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                                                                   EXHIBIT 10.49

                                           *** Text Omitted and Filed Separately
                                               Confidential Treatment Requested
                                               Under 17 CFR Sections 200.80,
                                               200.83 and 230.406

                               FIRST AMENDMENT TO
                   RESEARCH, DEVELOPMENT AND LICENSE AGREEMENT

        THIS FIRST AMENDMENT (the "Amendment") to the Research, Development and
License Agreement by and between ARES TRADING S.A., a Swiss company ("ARES"),
and SIGNAL PHARMACEUTICALS, INC., a California corporation ("SIGNAL") dated as
of November 25, 1997 (the "Agreement") is entered into by and between ARES and
SIGNAL as of April 15th, 1999.

                                    RECITALS

        WHEREAS, ARES and SIGNAL wish to amend the Agreement pursuant to Section
8.17 of the Agreement to expand the Territory under the Agreement to include
Asia (hereinafter defined), to provide for certain payments to SIGNAL in
consideration of the expansion of the Territory and to make certain related
changes, all as set forth in this Amendment.

                                    AGREEMENT

        NOW THEREFORE, in consideration of the mutual promises hereinafter set
forth, the parties hereto agree as follows:

1.      AMENDMENT TO ARTICLE I. A new Section 1.04A is hereby added to the
        Agreement as follows:

        "Section 1.04A. Asia. Japan, China, South Korea, Taiwan, Cambodia, Laos,
        Vietnam, Nepal, the Philippines, Singapore, Malaysia, Hong Kong, Myanmar
        and Brunei."

2.      AMENDMENT TO SECTION 1.22. Section 1.22 of the Agreement is hereby
        deleted.

3.      AMENDMENT TO SECTION 1.24. Section 1.24 of the Agreement is hereby
        amended and restated in its entirety as follows:

        "Section 1.24.  Territory.  The world."

4.      AMENDMENT TO SECTION 2.05. Section 2.05 of the Agreement is hereby
        amended and restated in its entirety as follows:

        "Section 2.05. Exclusive Relationship. During the term of the Research,
        SIGNAL represents and warrants that it shall not perform any research
        relating to the Field other than the Research."

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5.      AMENDMENT TO SECTION 2.10. The second sentence of Section 2.10 of the
        Agreement is hereby amended to delete the language "(including Tanabe)".

6.      AMENDMENT TO SECTION 2.11. Section 2.11 of the Agreement is hereby
        amended to add the following language at the end of such section:

        "In addition to the Research funding provided by ARES to SIGNAL under
        this Section 2.11, during the period from the date of this Amendment
        until the end of the Initial Term, SIGNAL agrees to expend a minimum of
        [***] United States Dollars (US$[***]) of its own funds on SIGNAL's, its
        agents', consultants' and academic collaborators' performance of the
        Research."

7.      AMENDMENT TO SECTION 3.03. Section 3.03 of the Agreement is hereby
        amended to provide that Subsections 3.03.01 and 3.03.02 shall apply only
        to the development and registration of Licensed Products by ARES, its
        Affiliates or sublicensees in the Territory excluding Asia and to add
        the following Subsection 3.03.04 at the end of such Section:

               "3.03.04. Licensed Products in Asia. For each Licensed Product
        developed and registered by ARES, its Affiliates or sublicensees in
        Asia, ARES shall pay, or cause to be paid, to SIGNAL a nonrefundable
        license fee of [***] United States Dollars (U.S. $[***]) upon the first
        anniversary of the first commercial sale of such Licensed Product in
        Asia, following receipt of marketing approval thereof."

8.      AMENDMENT TO SECTION 3.05. Section 3.05 of the Agreement is hereby
        amended and restated in its entirety as follows:

               "Section 3.05.Ongoing Royalty. Subject to the provisions of this
        Article III, ARES shall during the Term pay or cause to be paid to
        SIGNAL royalties on Net Sales of Licensed Products or Combination
        Products at the following rates:

                      3.05.01. Outside of Asia. With respect to Net Sales of
        Licensed Products and Combination Products in the Territory, excluding
        Asia:

                               (i) [***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products at or below [***]
        United States Dollars (U.S. $[***]);

                               (ii) [***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products above [***] United
        States Dollars (U.S. $[***]);

                               (iii)[***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products above [***] United
        States Dollars (U.S. $[***]); and

                               (iv) [***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products above [***] United
        States Dollars (U.S. $[***]);

*** CONFIDENTIAL TREATMENT REQUESTED
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        provided, however, that upon the expiration or invalidation of the last
        remaining Valid Claim of a SIGNAL Patent or Joint Patent in effect in a
        country that covers such Licensed Product or Combination Product,
        royalties payable for such country with respect to such Licensed Product
        or Combination Product shall be reduced by [***] percent ([***]%).

                      3.05.02. In Asia. With respect to Net Sales of Licensed
        Products and Combination Products in Asia:

                               (i) [***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products at or below [***]
        United States Dollars (U.S. $[***]);

                               (ii) [***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products above [***] United
        States Dollars (U.S. $[***]);

                               (iii)[***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products above [***] United
        States Dollars (U.S. $[***]); and

                               (iv) [***] percent ([***]%) of total annual Net
        Sales of Licensed Products and Combination Products above [***] United
        States Dollars (U.S. $[***]);

        provided, however, that upon the expiration or invalidation of the last
        remaining Valid Claim of a SIGNAL Patent or Joint Patent in effect in a
        country that covers such Licensed Product or Combination Product,
        royalties payable for such country with respect to such Licensed Product
        or Combination Product shall be reduced by [***] percent ([***]%).

9.      AMENDMENT TO SECTION 6.05. Section 6.05 of the Agreement is hereby
        amended to change the reference in the first sentence to "Section
        101(56) of the Bankruptcy Code" to a reference to "Section 101(35A) of
        the Bankruptcy Code."

10.     AMENDMENT TO SECTION 7.01. Section 7.01 of the Agreement is hereby
        amended to delete the language "with the exception of rights granted to
        Tanabe" from clauses (iii) and (iv) thereof.

11.     AMENDMENT TO SECTION 8.06. Section 8.06 is hereby amended to delete the
        proviso at the end of that Section.

12.     PAYMENT OF LICENSE FEE. In consideration of the expansion of the
        Territory to include Asia and the other agreements of SIGNAL contained
        herein, ARES shall pay SIGNAL a nonrefundable license fee of Two Million
        United States Dollars (U.S. $2,000,000) within thirty (30) days of the
        execution and delivery of this Amendment.

13.     FULL FORCE AND EFFECT. Except as specifically amended by this Amendment,
        the terms and conditions of the Agreement shall remain unchanged and in
        full force and effect.

*** CONFIDENTIAL TREATMENT REQUESTED
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14.     GOVERNING LAW. The form, execution, validity, construction and effect of
        this Amendment shall be determined in accordance with the laws of the
        Commonwealth of Massachusetts and the United States of America,
        regardless of the choice of law principles of those or any other
        jurisdictions.

15.     COUNTERPARTS. This Amendment may be signed in any number of counterparts
        with the same effect as if the signatures to each counterpart were upon
        a single instrument, and all such counterparts together shall be deemed
        an original of this Amendment.

        IN WITNESS WHEREOF, the parties have executed and delivered this
Amendment as of the day and year first written above.

ARES TRADING S.A.                          SIGNAL PHARMACEUTICALS, INC.

By: /s/ Ernesto Bertarelli                 By: /s/ Douglas E. Richards
   -----------------------------------        ----------------------------------
                                              Douglas E. Richards
Name: Ernesto Bertarelli                      Vice President, Corporate
     ---------------------------------        Development

Title: Chief Executive Officer
      --------------------------------

                                       4<PAGE>   1
                                                                   EXHIBIT 10.50

                                   MEMORANDUM

This memorandum made and effective as of this 9th day of February, 2000 by and
between

NIPPON KAYAKU CO., LTD. ("NKC")

and

SIGNAL PHARMACEUTICALS INC. ("SIGNAL"),

                      WITNESSETH THAT:

WHEREAS, NKC and SIGNAL concluded a collaboration agreement as of February 9,
1998 ("Collaboration Agreement"); and

WHEREAS, NKC and SIGNAL desire to establish a collaborative relationship to
develop and commercialize novel drug products based on or derived from compounds
identified under Collaboration Agreement for the treatment and prevention of
diseases and disorders of the peripheral nervous system and central nervous
system; and

WHEREAS, SIGNAL has made a draft of Joint Development and Commercialization
Agreement ("Joint Agreement") and sent it to NKC and NKC sent a revised draft
dated January 31, 2000 to SIGNAL; and

WHEREAS, NKC and SIGNAL have intent to conclude Joint Agreement and are
negotiating with each other on the revised draft in good faith;

NOW THEREFORE, the parties hereto agree as follows:

1. Notwithstanding the provisions of Collaboration Agreement, the parties hereto
shall conclude Joint Agreement by the end of March 2000 and the effective date
of Joint Agreement shall be February 9, 2000.

2. In order to expedite the research and development under Joint Agreement, the
parties hereto shall carry out the following activities prior to and until
conclusion of Joint Agreement.

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        (1) Each party's representative of RMC shall agree to and sign a
protocol for studies on which the both parties hereto shall bear costs and
expenses jointly.

        (2) Both of the parties hereto shall sign agreements with contract
laboratories for entrusting studies.

        (3) The parties hereto deal costs and expenses according to the method
as before pursuant to Collaboration Agreement.

        (4) The parties hereto determine long-range, annual and quarterly
research and development plans until the start of commercialization as well as
budgets and personnel plans in accordance with such research and development
plans.

        (5) The parties hereto shall determine research and development plans,
budgets and personnel plans on research related to additional indications and
research of succeeding compounds.

        IN WITNESS WHEREOF, the parties hereto have caused this memorandum in
English language to be executed in duplicate by their respective duly authorized
representatives.

                                        NIPPON KAYAKU CO., LTD.

                                        /s/ Tomiyo Harada
                                        ----------------------------------------
                                        Tomiya HARADA
                                        General Manager
                                        Intellectual Property Division

                                        Date: February 9, 2000

                                        SIGNAL PHARMACEUTICALS INC.

                                        /s/ Alan J. Lewis
                                        ----------------------------------------
                                        Alan J. LEWIS
                                        President and Chief Executive Officer

                                        Date:  February 9, 2000

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