable powders

If the active substances of formula I are présent in admixture with physioiogically acceptable excipients, the following physioiogically acceptable excipients may be used to préparé the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. Methods of preparing the inhalable powders according to the invention by grinding and micronising and by finally mixing the components together are known from the prior art.

Propellant-containing inhalable aérosols

The propellant-containing inhalable aérosols which may be used according to the invention may contain the compounds of formula I dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to préparé the inhalation aérosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated dérivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane dérivatives selected from TGI34a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafiuoropropane) and mixtures thereof. The propellant-driven inhalation aérosols used within the scope of the use according to the invention may also contain other ingrédients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. Ail these ingrédients are known in the art.

Propellant-free inhalable solutions

The compounds of formula I according to the invention are preferably used to préparé propellant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water on its own or a mixture of water and éthanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartane acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which hâve already formed an acid addition sait with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which hâve other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context dénoté any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances hâve no pharmacological effect or, in connection with the desired therapy, no appréciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonie agents. The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. '

For the treatment forms described above, ready-to-use packs of a médicament for the treatment of respiratory complaints are provided, containing an enclosed description including for example the words respiratory disease, COPD or asthma, together with dihydrothienopyrimidine and one or more combination partners selected from those described above.

Claims

PATENT CLAIMS wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two

1,11 or IH according to one of claims 1 to 15 in combination with one or more active substances selected from the group consisting of betamimetics, corticosteroids, anticholinergics, other PDE4 inhibitors, NSAIDS, COX2-inhibitors, EP4-receptor antagonists, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors, MRP4-inhibîtors and SYK inhibitors.

2. The compound of formula I according to claim l, wherein R is Cl and wherein R is located in the para-position of Ring A, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof.

15

3. The compound of formula I according to one of claims 1 or 2, wherein Ring A is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof.

4.

The compound according to one of claims 1 to 3, which is a compound of formula II and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof.

-LL1, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof.

5 HY in compound B is HCl.

5.15 Â, 3.95 Â and 3.36 Â.

5 nitrogen atoms and wherein R is CI and wherein R may be located either in the para-, meta- or ortho-position of Ring A, wherein S* is a sulphur atom that represents a chiral center, and ail pharmaceutically acceptable salts thereof, enantiomers and racemates thereof.

6. The compound according to one of claims l to 5, wherein S* represents a sulphur atom which represents a chiral center being in the R-configuration .

7. The compound according to one of claims 1 to 5, wherein S* respresents a sulphur atom which represents a chiral center being in the S-configuration.

8. Crystalline anhydrous compound of formula III according to claim 5, which shows a reflex peak in the X-ray powder diffraction diagram with a d-value of 4.62 Â.

9. Crystalline anhydrous compound of formula III according to claim 5, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Â, 6.82 Â and 10.09 Â.

10 comprising the steps A), B) and C), wherein in step A) 4-cyano-piperidine is contacted first with an acid and is then reacted with ammonia in order to obtain intermediate E and wherein in step B) intermediate E is reacted with compound D in the presence of a

10. Crystalline anhydrous compound of formula 111 according to claim 5, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Â, 4.17 Â and 3.66 Â.

11. Crystalline anhydrous compound of formula III according to claim 5, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Â, 6.82 Â, 10.09 Â, 3.93 Â and 4.94 Â.

12. Crystalline anhydrous compound of formula III according to claim 5, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.62 Â, 4.17 Â, 3.66 Â, 3.73 Â and 18.47 Â.

13. Crystalline dihydrate compound of formula III according to claim 5, which shows a reflex peak in the X-ray powder diffraction diagram with a d-value of 4.12 Â.

14. Crystalline dihydrate compound of formula III according to claim 5, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.12 Â, 4.29 Â and 5.15 Â. vM'

15 base (PF_e)-

D and wherein in step C) the acid HX is added.

15.

15. Crystalline dihydrate compound of formula III according to claim 5, which shows reflex peaks in the X-ray powder diffraction diagram with d-values of 4.12 Â, 4.29 Â,

16. The compound of one of claims 1 to 15 for use as a médicament.

17. Use of a compound according to one of claims 1 to 15 for the manufacture of a médicament for the treatment of a disease which can be treated by the inhibition of the PDE4-enzyme.

18. The use of claim 17, wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from a respiratory disease, a gastrointestinal disease, an inflammatory disease of the joints, the skin or the eyes, cancer and a disease of the peripheral or central nervous system.

19. The use of claim 18, wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from a respiratory or pulmonary disease which is accompanied by increased mucus production, inflammations and/or obstructive diseases of the respiratory tract.

20. The use of claim 19, wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from COPD, idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, chronic sinusitis, asthma and chronic bronchitis.

21. The use of claim 17, wherein the disease that can be treated by the inhibition of the PDE4-enzyme is an inflammatory disease of the joints, the skin or the eyes selected from the group consisting of rheumatoid arthritis, sarcoidosis, dry eyes syndrome and glaucoma,

22. The use of claim 17, wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from Crohn’s disease or ulcerative colitis.

23. The use of claim 17, wherein the disease that can be treated by the inhibition of the PDE4-enzyme is selected from dépréssion, bipolar or manie dépréssion, acute and chronic anxiety states, schizophrenia, Alzheimer’s disease, Parkinson’s disease, acute and chronic multiple sclerosis or acute and chronic pain and brain damage caused by stroke, hypoxia or cranio-cerebral trauma, dry eyes syndrome and glaucoma.

24. Pharmaceutical composition comprising a compound according to one of claims 1 to

25. Pharmaceutical composition characterised in that they contain a compound of formula

26. A method of manufacturing the compound A π^Χ'Όη

A wherein HX is a pharmaceutically acceptable acid, comprising the steps a) and b), wherein in step a) compound B wherein HY is a pharmaceutically acceptable acid, is reduced by borane and wherein in step b) a pharmaceutically acceptable acid HX is added in order to obtain compound A.

27. The method of claim 26, wherein the borane for the réduction in step a) is added directly.

28. The method of claim 26, wherein the borane for the réduction in step a) is generated in-situ.

29. The method of claim 26, wherein the borane for the réduction in step a) is generated either from the combination of NaBHj and I₂ or from the combination of NaBFL and BF3~OEt₂. —

30. The method of one of claims 26 to 29, wherein HX is either tosylic acid or hydrochloricacid.

31. The method of one of claims 26 to 29, wherein the pharmaceutically acceptable acid

32. A method of manufacturing compound C

C t

wherein HX is tosylic acid, hydrochloric acid or sulphuric acid,

33. The method of claim 32, wherein in step A) 4-cyano-piperidine is contacted with hydrochloric acid and is then reacted with ammonia in order to obtain intermediate E.

34. The method of one of claims 32 to 33, wherein in step B) intermediate E is reacted with compound D in the presence of sodium methanolate.

35. Intermediate offormula VIII and its salts.

36. Intermediate of formula IX wherein S* stand for a sulphur atom that représente a chiral center, and its salts.